Bacterial Pathogens in the Hospital and
Community: The Need for Newer Antibiotics
So What Happened?
 Antibiotic overuse/misuse
So What Happened?
 Antibiotic overuse/misuse
 Fitness of organisms
• clonal spread
Spain 23F – one pneumococcal clone
Finland
France
BM4200
1978 ?
Spain
Cleveland
South Korea
Tennessee
Taiwan
Hong Kong
Thailand Philippines
Mexico
Colombia
Malaysia
Singapore
Brazil
Chile
Uruguay
Argentina
South Africa
Bad Bugs, No Drugs1
• The Antimicrobial Availability Task Force
of the IDSA1 identified as particularly
problematic pathogens
– A. baumannii and P. aeruginosa
– ESBL-producing Enterobacteriaceae
– MRSA
– Vancomycin-resistant enterococcus
• Declining research investments in
antimicrobial development2
1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews.
http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.
Between 1962 and 2000, no major
classes of antibiotics were introduced
Fischbach MA and Walsh CT Science 2009
A Changing Landscape for
Numbers of Approved Antibacterial Agents
16
14
12
Resistance
Number of agents approved
18
10
8
6
4
2
0
0
1983-87
1988-92
1993-97
1998-02
2003-05
2008
Bars represent number of new antimicrobial agents approved by the FDA during the period listed.
Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;
New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912
The Problems
• Gram negatives
– Resistant Enterobacteriaceae
• β-Lactamases
– Pseudomonas/Acinetobacter
– N. gonorrheae
• Gram positives
– MRSA
– Pneumococcus
The Gram Negatives
Prevalence of Isolates of Multidrug-Resistant Gram
Negative Rods Recovered Within The First 48 h
After Admission to the Hospital
Pop-Vicas and D'Agata CID 2005;40:1792-8.
Enterobacteriaceae
• The rapid and disturbing spread of:
– extended-spectrum ß-lactamases
– AmpC enzymes
– carbapenem resistance
• metallo-β-lactamases
• KPC and OXA-48 β-lactamases
– quinolone resistance
Rise in the proportions of E. coli from bacteraemias in England, Wales and Northern Ireland
resistant to fluoroquinolones (white), oxyimino-cephalosporins (grey) and both (black)
Livermore, D. M. J. Antimicrob. Chemother. 2009 64:i29-36i; doi:10.1093/jac/dkp255
Copyright restrictions may apply.
Increase in numbers of Group 1, 2 and
3 β-lactamases from 1970 to 2009
Group 2/class A and class D β-lactamases
Group 1/class C cephalosporinases
Group 3/class B metalloβ-lactamases
Bush K and Jacoby G AAC 2010
Major families of β-lactamases of clinical importance
Bush K and Jacboy G AAC 2010
Extended-Spectrum β-Lactamases
• β-lactamases capable of conferring bacterial
resistance to
–
–
–
–
the penicillins
first-, second-, and third-generation cephalosporins
aztreonam
(but not the cephamycins or carbapenems)
• These enzymes are derived from group 2b βlactamases (TEM-1, TEM-2, and SHV-1)
– differ from their progenitors by as few as one AA
E. coli and Klebsiella ESBL Phenotype Rates by Country
(SENTRY Program)
65
60
55
Frequency (%)
50
45
40
35
30
25
20
15
10
5
0
Switzer Sweden
Spain
Ireland Germany
UK
France
Country
Klebsiella
E. coli
Italy
Israel
Turkey
Greece
Poland
CTX-M-type ESBLs
• Until 2000, most ESBL producers were hospital
Klebsiella spp. with TEM and SHV mutant β-lactamases
• Now, the dominant ESBLs across most of Europe and
Asia are CTX-M enzymes, which originated as genetic
escapes from Kluyvera spp
• Currently recognized as the most widespread and
threatening mechanism of antibiotic resistance, both in
clinical and community settings
– 80% of ESBL-positive E. coli from bacteraemias in the UK and
Ireland are resistant to fluoroquinolones
– 40% are resistant to gentamicin
Livermore, DM J. Antimicrob. Chemother 2009
Carbapenemases
• Ability to hydrolyze penicillins, cephalosporins,
monobactams, and carbapenems
• Resilient against inhibition by all commercially viable
ß-lactamase inhibitors
– Subgroup 2df: OXA (23 and 48) carbapenemases
– Subgroup 2f : serine carbapenemases from molecular
class A: GES and KPC
– Subgroup 3b contains a smaller group of MBLs that
preferentially hydrolyze carbapenems
• IMP and VIM enzymes that have appeared globally, most
frequently in non-fermentative bacteria but also in
Enterobacteriaceae
KPC (K. pneumoniae carbapenemase)
• KPCs are the most prevalent of this group of
enzymes, found mostly on transferable
plasmids in K. pneumoniae
• Substrate hydrolysis spectrum includes
cephalosporins and carbapenems
K. pneumoniae carbapenemase-producing bacteria
Nordmann P et al. LID 2009
Major families of β-lactamases of clinical importance
Bush K and Jacboy G AAC 2010
AmpC β-lactamases
• Once expressed at high levels, confer resistance
to many β-lactam antimicrobials (excluding
cefepime and carbapenems)
• In E. coli, constitutive over expression of AmpC
β-lactamases can occur because
– of mutations in the promoter and/or attenuator region
(AmpC hyperproducers)
– the acquisition of a transferable ampC gene on a
plasmid or other transferable elements (plasmidmediated AmpC β-lactamases)
Emerging Metallo-β-Lactamases
with Mobile Genetics
(SENTRY Program 2001-2005)
Genetic group
Geographic origin
Characterized enzymes
imp
Japan
vim
spm
gim
vim
sim
Italy
Brazil
Germany
USA
Korea
IMP-1 through IMI-13a
IMP-14, and IMP-16a
VIM-1 through VIM-7a
SPM-1a
GIM-1a
VIM-7a,b
SIM-1
Enterobacteriaceae: Breakpoints
revised
CLSI 2009
Agent
CLSI 2010
S
I
R
S
I
R
Cefazolin
≤8
16
≥32
≤1
2
≥4
Cefotaxime
≤8
16-32
≥64
≤1
2
≥4
Ceftriaxone
≤8
16-32
≥64
≤1
2
≥4
Ceftazidime
≤8
16
≥32
≤4
8
≥16
Aztreonam
≤8
16
≥32
≤4
8
≥16
Cefipime
≤8
16
≥32
≤8
16
≥32
Neisseria gonorrhoeae
Wang SA et al. Ann Int Med 2008
Prevalence of and risk factors for quinoloneresistant Neisseria gonorrhoeae infection in Ontario
Oto KV et al. CMAJ 2009
Treatment of N. gonorrhoeae
• Only current CDC-recommended options for
treating N. gonorrhoeae infections are from a
single class of antibiotics, the cephalosporins.
– Ceftriaxone, available only as an injection, is the
recommended treatment for all types of gonorrhea
infections (i.e., urogenital, rectal, and pharyngeal).
– Cefixime is the only oral agent recommended for
treatment of uncomplicated urogenital or rectal
gonorrhea
Reduced susceptibility to cefixime being described in
Japan and other countries
The Gram Positives
• Staphylococcus aureus
– MRSA
– Reduced-vancomycin susceptibility MRSA
• MDR Streptococcus pneumoniae
MRSA
DeLeo and Chambers JCI 2009
adapted from Klevens et al. JAMA I2007
Worldwide Prevalance of MRSA
Among S. aureus Isolates
Grundmann H et al. Lancet 2006;368:874.
Community -Associated
MRSA
•
•
•
•
•
•
•
•
•
Sports participants
Inmates in correctional facilities
Military recruits
Children in daycare
Native Americans, Alaskan
Natives, Pacific Islanders
Men who have sex with men
Hurricane evacuees in shelters
Foal watchers
Rural crystal methamphetamine
users
MRSA Infections Among Patients
In The Emergency Department
• Adult patients with acute, purulent skin and softtissue infections presenting to 11 Universityaffiliated EDs during August 2004
• S. aureus was isolated from 320/422 patients
• 59% overall were MRSA (15% to 74%)
• 97% of MRSA were USA300
– 74% were a single strain (USA300-0114)
• 98% of MRSA had SCCmec type IV and the
PVL toxin gene
Moran GJ et al. NEJM 2006; 355:666-74.
MRSA Infections Among Patients
In The Emergency Department
Portland
54%
Los Angeles
51%
Moran GJ et al. NEJM 2006 355:666-74.
Minneapolis
39%
New York
15%
Philadelphia
55%
Charlotte
Kansas City
Phoenix
68%
74%
60%
Atlanta
72%
Albuquerque New Orleans
67%
60%
Chambers H www.mrsai.org
S. aureus resistant or with
reduced susceptibility to
vancomycin
VRSA, VISA and hVISA
Streptococcus pneumoniae
• Most important pathogen in
mild-to-moderate RTIs
• Greatest morbidity
• Greatest mortality
Invasive Pneumococcal Disease in Children 5
Years After Conjugate Vaccine Introduction
1998 - 2005
• The overall incidence
of IPD among
children aged <5
years declined from
99 cases/100,000
during 1998 - 1999 to
23 cases/100,000 in
2005
MMWR Feb 2008.
Impact of PCV7 Vaccination On NVT-IPD in
Children <5 Years, USA 1998-2003
ABCs data. 2003 vs 1998/99.
Serotype distribution of S. pneumoniae isolated
from invasive disease in children and adults
(France: 2007)
Dortet L et al. Diag Micro ID 2009
Multi-locus sequence typing of MDR
serotype 19A isolates (n = 97)
Pillai D et al. BMC Genomics 2009
Minimum spanning tree of MDR
and non-MDDR serotype 19A
Pillai D et al. BMC Genomics 2009
Emergence of a multidrug-resistant clone (ST320)
among invasive serotype 19A pneumococci in Spain
Distribution of penicillin-resistant serotype 19A isolates belonging to different clones throughout the study period.
The bars indicate the proportion of each serotype 19A clone among penicillin-resistant pneumococci
S. pneumoniae Serotype 19A in
Children, South Korea
• From 1991 through 2006, 538 strains of S.
pneumoniae were obtained from various
clinical specimens
Choi EH et al. EID 2008
S. pneumoniae Serotype 19A in
Children, South Korea
Choi EH et al. EID 2008
Novel -lactams
– Ceftaroline
– Ceftobiprole
• Oral penem
– Faropenem
Hebeisen P et al. Antimicrob Agents Chemother. 2001.
Sader HS et al. Antimicrob Agents Chemother. 2005.
Granizo JJ et al. Clin Ther. 2006.
Schurek KN et al. Expert Rev Anti Infect Ther. 2007.
Spectrum of Activity
Organism
MIC90 (g/mL)
CTL
CBP
FAR
Pen-S
0.016
0.015
0.25
Pen-I
0.06
0.12
0.008
Pen-R
0.25
1
1
CTX-R*
0.5
1
ND‡
*Multiple mutations in PBP1a, 2b, and 2x.
‡ MIC
90 of 2 mg/L vs. cefuroxime-resistant strain
Davies TA et al. ICAAC. 2005.
Sahm DF et al. ICAAC. 2006.
Van Bambeke F et al. Drugs. 2007.
McGee L et al; Morrissey I et al. ICAAC. 2007.
Clinical Utility
ABx Route
In vivo Efficacy
CTL
IV
Good lung
penetration in
rabbit model
CBP
IV
Equal to CTX in
murine model
FAR
PO
Eradication of S.
pneumoniae; NI to
AMX  CLV, CPX
CrossResistance
Limitations
None - all
active
against
MDR
strains
Presumed or
reported crosshypersensitivity
to -lactams
Boswell FJ et al; Jones RN et al. J Antimicrob Chemother. 2002.
AzoulayDupuis E et al. Antimicrob Agents Chemother. 2004.
Echols R et
al; Kowalsky S et al; Lentnek A et al; Drehobl M et al. ICAAC. 2005.
Jacqueline C et al; Young C et al; Rubino CM et al. ICAAC. 2006.
Novel Glycopeptides
• Dalbavancin
– Once weekly IV dosing
• Oritavancin
• Telavancin
• Versus vancomycin:
– Additional mechanisms of action
– Renal and hepatic excretion
– No known nephrotoxicity or dose adjustments
Malabarba A et al. J Antimicrob Chemother. 2005
Spectrum of Activity
Organism
Pen-S
Pen-NS
MDR
MIC90 (g/mL)
VAN
DAL*‡
ORI*‡
TEL*‡
0.5
0.03
0.004
0.03
0.25-2
0.03
0.008
0.015
ND
ND
0.008
0.03
*Rapidly bactericidal
‡ Also active against macrolide- and FQ-resistant strains
Streit JM et al. Diag Micro Infect Dis. 2004.
Lin G et al. ICAAC. 2005.
Thornsberry C et al. ICAAC. 2006.
Draghi DC et al; Grover PK et al; Fritsche TR et al. ICAAC. 2007.
Clinical Utility
ABx Route
In vivo Efficacy
DAL
IV
Animal model of PCNresistant NBPP
ORI
IV
High AUC:MIC ratios in
ELF and plasma in
murine NBPP
TEL
IV
Good penetration into
ELF and AMs in human
volunteers; Phase III trial
pending
CrossResistance
AEs
Partial with
vancomycin;
clinical
significance
unclear
Redman
syndrome
with TEL;
Rare  in
platelets
Gotfried M et al. ICAAC. 2005.
Lehoux D et al. ICAAC. 2007.
Novel Fluoroquinolone
• Garenoxacin (PO/IV)
– Bactericidal
– MIC90 = 0.06 g/mL for
penicillin-, macrolide-, and 
6 drug- resistant S.
pneumoniae
– MIC90 = 1 g/mL for CIPand LEV- resistant S.
pneumoniae
– More potent than MOX
Wu P et al. Antimicrob Agents Chemother. 2001.
Jones RN et al. Diag Micro Infect Dis. 2007.
Polymyxins
• a group of polypeptide antibiotics that
consists of 5 chemically different compounds
(polymyxins A-E), were discovered in 1947
• Only polymyxin B and polymyxin E (colistin)
have been used in clinical practice
• the primary route of excretion is renal
56
Colistin
• The target of antimicrobial activity of colistin is
the bacterial cell membrane
• Colistin has also potent anti-endotoxin activity
– The endotoxin of G-N bacteria is the lipid A portion
of LPS molecules, and colistin binds and
neutralizes LPS
57
Colistin
• Active:
– Acinetobacter species,
– Pseudomonas aeruginosa,
– Enterobacteriaciae
58
Colistin
• 160 mg (2 million IU) ever 8 h
• 240 mg (3 million IU) every 8 h for lifethreatening infections
59
Colistin
• Dose adjustment for renal failure
• Adverse effects:
– nephrotoxicity (acute tubular necrosis)
– neurotoxicity (dizziness, weakness, facial
paresthesia, vertigo, visual disturbances,
confusion, ataxia, and neuromuscular blockade,
which can lead to respiratory failure or apnea)
60
MIC distribution
• MIC break point to
identify bacteria
susceptible to
colistimethate sodium is
≤4 mg/L.
• MIC is >8 mg/L should
be considered resistant
61
Use of Parenteral Colistin for the
Treatment of Serious Infection Due to
Antimicrobial-Resistant P. aeruginosa
• Colistin was used as salvage therapy for 23 critically
ill patients with multidrug-resistant P. aeruginosa
infection
– Peumonia (n = 18)
– Intra-abdominal infection (n = 5).
• Colistin was administered for a median of 17 days
(range, 7-36 days).
• A favorable clinical response was observed in 14
patients (61%); only 3 patients experienced relapse
Linden et al CID 2003
62
Safety and effectiveness of colistin
compared with tobramycin for MDR
A. baumannii infections
• A retrospective cohort study of patients
treated with colistin or tobramycin for A.
baumannii infections in ICUs
• 240 mg (3 MUs) 8 hourly and adjusted for
renal failure
• 32 patients, with similar admission APACHE
scores and serum creatinine, were treated
with each antimicrobial
Gounden R et al. BMC Infect Dis 2009 63
Safety and effectiveness of colistin
compared with tobramycin for MDR
A. baumannii infections
• There were no significant differences
between the colistin and tobramycin groups in
– ICU mortality (p = 0.54)
– Nephrotoxicity (p = 0.67)
– Change in creatinine from baseline to highest
subsequent value (p = 0.11)
– Time to microbiological clearance (p = 0.75)
Gounden R et al. BMC Infect Dis 2009 64
Ceftobiprole (Zeftera®)
June 30, 2008 -- Health Canada has
authorised the marketing of ceftobiprole
medocaril for injection (Zeftera and
marketed by Janssen Ortho) for the
treatment of complicated skin and soft
tissue infections including diabetic foot
infections
Ceftobiprole in vitro Activity vs Staphylococci
Staphylococci
Tested
# Isolates
MIC Range
(μg/ml)
MIC 90
(μg/ml)
S. aureus
1773
<0.12-4
1
OSSA
498
<0.12-1
0.5
ORSA
1275
<0.12-4
1
617
<0.12-4
1
Oxacillin-susceptible
162
<0.12-1
0.25
Oxacillin-resistant
455
<0.12-4
1
CoNS
In vitro activity does not necessarily correlate with clinical results.
Sahm DF et al . Poster E-0113 presented at the 46th ICAAC; Sept. 27-30, 2006; San Francisco, CA.
Ceftobiprole in vitro Activity vs
Streptococci and Enterococci
Organism
Total
E. faecalis1,2
Vanco-R E. faecalis3
E. faecium
Amp-S1
Amp-R 1,2
S. pneumoniae4
Pen-S
Pen-I
Pen-R
MIC Range (μg/ml) MIC90 (μg/ml)
76
17
0.12 - >32
<0.015 – 4
4
1
16
71
1-8
0.25 - >32
8
>32
299
0.008- 4
0.008 - 0.03
0.008 – 1
0.016 - 4
0.016
0.5
1
In vitro activity does not necessarily correlate with clinical results
1. Hebeisen P et al. Antimicrob Agents Chemother 2001;45:825-836. 2. Jones RN et al. J Antimicrob
Chemother 2002;50:915-932. 3 Arias Antimicrob Agents Chemother 2007; 51(6): 2043-47; 4.
Kosowska et al. Antimicrob Agents Chemother 2005;49:1932-42.
Ceftobiprole in vitro Activity vs
Gram-Negatives
Pathogen
Total
MIC Range
(g/ml)
MIC90
(g/ml)
E. coli
E. coli (ESBL+)
K. pneumoniae
K. pneumoniae (ESBL+)
S. marcescens
P. mirabilis
E. cloacae
E. aerogenes
Citrobacter species
1076
40
550
47
231
283
407
47
371
<0.015 – >32
0.03 - >32
<0.015 – >32
<0.015 – >32
0.03 - >32
< 0.015 - 8
<0.015 – >32
<0.015 - >32
<0.015– >32
0.06
>32
0.12
>32
0.25
0.06
8
4 or >32
4
In vitro activity does not necessarily correlate with clinical results.
1. Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA;
2. Hebeisen P et al. Antimicrob Agents Chemother 2001;45:825-836; 3. Issa NC et al. Diagn Micro
Infect Dis 2004; 4. Jones R et al. J Antimicrob Chemother 2002; 50:915-932
Comparative in vitro activity vs P. aeruginosa
(n=403)
Antimicrobial
agent
MIC50
(g/ml)
MIC90
(g/ml)
MIC Range
(g/ml)
Ceftobiprole
4
16
0.25->32
Ceftazidime
2
32
0.25->32
Cefepime
4
16
0.12–>32
PiperacillinTazobactam
16
>128
0.5->128
In vitro activity does not necessarily correlate with clinical results.
Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA
Daptomycin (Cubicin®)
On September 24, 2007, Health Canada
approved daptomycin intravenous infusion
(Cubicin, Cubist Pharmaceuticals, Inc, and
marketed by Oryx Pharmaceuticals, Inc) for the
treatment of complicated skin and skin structure
infections caused by certain gram-positive
infections and for bloodstream infections,
including right-sided infective endocarditis,
caused by S. aureus.
Daptomycin (Cubicin®)
• New drug class (lipopeptide)
• Rapidly bactericidal
• New mechanism of action: acts by binding to
cell membrane and disrupting the cell
membrane potential
• No cross resistance
• Dose: 4-6 mg/kg once daily
Daptomycin’s Mechanism of Action
• Irreversibly binds to cell
membrane of Grampositive bacteria
– Calcium-dependent
membrane insertion of
molecule
• Rapidly depolarizes the
cell membrane
– Efflux of potassium
– Destroys ion-concentration
gradient
Daptomycin In Vitro* Antimicrobial
Activity Against Other Gram-positive
Organisms
Daptomycin MIC Values (µg/mL)
Organism
N
Range
MIC50
MIC90
E. faecalis
(VR-strains)
34
0.25 – 2
0.5
2
E. faecalis
(VS-strains)
917
≤0.06 – 4
0.5
1
E. faecium
(incl. VR-strains)
398
0.25 – 4
2
4
S. epidermidis
(incl. MRstrains)
164
0.12 – 1
0.5
0.5
MIC=minimum inhibitory concentration; C. jeukium=Corynebactrium jeikeium; E.faecalis=Enterococcus faecalis; S.epidermidis=Streptococcus epidermidis;
S. haemolyticus=Staphylococcus haemolyticus; S. dysgalactiae=Streptococcus dysgalactiae; VR=vancomycin resistant; VS=vancomycin susceptible
*The clinical significance of in vitro data has not been established.
CUBICIN® Product Monograph September 2007.
Daptomycin
• Favorable initial trials in skin and soft tissue
infections with qd dosing; significantly less
need for step-down oral therapy (4 mg/kg)
• Less effective than ceftriaxone in communityacquired pneumonia (CAP)
• Bacteremia and endocarditis studies with
larger single daily dose (6 mg/kg)