Staphylococcus aureus Critical Thinking and Care

1
Staphylococcus aureusCritical Thinking and Care

• Alan D Tice, MD, FACP
• Infections Limited Hawaii
• John A Burns School of Medicine
• University of Hawaii
• alantice_at_IDLinks.com
• Critical Care Congress Feb 2, 2008

2
Alan D Tice MD, FACP, FIDSAInfectious Diseases
Specialist

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

3
Staphylococcus aureus in the Hospital and at Home
4
S aureusA Unique Organism
PVL
Adapted from Lowy. N Engl J Med.
1998339520-532.
5
History of Staphylococcus

• Outbreak in the 1950s methicillin and phisohex
  and infection control
• Developed resistance to every drug used
• In the hospital first
• A matter of life and death survivor
• Community-associated strain (CA-MRSA)
• Sleek and fast resistance gene
• Associated virulence factors PVL, ACME, etc

6
Trends in S. aureus Antimicrobial Resistance
7
CA-MRSA Prevalence is Increasing
CA-MRSA cases in Four Facilities in Hawaii,
2001-2003
Estivariz EIS, Hawaii EpiAid Trip Report
2001 2002
2003
8
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 9 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.
9
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.
10
Biofilm glycocalyx with Staphylococcus epidemidis
11
Epidemiology of S aureus Infections

• Predominant reservoir of organisms human beings
• One third of normal people harbor S aureus in
  nares or pharynx
• 1/3 never, 1/3 intermittent, 1/3 forever
• Some carry in vagina (1/10 premenopausal) and
  rectum
• Patients with MRSA infections more likely to have
  gastrointestinal colonization or carriage (up to
  60)
• Spread by direct person-to-person contact
• Not much in the environment - but some

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.
12
(No Transcript)
13
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

14
CA-MRSA Factors for Transmission
15
St. Louis RamsCA-MRSA Abscesses

• Association with
• BMI30
• Recent Abx use
• Lineman/Linebacker
• Abx use
• 2.6 scripts/yr for Rams
• 0.2 scripts/yr for gen popn
• Common USA 300 clone

Kazakova et al NEJM 2005352468-75.
16
CA-MSSA USA 300 in kids

• Texas Childrens Hospital
• 122 cases 2001-2006
• Increased 14 to 36 cases
• 14 to 35 USA 300
• USA 300 strains associated with
• Panton Valentine Leucocidin (PVL), ESR, CRP, WBC,
  osteomyelitis
• McCaskill PIDJ Dec, 2008

17
Waikiki
18
CA-MRSA is distinct -clinical syndrome and clones

• Folliculitis
• Focal areas of necrosis and pus
• Abscesses and boils
• USA 300 by pulse field gel analysis
• Spa typing, PVL, mec genes, antibiograms

19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
Streptococcus
23
Necrotizing fasciitis
24
MRSA Skin InfectionsTreatment Options

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

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

25
Vancomycin

• Glycopeptide class - inhibits cell wall synthesis
• Gram-positive activity
• MRSA, streptococci, and gram-positive anaerobes
• Increasing MIC and resistance VISA, VRSA
• Bactericidal but slow, time-dependent killing
• t1/2 4-6 h, Q12H dosing, renal elimination
• Red man syndrome with rapid infusions rare
  neutropenia
• Cheap

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.
26
Change in DefinedBreakpoints for Vancomycin
27
Linezolid

• Oxazolidinone class - Binds 50S rRNA, inhibiting
  formation of 70S initiation complex
• MRSA and enterococci but bacteriostatic (3 logs)
• IV and oral forms, OK for kids
• t1/2 5 7 h, non-renal elimination
• Toxicity marrow, MAO inhibitors, neuropathy,
  lactic acidosis
• 100-150 per day oral and IV

Moellering. Ann Intern Med. 2003138135-142
Perry, Jarvis. Drugs. 200161525-551.
28
Daptomycin

• Lipopeptide - depolarizes bacterial cell membrane
  and disrupts membrane potential
• Gram-positives - MRSA, VRE, etc
• Bactericidal - concentration-dependent killing
• IV administration - t1/2 8 9 h, renal
  elimination
• MIC 0.25 1 µg/mL
• NOT for pneumonia (binds surfactant) but good for
  sepsis
• Some muscle enzyme changes check CPKs

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.
29
Daptomycin for bacteremia/endocarditis (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.
30
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

31
Outcomes after Staph aureus bacteremia in infants

• Pediatric Pharmacology Research Network
• 53 cases of S aureus bacteremia 6 died
• 60 MSSA
• 40 MRSA -
• Longer bacteremia
• 90 resistant to clinda, erythro, TMP/Sulfa
• Cohen-Wolkowiez PIDJ Dec, 2008

32
Tigecycline

• Glycylcycline class - Binds 30S rRNA inhibiting
  protein synthesis
• Broad-spectrum activity including MRSA, VRE, GNR
• Bacteriostatic
• Time-dependent killing
• IV - t1/2 42 h
• 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.
33
MRSA Skin Infections Investigational
Agents

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

34
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.
35
Dalbavancin

• Lipoglycopeptide - inhibits cell wall synthesis
• Gram-positive activity - MRSA, VRE, all
  streptococci
• Bactericidal with time-dependent killing
• IV
• t1/2 123 210 h therefore weekly dosing
• 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.
36
Oritavancin (LY333328)

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

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.
37
Cephalosporins

• 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

• 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

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.
38
Prevention of MRSA

• Vaccines unlikely
• Infection control in hospital
• Early diagnosis/quarantine
• Isolation until culture or genes negative
• Topical agents mupirocin, retapamulin
• Avoid spread infection control
• Reduce antibiotic use and resistance pressure
• Infection control at home
• Wash hands, dont pick nose
• Avoid people and hospital

39
ADMITTING OFFICE
40
How to use antibiotics in Hospital

• Empiric
• Help coming from the lab antibiograms, rapid
  assays
• STOP ASAP
• Culture or gene negative
• Maximum of 3 days?
• Decolonize?

41
Antibiotics for MRSA at home

• OPAT Vancomycin, daptomycin, clindamycin,
  linezolid, tigecycline
• Oral linezolid, clindamycin, trimeth/sulfa,
  tetracyclines, quinolones
• Adjuncts rifampin, clindamycin
• None only incision and drainage

42
CDC Health Advisory Jan 2008

• 73 children died of influenza Oct 2006-Sept, 2007
• Of 69, 44 had bacterial co-infection and 73 of
  those had Staph aureus (5 times prior years)
• Therefore
• Test for influenza
• Look for co-infections and consider empiric
  therapy
• Report and send bugs to CDC

43
Necrotizing Pneumonia
Banthia et al. Infect Dis Clin Pract.
200513132-138.
44
Necrotizing Pneumonia
Banthia et al. Infect Dis Clin Pract.
200513132-138.
45
The Future

• VISA
• VRSA
• ESBLs
• The Perfect Storm?
• Sharing genes among bacteria
• Staph and Vancomycin resistant enterococci
• Coag-neg and positive staph
• CA-MRSA and HA-MRSA

46
Conclusions

• More bugs than humans
• Staphylococci are normal flora
• Beware and be careful like pit bull
• Live with them, not against them
• Empiric therapy may be indicated
• Limit antibiotic use
• Infection control
• Work with the community

47
Relative Risks -

• Hospitals
• Full of sick people
• Extreme human pathogens
• MDR microbes
• Constant exposure
• Dermatitis from infection control
• 1,000/day
• Bad food

• Waikiki water
• A few sharks
• A few staph
• Cleansing water
• Classic antiseptics readily available rum,
  Mai-tais, etc

48
Come to Hawaii -
- and help us study the sea
49
STAPHYLOCOCCUS INSTITUTEwww.IDLinks.com

• Summer Program
• Research scholarships
• Weekly STAPH MEETINGS
• National Conference
• Sponsors
• John A Burns School of Medicine
• University of Hawaii
• Diagnostic Laboratory Services

50
Staphylococcus aureusCritical Thinking and Care

• Alan D Tice, MD, FACP
• Infections Limited Hawaii
• John A Burns School of Medicine
• University of Hawaii
• alantice_at_IDLinks.com
• Critical Care Congress Feb 2, 2008