Staphylococcus aureus New Insights and Continued Challenges

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Staphylococcus aureusNew Insights and Continued
Challenges

• Alan D Tice, MD, FACP
• John A Burns School of Medicine
• University of Hawaii
• alantice_at_IDLinks.com
• www.OPAT.com
• HI - Sept 5, 2007

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Alan D Tice MD, FACP, FIDSAInfectious Diseases
Specialist

• University of Hawaii - Medical School
• Private Practice and Community Health Centers
• IDSA Quality Measures Task Force
• OPAT Guidelines
• Partners Astellas/Theravance, Cubist, Merck,
  Pfizer, Replidyne, Roche, Schering, IDSA, APIC,
  ACP, AMA, Surfrider Foundation, Constance

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Educational Objectives

• Explain the epidemiologic and genetic patterns of
  MRSA resistance
• Analyze the reasons for lack of effectiveness of
  available MRSA antimicrobial agents
• Assess the role newer agents may play in
  advancing the standard of care

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Staphylococcus aureus in the Community
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Methicillin-Resistant S aureusHistorical Aspects

• 1959 First clinical use of methicillin
• 1961 First description of MRSA
• 1967 First report of nosocomial infection in
  the US (2 cases)
• 1968 Increase in MRSA in the UK
• 1968-1979 Rise and subsequent wane of
  prevalence of MRSA
• (especially nosocomial infections) in Europe,
  Australia, and elsewhere (except US)
• 1975-1980 First reports of problems with MRSA
  in the US most
• occurred in large tertiary care hospitals
  (especially
• burn units and ICUs)
• 1980 MRSA increase in prevalence in US
  nursing homes
• CA-MRSA infections in the US
• 1998 Emergence of CA-MRSA

Jevons. BMJ. 19611124 Westh et al. Clin Infect
Dis. 1992141186-1194Chambers. Clin Microbiol
Rev. 199710781-791 Bradley. Am J Med.
19991062S-10S.
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VISA / GISA

• VISA Vancomycin-intermediate S aureus (also
  known as glycopeptide-intermediate S aureus,
  GISA)
• Resistance MIC 16 µg/mL (vancomycin-resistant
  S aureus, VRSA) in the US
• Intermediate resistance MIC 4 8 µg/mL

Sakoulas et al. Clin Infect Dis. 200642S40-S50
Levine. Clin Infect Dis. 200642S5-S12 Jones.
Clin Infect Dis. 200642S13-S24.
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S aureusA Unique Organism
PVL
Adapted from Lowy. N Engl J Med.
1998339520-532.
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S aureus Chromosome (N315, MRSA) andMu50
(VISA)-Specific Genetic Elements

• Entire genome sequenced in 2001
• 2600 genes, many acquired laterally from other
  organisms
• 11 genes encode resistance to gt9 classes of
  antibiotics
• 70 new candidate genes for virulence factors
  (toxin production)

Genetic diversity demonstrates ability of
organism to acquire resistance and virulence
traits in response to environmental changes
Kuroda et al. Lancet. 20013571225-1240.
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Structural Comparisonof SCCmec Elements
mec
ccr

• Genes that encode altered penicillin-binding
  proteins(PBP2a) are found on mobile genetic
  elements known as SCCmec elements
• 5 types of elements vary with origin of strain
• Types 1, 2, and 3 primarily found in
  hospital-acquired strains
• Types 4 and 5 primarily found in
  community-acquired strains
• Variable with respect to associated resistance
  elements, which are common with types 1, 2, and
  3, but not seen with types 4 and 5

CA
HA
Chongtrakool et al. Antimicrob Agents Chemother.
2006501001-1012.
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Biofilm glycocalyx with Staphylococcus epidemidis
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CA-MRSA Outbreaks

• Often first detected as clusters of abscesses or
  spider bites
• Various settings
• Sports participants football, wrestlers, fencers
• Correctional facilities prisons, jails
• Military recruits
• Day care and other institutional centers
• Men who have sex with men
• Now in general population

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Streptococcus - NOT Staphylococcus
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Necrotizing fasciitis
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Epidemiology of S aureus Infections

• Predominant reservoir of organisms human beings
• Approximately 15 35 of normal people harbor S
  aureus in nares or pharynx at a given point.
  Longitudinal view of carriage
• 30 prolonged, 50 intermittent, 20 never
• Vaginal carriage in 10 of premenopausal women
• Rectal and perineal carriage also occur
• Patients with MRSA infections may have high
  prevalence (60) of gastrointestinal colonization
  or carriage
• Organism usually spread by direct
  person-to-person contact
• Spread from inanimate objects is rare, but has
  been documented, such as outbreaks among football
  players, river raft guides, etc.
• Common denominator repeated trauma in defined
  area

Sheagren. N Engl J Med. 19843101368-1373. Rimlan
d et al. J Clin Microbiol. 198624137-138. Center
s for Disease Control (CDC). MMWR Morb Mortal
Wkly Rep. 198231605-607.
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Waikiki
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CA-MRSA Prevalence is Increasing
CA-MRSA cases in Four Facilities in Hawaii,
2001-2003
Estivariz EIS, Hawaii EpiAid Trip Report
2001 2002
2003
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MRSA Skin InfectionsTreatment Options

• Investigational agents
• Telavancin
• Dalbavancin
• Oritavancin
• PBP-2atargeted ?-lactams (eg, ceftobiprole,
  ceftaroline)

• FDA-approved
• Vancomycin
• Linezolid
• Daptomycin
• Tigecycline
• Not FDA-approved, but sometimes used
• TMP-SMX
• Clindamycin
• Tetracyclines

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PharmacodynamicIndices and Outcome
Cmax Peak
Cmax / MIC
Aminoglycosides, fluoroquinolones, lipopeptides,
and lipoglycopeptides
Fluoroquinolones Glycopeptides Macrolides Lipopept
ides Ketolides Lipoglycopeptides Clindamycin Oxa
zolidinones Tetracyclines Glycylcyclines
AUC / MIC
Concentration
MIC
PAE
T gt MIC
Beta-lactams MRSA-active cephalosporins
Cmin Trough
Time
Craig. Infect Dis Clin North Am.
200317479-501. Rybak. Am J Med.
2006119S37-S44.
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Vancomycin

• Glycopeptide class
• Inhibits cell wall synthesis
• Gram-positive activity
• MRSA, streptococci, and gram-positive anaerobes
• Rare resistance in MRSA, increasing VISA
• Bactericidal but slow, time-dependent killing
• IV with BID dosing
• t1/2 4-6 h
• Protein binding 30-50
• Elimination renal

Reviewed in Stevens et al. Clin Infect Dis.
2006341481-1490 and Pace et al. Biochem
Pharmacol. 200671968-980 Karam et al.
Pharmacother. 199919257-266 St Peter et al.
Clin Pharmacokinet. 199222169-210 Tenover et
al. Emerg Infect Dis. 20017327-332.
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Vancomycin

• Disadvantages
• Slow bactericidal activity
• Rare VRSA increasing incidence of VISA and
  hetero-resistant MRSA
• Low penetration into ELF (10-30 of serum
  concentrations)
• Prolonged durations of low serum concentration
  with current dosing regimens in renally impaired
  patients
• Red man syndrome with rapid infusions rare
  neutropenia
• Advantages
• Low cost

Reviewed in Stevens et al. Clin Infect Dis.
2006341481-1490 Pace et al. Biochem Pharmacol.
200671968-980 Scheetz et al. Pharmacother.
200626539-550 Matzkeet al. Clin
Pharmacokinet. 198611257-282 and Tenover et
al. Emerg Infect Dis. 20017327-332 Healy et
al. Antimicrob Agents Chemother. 199034550-554
Sivagnanam and Deleu. Crit Care. 20037119-120.
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Change in DefinedBreakpoints for Vancomycin
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Linezolid

• Oxazolidinone class
• Binds 50S rRNA, inhibiting formation of 70S
  initiation complex
• Gram-positive activity
• MRSA, VRE, etc
• Bacteriostatic (when bactericidal activity is
  defined by 3 log drop in cfu by 24 h)
• Time-dependent killing
• IV / PO
• t1/2 5 7 h
• Plasma protein binding 31
• Elimination nonrenal
• MIC 1 4 µg/mL

Moellering. Ann Intern Med. 2003138135-142
Perry, Jarvis. Drugs. 200161525-551.
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Linezolid (contd)

• Advantages
• Unique mechanism of action
• No cross-resistance
• Broad spectrum of activity against
  pathogenic,multiresistant gram-positive bacteria
• Low propensity for development of
  resistance(staphylococci ? enterococci)
• Excellent bioavailability
• Excellent tissue penetration
• Little or no interaction with cytochrome P450
  system

Moellering. Ann Intern Med. 2003138135-142
Perry, Jarvis. Drugs. 200161525-551.
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Linezolid (contd)

• Disadvantages
• Bacteriostatic
• Some emergence of resistance among enterococci
• BID dosing
• Toxicity (especially bone marrow suppression with
  primarily thrombocytopenia and anemia), MAO
  inhibition (serotonin re-uptake syndrome),
  peripheral neuropathy, lactic acidosis, and optic
  neuritis (rare)

Rubenstein et al. Antimicrob Agents Chemother.
2003471824-1831 Attassi et al. Clin Infect
Dis. 20023695-698 Wu et al. Clin Infect Dis.
20064266-72 Ferry et al. Infection.
200533151-154 Saijo et al. Am J Ophthalmol.
20051391114-1116 Gillman. Clin Infect Dis.
2003371274-1275 Lawrence et al. Clin Infect
Dis. 2006421578-1583.
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Daptomycin

• Lipopeptide
• Depolarizes bacterial cell membrane and disrupts
  membrane potential
• Broad spectrum gram-positive activity
• MRSA, VRE, etc
• Bactericidal
• Concentration-dependent killing

• IV administration
• t1/2 8 9 h
• Plasma protein binding 92
• Elimination renal
• MIC 0.25 1 µg/mL

Tally, DeBruin. J Antimicrob Chemother.
200046523-526. Louie et al. Antimicrob Agents
Chemother. 200145845-851. Cha et al. Antimicrob
Agents Chemother. 2003471598-1603. Safdar et
al. Antimicrob Agents Chemother. 20044863-68.
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Daptomycin (contd)

• Advantages
• Broad spectrum of activity against resistant
  gram-positive organisms
• Unique mechanism of action
• Rapidly bactericidal
• Once-daily dosing
• Disadvantages
• Inactivated by lung surfactant
• Potential for myotoxicity (markedly ? by
  once-daily dosing)

Tally, DeBruin. J Antimicrob Chemother.
200046523-526, Silverman et al. J Infect Dis.
20051912149-2152, Guay. Consult Pharm.
200419614-628.
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Tigecycline

• Glycylcycline class
• Binds 30S rRNA inhibiting protein synthesis
• Broad-spectrum activity including
• MRSA
• VRE
• PRSP
• Bacteriostatic
• Time-dependent killing
• IV
• t1/2 42 h
• Plasma protein binding 71 89
• Elimination biliary / fecal
• MIC 0.03 0.5 µg/mL

Peterson et al. Antimicrob Agents Chemother.
2002462595-2601 Hoban et al. Diagn Microbiol
Infect Dis. 200552215-227 Rello. J Chemother.
20051712-22 Cercenado et al. J Antimicrob
Chemother. 200352138-139 van Ogtrop et al.
Antimicrob Agents Chemother. 200044943-949.
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Tigecycline (contd)

• Advantages
• Excellent activity against resistant
  gram-positive bacteria (including MRSA, VRE, and
  PRSP)
• Broad spectrum (including anaerobes,
  Enterobacteriaceae, and some resistant
  nonfermenters, such as Acinetobacterand
  Stenotrophomonas)
• Disadvantages
• Bacteriostatic
• IV only
• Dose-limiting gastrointestinal toxicity (nausea
  and vomiting)
• Not effective for Pseudomonas aeruginosa

Bouchillon et al. Diagn Microbiol Infect Dis.
200552173-179 Fritsche, Jones. Int J
Antimicrob Agents. 200424567-571 Ellis-Grosse
et al. Clin Infect Dis. 200541S341-S353
Muralidharan et al. Antimicrob Agents Chemother.
200549220-229.
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MRSA Skin Infections Investigational
Agents

• Lipoglycopeptides
• Telavancin
• Dalbavancin
• Oritavancin
• PBP-2atargeted ?-lactams
• Ceftobiprole
• Ceftaroline

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Telavancin

• Semisynthetic lipoglycopeptide
• Multiple mechanisms of action including
  inhibition of cell wall synthesis and disruption
  of cell membrane barrier functions
• Spectrum of activity
• MRSA, MRCoNS, hVISA, VISA, PRSP, MDRSP,
  gram-positive anaerobes

• Rapidly bactericidal
• Concentration-dependent killing
• IV QD dosing
• t½ 7 11 h
• Plasma protein binding 90
• Elimination renal
• MIC range 0.002 2 µg/mL

Pace et al. Curr Opin Investig Drugs.
20056216-225 Higgins et al. Antimicrob Agents
Chemother. 2005491127-1134 Leuthner et al. J
Antimicrob Agents Chemother. 200658338-343
Shaw et al. Antimicrob Agents Chemother.
200549195-201 King et al. J Antimicrob
Chemother. 200453797-803.
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Telavancin The ATLAS Trials

• Two identical phase 3, double-blind studies1
• Telavancin 10 mg/kg q24h vs vancomycin1 g IV
  q12h1
• 1867 treated patients
• 719 patients with MRSA in the combined data set
• Of the 579 microbiologically evaluable patients
  with MRSA, about 85 are PVL positive (vs
  approximately 30 of MSSA patients)

1. Corey et al. Presented at IDSA 2006
Toronto, Ontario, Canada. Abstract LB-17.
Personal communication, Dr. Vance Fowler.
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TelavancinThe ATLAS Trials Pooled Data
Corey et al. Presented at IDSA 2006 Toronto,
Ontario, Canada. Poster LB-17.
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Dalbavancin

• Lipoglycopeptide
• Inhibits cell wall synthesis
• Gram-positive activity
• MRSA, VRE, all streptococci, and gram-positive
  anaerobes
• Bactericidal with time-dependent killing
• IV
• Weekly dosing
• t1/2 123 210 h
• Protein binding 93
• Elimination nonrenal
• MIC range 0.008 1 µg/mL

Malabarba, Goldstein. J Antimicrob Chemother.
200555ii15-20 Lin et al. Ann Pharmacother.
200640449-460 Jones et al. Diagn Microbiol
Infect Dis. 200654149-153.
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Oritavancin (LY333328)

• Glycopeptide class
• Active against a wide variety of gram-positive
  organisms, including MRSA and VRE
• Bactericidal, concentration-dependent killing
• Long PAE
• Non-renal elimination
• Protein binding 90
• Long terminal t1/2 360 h

Nicas et al. Antimicrob Agents Chemother.
1996402194-2199. Zelenitsky et al. Antimicrob
Agents Chemother. 199943592-597. Zhanel et al.
Antimicrob Agents Chemother. 1998422327-2430. No
velli et al. Presented at ICAAC 1997 Toronto,
Ontario, Canada. Abstract F-16. Hershberger et
al. Antimicrob Agents Chemother.
199943717-721. Bhavnani et al. Antimicrob
Agents Chemother. 200650994-1000. Ward et al.
Expert Opin Investig Drugs. 200615417-429.
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Cephalosporins

• Ceftaroline4-6
• Broad-spectrum cephalosporin
• Enhanced gram-positive spectrum, including MRSA,
  VISA, and EF
• Bactericidal
• IV with q8h q12h dosing
• t1/2 2 3 h
• Elimination renal
• MIC range 0.5 2 mg/L

• Ceftobiprole1-3
• Broad-spectrum cephalosporin
• Enhanced gram-positive spectrum including MRSA,
  VISA, and EF
• Bactericidal
• IV with q8h q12h dosing
• t1/2 3 4 h
• Elimination renal
• MIC range 0.5 2 mg/L

1. Chambers. Clin Microbiol Infect.
20061217-22. 2. Appelbaum. Clin Microbiol
Infect. 2006123-10. 3. Lodise et al. Presented
at ECCMID 2006 Nice, France. Abstract 1524. 4.
Ge et al. Presented at 46th ICAAC, 2006 San
Francisco, Calif. Abstract 1935. 5. Ge et al.
Presented at 46th ICAAC, 2006 San Francisco,
Calif. Abstract 1937. 6. Ge et al. Presented at
46th ICAAC, 2006 San Francisco, Calif. Abstract
1939.
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Necrotizing Pneumonia
Banthia et al. Infect Dis Clin Pract.
200513132-138.
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Necrotizing Pneumonia
Banthia et al. Infect Dis Clin Pract.
200513132-138.
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MRSA Pneumonia

• Hospital acquired / health care associated
• SCCmec I-III MRSA
• Accounts for 2040 of HAP / VAP
• Community acquired
• SCCmec IV MRSA (USA 300/400)
• Infrequent but necrotizing with mortality of
  3063
• 15 postinfluenza MRSA cases reported in the US in
  2004

Gillet et al. Lancet. 2002359753-759.
Hageman et al. Emerg Infect Dis. 200612894-899.
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Linezolid Pneumonia

• 402 patients randomized1 32 with MRSA
• Clinical cure 66 linezolid vs 68 vancomycin
• MRSA eradication rate 65 linezolid vs 78
  vancomycin
• 623 patients randomized2 42 with MRSA
• Clinical cure 68 linezolid vs 65 vancomycin
• MRSA eradication rate 63 linezolid vs 43
  vancomycin
• Reanalysis3 123 patients with MRSA
• Clinical cure in MRSA subgroup 59 linezolid vs
  36 vancomycin (Plt.01)
• New trials ongoing

• Rubenstein et al. Clin Infect Dis.
  200132402-412.
• Wunderink et al. Clin Ther. 200325980-992.
• Wunderink et al. Chest. 20031241789-1797.

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Teaching Points SAB is BAD

• Overall mortality is 24
• Metastatic complications occur in 34
• Infective endocarditis is present in 12
• In patients with prosthetic joints, 28 are found
  to be infected!
• Relapse occurs in 10

SAB S aureus bacteremia.
Fowler et al. Arch Intern Med. 20031632066-2072.
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Vancomycin The GoldStandard for MRSA Bacteremia?

• NOT ideal
• Poor outcomes
• Persistent bacteremia especially MRSA
• Relapses
• Proposed explanation
• Inadequate dosing
• Poor tissue penetration
• Slowly bactericidal
• Concerns about ? susceptibility
• Heteroresistant SA, VISA, VRSA

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MRSA and MSSA Successat TOC ITT Population
ASP antistaphylococcal penicillin. Fowler et
al. N Engl J Med. 2006355653-665.
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Length of Treatment

• 2 weeks in extremely well-defined patients with
  ALL of the following
• Catheter-associated bacteremia / catheter removed
• Follow-up BC negative on antibiotics
• Patient defervesces in 72 hours
• TEE normal (not negative)
• No prosthetic material in joints or intravascular
  space
• No symptoms suggestive of metastatic infection
• 4 6 weeks for everyone else

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ADMITTING OFFICE
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MRSA positive ward
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Come to Hawaii -
- and help us study the sea
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Staphylococcus aureusNew Insights and Continued
Challenges

• Alan D Tice, MD, FACP
• John A Burns School of Medicine
• University of Hawaii
• alantice_at_IDLinks.com
• www.OPAT.com