Staphylococcus

aureus
Alan D Tice, MD, FACP

New Insights and Continued Challenges

John A Burns School of
Medicine
University of Hawaii
alantice@IDLinks.com
www.OPAT.com

HI - Sept 5, 2007

Alan D Tice MD, FACP, FIDSA

Infectious 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

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

Staphylococcus aureus
in the Community

Methicillin-Resistant S
aureus
1959
First clinical use of methicillin
Historical
Aspects
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,
and elsewhere (except US)

Australia,
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. 1961;1:124; Westh et al. Clin Infect Dis. 1992;14:1186-1194;

Chambers. Clin Microbiol Rev. 1997;10:781-791; Bradley. Am J Med. 1999;106:2S-10S.

VISA / GISA
VISA Vancomycin-intermediate S

aureus (also known as glycopeptideintermediate S aureus, GISA)

Resistance = MIC 16 g/mL

(vancomycin-resistant S aureus, VRSA)

in the US

Intermediate resistance = MIC 4 8

g/mL

Sakoulas et al. Clin Infect Dis. 2006;42:S40-S50; Levine. Clin Infect Dis. 2006;42:S5-S12;
Jones. Clin Infect Dis. 2006;42:S13-S24.

S aureus
A Unique Organism
PVL

Adapted from: Lowy. N Engl J Med. 1998;339:520-532.

S aureus Chromosome (N315,

MRSA) and
Mu50 (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. 2001;357:1225-1240.

Structural Comparison
of SCCmec Elements
mec

ccr

CA

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

HA

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

Chongtrakool et al. Antimicrob Agents Chemother. 2006;50:1001-1012.

Biofilm glycocalyx with Staphylococcus epidemidis

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

Streptococcus - NOT Staphylococcus

Necrotizing fasciitis

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. 1984;310:1368-1373.
Rimland et al. J Clin Microbiol. 1986;24:137-138.
Centers for Disease Control (CDC). MMWR Morb Mortal Wkly Rep. 1982;31:605-607.

Waikiki

CA-MRSA Prevalence is Increasing

CA-MRSA cases in Four Facilities in Hawaii, 2001-2003

Estivariz EIS, Hawaii
EpiAid Trip Report
2001

2002

2003

DHQP

MRSA Skin Infections:

Treatment Options
FDA-approved

Investigational agents

Vancomycin

Telavancin

Linezolid

Dalbavancin

Daptomycin

Oritavancin

Tigecycline

PBP-2atargeted -lactams
(eg, ceftobiprole,
ceftaroline)

Not FDA-approved,

but sometimes used

TMP-SMX
Clindamycin
Tetracyclines

Pharmacodynamic
IndicesC and
Outcome
= Peak
max

Concentration

Cmax / MIC

Aminoglycosides, fluoroquinolones, lipopeptides,

and lipoglycopeptides

AUC / MIC

Fluoroquinolones
Macrolides
Ketolides
Clindamycin
Tetracyclines

Glycopeptides
Lipopeptides
Lipoglycopeptides
Oxazolidinones
Glycylcyclines

MIC
PAE

T > MIC
Beta-lactams
MRSA-active cephalosporins

Time
Craig. Infect Dis Clin North Am. 2003;17:479-501.
Rybak. Am J Med. 2006;119:S37-S44.

Cmin = Trough

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. 2006;34:1481-1490 and Pace et al.
Biochem Pharmacol. 2006;71:968-980; Karam et al. Pharmacother. 1999;19:257-266;
St Peter et al. Clin Pharmacokinet. 1992;22:169-210; Tenover et al. Emerg Infect Dis.
2001;7:327-332.

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. 2006;34:1481-1490; Pace et al. Biochem
Pharmacol. 2006;71:968-980; Scheetz et al. Pharmacother. 2006;26:539-550; Matzke
et al. Clin Pharmacokinet. 1986;11:257-282; and Tenover et al. Emerg Infect Dis.
2001;7:327-332; Healy et al. Antimicrob Agents Chemother. 1990;34:550-554;
Sivagnanam and Deleu. Crit Care. 2003;7:119-120.

Change in Defined
Breakpoints for Vancomycin
Previous NCCLS
Breakpoints for
Vancomycin
4 g/mL = S

CLSI Breakpoints
for Vancomycin (1/06)
2 g/mL = S

8 16 g/mL = I (VISA, GISA)

4 8 g/mL = I

32 g/mL = R

16 g/mL = R

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 g/mL
Moellering. Ann Intern Med. 2003;138:135-142; Perry, Jarvis. Drugs. 2001;61:525-551.

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. 2003;138:135-142; Perry, Jarvis. Drugs. 2001;61:525-551.

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. 2003;47:1824-1831; Attassi et al. Clin Infect
Dis. 2002;3:695-698; Wu et al. Clin Infect Dis. 2006;42:66-72; Ferry et al. Infection. 2005;33:151154; Saijo et al. Am J Ophthalmol. 2005;139:1114-1116; Gillman. Clin Infect Dis. 2003;37:12741275; Lawrence et al. Clin Infect Dis. 2006;42:1578-1583.

Daptomycin
Lipopeptide

IV administration

Depolarizes bacterial cell

t1/2 = 8 9 h

membrane and disrupts

membrane potential

Broad spectrum gram-positive

activity

Plasma protein binding = 92%

Elimination: renal
MIC = 0.25 1 g/mL

MRSA, VRE, etc

Bactericidal
Concentration-dependent
killing

Tally, DeBruin. J Antimicrob Chemother. 2000;46:523-526.

Louie et al. Antimicrob Agents Chemother. 2001;45:845-851.
Cha et al. Antimicrob Agents Chemother. 2003;47:1598-1603.
Safdar et al. Antimicrob Agents Chemother. 2004;48:63-68.

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 oncedaily dosing)
Tally, DeBruin. J Antimicrob Chemother. 2000;46:523-526, Silverman et al. J Infect Dis.
2005;191:2149-2152, Guay. Consult Pharm. 2004;19:614-628.

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 g/mL
Peterson et al. Antimicrob Agents Chemother. 2002;46:2595-2601; Hoban et al. Diagn Microbiol Infect
Dis. 2005;52:215-227; Rello. J Chemother. 2005;17:12-22; Cercenado et al. J Antimicrob Chemother.
2003;52:138-139; van Ogtrop et al. Antimicrob Agents Chemother. 2000;44:943-949.

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 Acinetobacter
and Stenotrophomonas)

Disadvantages
Bacteriostatic
IV only
Dose-limiting gastrointestinal toxicity (nausea and vomiting)
Not effective for Pseudomonas aeruginosa
Bouchillon et al. Diagn Microbiol Infect Dis. 2005;52:173-179; Fritsche, Jones. Int J Antimicrob
Agents. 2004;24:567-571; Ellis-Grosse et al. Clin Infect Dis. 2005;41:S341-S353; Muralidharan et al.
Antimicrob Agents Chemother. 2005;49:220-229.

MRSA Skin Infections:

Investigational Agents
Lipoglycopeptides
Telavancin
Dalbavancin
Oritavancin

PBP-2atargeted -lactams
Ceftobiprole
Ceftaroline

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, grampositive anaerobes

Rapidly bactericidal
Concentration-dependent
killing
IV QD dosing
t = 7 11 h
Plasma protein binding = ~90%
Elimination: renal
MIC range 0.002 2 g/mL

Pace et al. Curr Opin Investig Drugs. 2005;6:216-225; Higgins et al. Antimicrob Agents
Chemother. 2005;49:1127-1134; Leuthner et al. J Antimicrob Agents Chemother.
2006;58:338-343; Shaw et al. Antimicrob Agents Chemother. 2005;49:195-201; King et al.
J Antimicrob Chemother. 2004;53:797-803.

Telavancin: The ATLAS Trials

Two identical phase 3, double-blind studies1
Telavancin 10 mg/kg q24h vs vancomycin
1 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.

Telavancin:
The ATLAS Trials Pooled
Data
Clinical Cure
MRSA

Telavancin

Vancomyci
n

88.3%
(n=745)

87.1%
(n=744)

(-2.1, 4.6)

90.6%
(n=278)

86.4%
(n=301)

(-1.1, 9.3)

89.9%
(n=278)

84.7%
(n=301)

(-0.3,
10.5)

95% CI

Overall Therapeutic
Response
MRSA

Corey et al. Presented at: IDSA 2006; Toronto, Ontario, Canada. Poster LB-17.

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 g/mL
Malabarba, Goldstein. J Antimicrob Chemother. 2005;55:ii15-20; Lin et al. Ann
Pharmacother. 2006;40:449-460; Jones et al. Diagn Microbiol Infect Dis. 2006;54:149-153.

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. 1996;40:2194-2199.

Zelenitsky et al. Antimicrob Agents Chemother. 1999;43:592-597.
Zhanel et al. Antimicrob Agents Chemother. 1998;42:2327-2430.
Novelli et al. Presented at: ICAAC 1997; Toronto, Ontario, Canada. Abstract F-16.
Hershberger et al. Antimicrob Agents Chemother. 1999;43:717-721.
Bhavnani et al. Antimicrob Agents Chemother. 2006;50:994-1000.
Ward et al. Expert Opin Investig Drugs. 2006;15:417-429.

Cephalosporins
Ceftaroline4-6
Ceftobiprole1-3

Broad-spectrum cephalosporin

Broad-spectrum
cephalosporin

Enhanced gram-positive

Enhanced gram-positive

Bactericidal

Bactericidal

IV with q8h q12h dosing

IV with q8h q12h dosing

t1/2 = 3 4 h

t1/2 = 2 3 h

Elimination: renal

Elimination: renal

spectrum including MRSA, VISA,

and EF

spectrum, including MRSA,

VISA, and EF

0.5 2Infect.
mg/L
MIC range
1. Chambers.
Clin Microbiol
2006;12:17-22. MIC range 0.5 2 mg/L
2. Appelbaum. Clin Microbiol Infect. 2006;12:3-10.
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.

Necrotizing Pneumonia

Banthia et al. Infect Dis Clin Pract. 2005;13:132-138.

Necrotizing Pneumonia

Banthia et al. Infect Dis Clin Pract. 2005;13:132-138.

MRSA Pneumonia
Hospital acquired / health care associated
SCCmec I-III MRSA
Accounts for 20%40% of HAP / VAP

Community acquired
SCCmec IV MRSA (USA 300/400)
Infrequent but necrotizing with mortality of 30%63%
15 postinfluenza MRSA cases reported in the US in
2004
Gillet et al. Lancet. 2002;359:753-759.
Hageman et al. Emerg Infect Dis. 2006;12:894-899.

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 (P<.01)

New trials ongoing

1. Rubenstein et al. Clin Infect Dis. 2001;32:402-412.
2. Wunderink et al. Clin Ther. 2003;25:980-992.
3. Wunderink et al. Chest. 2003;124:1789-1797.

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. 2003;163:2066-2072.

Vancomycin: The Gold

Standard for MRSA
NOT ideal
Bacteremia?
Poor outcomes

Persistent bacteremia especially MRSA

Relapses
Proposed explanation
Inadequate dosing
Poor tissue penetration
Slowly bactericidal
Concerns about susceptibility
Heteroresistant SA, VISA, VRSA

MRSA and MSSA Success

at TOC: ITT Population
Success, %

70

Difference in Success
Rates (95% CI):

60

11.9% (-8.3, 32.1)

50

44.4

40

Difference in Success
Rates (95% CI):
-2.1% (-19.0, 14.9)
44.6

46.7

33
74

28
60

32.6

30
20
10
0

20
45

14
43

MRSA

ASP = antistaphylococcal penicillin.

Fowler et al. N Engl J Med. 2006;355:653-665.

MSSA

Daptomycin
Vancomycin
ASP

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

ADMITTING OFFICE

MRSA positive ward

Come to Hawaii -

- and help us study the sea

Staphylococcus
aureus
Alan D Tice, MD, FACP

New Insights and Continued Challenges

John A Burns School of
Medicine
University of Hawaii
alantice@IDLinks.com
www.OPAT.com