Slide 1 Ertapenem: An Antibiotic for Ambulatory Patients Hospitalized with Moderate to Severe Infections 2005 Clinical Update

Slide 1

Ertapenem: An Antibiotic for Ambulatory Patients Hospitalized

with Moderate to Severe Infections

2005 Clinical Update

Slide 2

Ertapenem, A Unique Carbapenem

• Medical need for a new nonpseudomonal carbapenem in the era of increasing gram-negative bacterial resistance

• Carbapenem classification

• Properties of ertapenem

• Clinical efficacy of ertapenem

• Appropriate use of carbapenems

Slide 3



• Carbapenem classification• Properties of ertapenem• Clinical efficacy of ertapenem• Appropriate use of carbapenems

Slide 4

• A worldwide problem

• Associated with increased morbidity, mortality, and hospital costs

• Occurs in both hospitals and the community

• Results from factors such as antibiotic misuse

Adapted from Infectious Diseases Society of American (IDSA). Available at http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. Accessed July 2005; Cosgrove SE et al Arch Intern Med 2002;162:185–190; Ben-David D, Rubenstein E Curr Opin Infect Dis 2002;15:151–156; Colodner R et al Eur J Clin Microbiol Infect Dis 2004;23:163–167.

Antibiotic Resistance

Slide 5

Third-generation cephalosporin-resistant Klebsiella pneumoniae

Fluoroquinolone-resistant Pseudomonas aeruginosa

Non–intensive care unit patientsIntensive care unit patients

Increasing Antimicrobial Resistance Among Pathogens Causing Hospital-Onset Infections

Source: US National Nosocomial Infections Surveillance System (NNIS)

Adapted from Centers for Disease Control and Prevention (CDC). Available at http://www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppm. Accessed August 2005.

0

2

4

6

8

10

12

14

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Res

ista

nce

(%

)

0

5

10

15

20

25

30

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Res

ista

nce

(%

)

Slide 6

Multidrug-Resistant P. aeruginosa Linked to Overuse of Traditional Antibiotics with

Antipseudomonal Activity• In a two-year case-control study of patients (N=2613) admitted

to three ICUs in a large teaching hospital in Paris, France – Prolonged receipt of antibiotics with specific antipseudomonal

activity (most notably ciprofloxacin) was associated with the emergence of multidrug-resistant P. aeruginosa

– These data suggest that “if treatment with an antibiotic active against gram-negative bacteria is needed, agents with little antipseudomonal activity should be preferred over those with specific antipseudomonal activity to limit the emergence of MDRPA [multidrug-resistant P. aeruginosa].”

Adapted from Paramythiotou E et al Clin Infect Dis 2004;38:670–677.

Slide 7

Years

ICU=intensive care unit

Adapted from Neuhauser MM et al JAMA 2003;289:885–888.

Increasing Fluoroquinolone Use Increasing Fluoroquinolone Use and Resistance Ratesand Resistance Rates

0

5

10

15

20

25

30

35

1994 1995 1996 1997 1998 1999 2000

Str

ain

s re

sist

ant

toci

pro

flo

xaci

n (

%)

0

50,000

100,000

150,000

200,000

250,000

Flu

oro

qu

ino

lon

e use (kg

)

P. aeruginosa

Gram-negative bacilli

Fluoroquinolone use

US surveillance study of gram-negative aerobic isolates from ICU patients

Slide 8

Recent Publications Confirm Community Spread of ESBL-Producing Bacteria

• Now disseminating outside hospitals– Reported in Europe and Israel

– Dramatic increase in prevalence of fecal carriage during nonoutbreak situation demonstrated in SpainOutpatients: 0.7% in 1991 vs. 5.5% in 2003 in a study in Spain

• These organisms are usually multidrug-resistant to beta-lactams (except carbapenem) and non–beta-lactams– Frequency of co-resistance in ESBL-producing isolates in 2003 in a

study in Spain: sulfonamides 75%; tetracycline 64%; streptomycin 57%; quinolones 54%; and trimethoprim 50%

ESBL=extended-spectrum beta-lactamase

Adapted from Munday CJ et al J Antimicrob Chemother 2004;54:628–633; Rodriguez-Baño J et al J Clin Microbiol 2004;42:1089–1094; Woodford N et al J Antimicrob Chemother 2004;54:735–743; Colodner R et al Eur J Clin Microbiol Infect Dis 2004;23:163–167; Valverde A et al J Clin Microbiol 2004;42:4769–4775.

Slide 9

Summary of potential “collateral damage” from use of cephalosporins and quinolones

Class of agent, pathogen(s) selected for

Third-generation cephalosporins

Vancomycin-resistant enterococci

Extended-spectrum beta-lactamase–producing Klebsiella species

Beta-lactam–resistant Acinetobacter species

Clostridium difficile

Quinolones

Methicillin-resistant Staphylococcus aureus

Quinolone-resistant gram-negative bacilli, including P. aeruginosa

Resistance Linked to Overuse of Traditional Antibiotics in Recent Publication

Neither third-generation cephalosporins nor quinolones appear

suitable for sustained use in hospitals as “workhorse”

antibiotic therapy

Collateral Damage=ecological adverse effects of antibiotic therapy,including• Selection of drug-resistant organisms• Unwanted development of colonization or infection with multidrug-resistant

organisms

Adapted from Paterson DL Clin Infect Dis 2004;38(suppl 4):S341–S345.

Slide 10

Use of carbapenem (primarily imipenem) was associated with

a significantly lower 14-day mortality due to ESBL-producing

K. pneumoniae than was use of other active antibiotics

Recent Publication Supports Role of Carbapenems in Treating

Infections Due to ESBL-Producing K. pneumoniae

Adapted from Paterson DL et al Clin Infect Dis 2003;39:31–37.

Antibiotic choice and mortality associated with bacteremia due to extended-spectrum beta-lactamase–producing K. pneumoniae

Type of therapyAll-cause

14-day mortality

Carbapenem monotherapy 1/27 (3.7)

Imipenem 1/24

Meropenem 0/3

Quinolone monotherapy (ciprofloxacin) 4/11 (36.4)

Cephalosporin monotherapy 2/5 (40)

Cefepime 1/2

Ceftriaxone 1/2

Cefotaxime 0/1

Beta-lactam/beta-lactamase inhibitor combination

2/4 (50)

Piperacillin-tazobactam 2/2

Ticarcillin-clavulanate 0/2

Aminoglycoside monotherapy (amikacin) 0/2 (0)

No active antibiotics 7/11 (63.6)

Slide 11

Appropriate Use of Antibiotics Is Crucial in the Era of Increasing Gram-Negative

Bacterial Resistance• Clinicians already see pan-resistance to certain antibiotics in isolates of

P. aeruginosa and Acinetobacter spp, and the absence of pan-resistance in Enterobacteriaceae is only due to the continued efficacy of carbapenems

• Evidence-based, judicious use of antibiotics is crucial in reducing further resistance selection, along with improved infection control Appropriate antibiotic treatment and prophylaxis Antibiotics with a low potential to select further antibiotic resistance Antibiotics without activity against P. aeruginosa unless this coverage is necessary Antibiotic administration for the shortest possible duration

Adapted from Livermore DM Clin Microbiol Infect 2004;10(suppl 4):1–9; CDC. Available at http://www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppm. Accessed August 2005.

Slide 12

Medical Need for a New Nonpseudomonal Carbapenem in the Era of Increasing Gram-Negative Bacterial Resistance

• Carbapenems are often considered drugs of choice in treating serious infections caused by multidrug-resistant ESBL-producing gram-negative bacteria

• Traditional antibiotics (cephalosporins and fluoroquinolones) are often linked to emergence of multidrug-resistant gram-negative bacteria – Need for a new agent in the antibiotic armamentarium

• Agents with little antipseudomonal activity should be preferred over those with specific antipseudomonal activity to limit the emergence of multidrug-resistant P. aeruginosa – Need for an effective, nonpseudomonal carbapenem in serious infections

or locales where ESBL producers are likely (without the need for Pseudomonas coverage)

Adapted from Jacoby GA, Munoz-Price LS N Engl J Med 2005;352:380–391; Hammond ML J Antimicrob Chemother 2004;53(suppl S2):ii7–ii9; Livermore DM Clin Microbiol Infect 2004;10(suppl 4):1–9; Paramythiotou E et al Clin Infect Dis 2004;38:670–677.

Slide 13




Slide 14

GROUP 1Carbapenems

(infections upon hospital admission–limited activity against

nonfermentative gram-negative bacilli)

GROUP 2Carbapenems

(hospital-acquired infections– Pseudomonas and

Acinetobacter activity)

GROUP 3Carbapenems

(MRSA activity)

Ertapenem Imipenem MeropenemPanipenemBiapenemDoripenem

(investigational)

CS-023(investigational)

Carbapenem Classification

MRSA=methicillin-resistant S. aureus

Adapted from Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542; Thomson KS, Smith Moland E J Antimicrob Chemother 2004;54:557–562; Mouton JW et al Clin Pharmacokinet 2000;39:185–201.

Slide 15




Slide 16

Ertapenem: Group 1 Carbapenem

A Potential Solution to Minimize the Problem of Multidrug Resistance

Slide 17

Ertapenem: Group 1 Carbapenem Ertapenem: Group 1 Carbapenem

N

H3C

O

OH CH3

S

NH2

HN

O

O

O

O

O

Na

Trans hydroxyethyl unique to carbapenems contributes to

beta-lactamase stability

1-beta-methyl slows renal hydrolysis,allows use as a single agent

Benzoate changes overallmolecular charge, increasing lipophilicity and protein binding; increased t1/2 allows once-a-day dosing

Adapted from Hammond ML J Antimicrob Chemother 2004;53(suppl S2):ii7–ii9.

Slide 18

Product Profile of ErtapenemProduct Profile of Ertapenem

• Approved for the following infections– Complicated intra-abdominal– Acute pelvic– Community-acquired pneumonia– Complicated urinary tract – Complicated skin and skin structure– Bacterial septicemia

• Tolerability profile shown in clinical trials comparable to ceftriaxone and piperacillin/tazobactam– Minimal drug–drug interactions– Convenient dosing: 1 g once a day**– Flexibility of intravenous or intramuscular administration

The only once-a-day parenteral carbapenem providing proven coverage of common gram-positive and gram-negative aerobic and anaerobic pathogens*

*Many strains of Enterococcus faecalis and most strains of E. faecium are resistant to ertapenem. Methicillin-resistant staphylococci are also resistant **500 mg daily for patients with creatinine clearance ≤30 ml/min/1.73 m2 including those on hemodialysis

Slide 19

Ertapenem: Ertapenem: In VitroIn Vitro Antimicrobial Spectrum Antimicrobial Spectrum

Number of isolates MIC90 (µg/ml)

Aerobes, gram-positive

S. aureus* 883 0.25

Streptococcus agalactiae 306 0.06

Streptococcus pneumoniae** 1096 1

Streptococcus pyogenes 411 0.016

Aerobes, gram-negative

Escherichia coli 1596 0.016

Haemophilus influenzae 726 0.06

K. pneumoniae 904 0.06

Moraxella catarrhalis 255 0.016

Proteus mirabilis 323 0.03

Anaerobes

Bacteroides fragilis 390 1

Clostridium spp 51 1

Eubacterium spp 47 1

Peptostreptococcus spp 12 0.5

Porphyromonas asaccharolytica 57 0.03

Prevotella spp 61 0.25MIC90=minimum inhibitory concentrations for 90% of isolates

*Methicillin susceptible; **Penicillin resistant and susceptible

Slide 20

In Vitro In Vitro Spectrum of Activity: Spectrum of Activity: Canadian Surveillance Study (1999–2003) Canadian Surveillance Study (1999–2003)

Streptococcus pneumoniae—MIC90 (μg/ml)

Respiratory*isolates (Number) CRM CFT A/C MER ERT

Bacteremic*Isolates (Number) CRM CFT A/C MER ERT

All (5054) 1 0.25 0.25 0.12 0.25 All (876) 0.25 0.06 0.06 0.06 0.12

penS (3987) 0.25 0.06 0.03 0.06 0.03 penS (745) 0.25 0.06 0.03 0.06 0.03

penI (691) 2 0.5 1 0.25 0.25 penI (85) 1 0.25 0.5 0.25 0.25

penR (354) 8 1 2 0.5 1 penR (46) 4 1 2 0.5 1

macR (445) 4 1 2 0.5 0.5 macR (73) 4 1 2 0.5 0.5

cipR (89) 4 0.5 1 0.25 0.5 cipR (12) 2 0.5 0.5 0.12 0.25

CRM=cefuroxime, CFT=cefotaxime, A/C=amoxicillin/clavulanate, ERT=ertapenem; MER=meropenem; penS=penicillin-susceptible; penI=intermediate susceptibility to penicillin; penR=penicillin resistant; macR=macrolide resistant; cipR=ciprofloxacin resistant

*Canadian isolates collected 1999–2003

Adapted from Hoban DJ et al. Presented at the 43rd ICAAC, Chicago, IL, USA, September 14–17, 2003 (Poster E-2009).

Slide 21

In VitroIn Vitro Spectrum of Activity Against Urinary Spectrum of Activity Against Urinary Pathogens: Pathogens: In Vitro In Vitro Study in Spain (2003)Study in Spain (2003)

Isolates (Number) ERT CFT A/C P/T GEN CIP CTX

E. coli (315) 0.06 >16 32/16 16/4 >8 >4 >4/76

Klebsiella spp (14) 0.25 >16 16/8 32/4 >8 >4 >4/76

P. mirabilis (42) 0.06 0.12 16/8 8/4 >8 >4 >4/76

P. vulgaris (10) 0.03 0.12 32/16 2/4 2 0.12 >4/76

M. morganii (39) 0.12 8 >32/16 4/4 >8 4 >4

Enterobacter spp (41) 1 >16 >32/16 32/4 1 4 1

P/T=piperacillin/tazobactam; GEN=gentamicin; CIP=ciprofloxacin; CTX=cotrimoxazole

Adapted from Alhambra A et al J Antimicrob Chemother 2004;53:1090–1094.

Antibiotic-resistant Enterobacteriaceae—MIC90 (mg/L)

Slide 22

In Vitro Spectrum of Activity: Ertapenem vs. Comparators

Beta-lactamase Ertapenem Imipenem Cefepime CeftazidimePiperacillin/Tazobactam

ESBL-producing Klebsiella 0.06 0.5 8 >128 >128

AmpC-hyperproducing Enterobacteriaceae

0.015–0.5 0.25–1.0 0.5–4.0 >128 >128

*Includes 181 ESBL-producing Klebsiella isolates (collected from ICU patients in western and southern Europe)

Adapted from Livermore DM et al Antimicrob Agents Chemother 2001;45:2831–2837.

“Acquired carbapenemases are rare but are increasingly being reported, mostly from nonfermenters but occasionally from Enterobacteriaceae.”

• A K. pneumoniae strain with IMP-1 metallo-beta-lactamase and loss of porin was resistant to all beta-lactams, including ertapenem

• Resistance to carbapenems, but not to other antibiotics, was reduced when expression of the porin was restored

Enterobacteriaceae with potent beta-lactamases*—MIC90 (μg/ml)

Slide 23

Ertapenem: Ertapenem: In VitroIn Vitro Bactericidal Activity Bactericidal ActivityAgainst ESBL-Negative Against ESBL-Negative E. coliE. coli

CFU=colony-forming units

Adapted from Dorso K et al. Presented at the American Society for Microbiology, Salt Lake City, UT, USA, May 19–24, 2002 (Poster A-156).

Kill rate vs. ESBL—E. coli CL 9305

CFU/ml reduction (log10)

24 Hours5.565.345.26

6 Hours5.565.343.57

ErtapenemCeftriaxonePiperacillin/tazobactam

0 2 4 6 8 10 12 14 16 18 20 22 24

1010

108

106

104

100

1

Time (hours)

CF

U/m

l

Ertapenem 10 μg/mlCeftriaxone 28 μg/mlPiperacillin/tazobactam 11.5/1.4 μg/mlGrowth control

Time-Kill Study of Intra-Abdominal Pathogens

Slide 24

Ertapenem: In Vitro Bactericidal Activity Against ESBL-Positive E. coli

Kill rate vs. ESBL+ E. coli CL 120821010

108

106

104

100

1

Time (hours)

CF

U/m

l

Ertapenem 10 μg/mlCeftriaxone 28 μg/mlPiperacillin/tazobactam 11.5/1.4 μg/mlGrowth control

CFU/ml reduction (log10)

24 Hours

5.30

4.25

Growth

6 Hours

5.30

2.10

Growth

Ertapenem

Ceftriaxone

Piperacillin/tazobactam

0 2 4 6 8 10 12 14 16 18 20 22 24

Adapted from Dorso K et al. Presented at the American Society for Microbiology, Salt Lake City, UT, USA, May 19–24, 2002 (Poster A-156).

Slide 25

Ertapenem: Bactericidal Activity Against Ertapenem: Bactericidal Activity Against ESBL-Positive or ESBL-Negative ESBL-Positive or ESBL-Negative E. coliE. coli and and

K. pneumoniae K. pneumoniae in a Murine Modelin a Murine Model

• Activity in a murine neutropenic thigh infection model evaluated as percentage of dosing interval that concentration of free ertapenem exceeded MIC (%T>MIC)– Mean values of %T>MIC were 19% (static exposure) and

33% ED80—consistent with those reported previously for carbapenems

– In vivo bactericidal efficacy at 100-fold higher inoculum (107 CFU/ml) did not alter compared to lower inoculum in ESBL-producing E. coli and K. pneumoniae

ED80=80% maximally effective exposure

Adapted from Maglio D et al Antimicrob Agents Chemother 2005;49:276–280.

Slide 26

In VitroIn Vitro Effect of Inoculum Size on MIC ( Effect of Inoculum Size on MIC (µµg/ml) g/ml) of ESBL-Producing of ESBL-Producing E. coliE. coli

MIC=minimum inhibitory concentration; ERT=ertapenem; MER=meropenem; IMI=imipenem; CRX=ceftriaxone; CFZ=ceftazidime; CPM=cefepime; AZT=aztreonam

Adapted from Kohler J et al Antimicrob Agents Chemother 1999;43:1170–1176.

Organism Enzyme CFU/ml ERT MER IMI CRX CFZ CPM AZT

E. coli 5121 SHV-1 9.6105

9.6106

0.0160.25

0.030.5

0.120.5

0.062

0.258

0.064

0.06>128

E. coli 5190 TEM-10 1.4106

1.4107

0.060.06

0.0160.25

0.060.12

4>128

>128>128

4128

64>128

E. coli 5115 TEM-1 1.0106

1.0107

0.0080.008

0.030.03

0.250.25

0.030.25

0.250.5

0.030.12

0.060.12

E. coli 5120 TEM-7 6.0105

6.0106

0.0160.03

0.030.12

0.120.25

0.516

32128

2128

132

E. coli 5197 TEM-12 1.3106

1.3107

0.120.12

0.030.12

0.120.25

164

64>128

4>128

2>128

Slide 27

In VitroIn Vitro Effect of Inoculum Size on MIC ( Effect of Inoculum Size on MIC (µµg/ml) g/ml) of ESBL-Producing of ESBL-Producing K. pneumoniaeK. pneumoniae

Organism Enzyme CFU/ml ERT MER IMI CRX CFZ CPM AZT

K. pneumoniae 5188

TEM-10, SHV-1

1.5106

1.5107

0.12

1

0.06

1

0.25

1

32

>128

>128

>128

16

>128

>128

>128

K. pneumoniae 5189

TEM-10, SHV-1

1.8106

1.8107

≤0.03

0.25

≤0.03

0.25

0.06

0.25

4

128

>128

>128

2

128

64

>128

K. pneumoniae 5128

TEM-5 1.1106

1.1107

0.12

1

≤0.03

0.12

0.06

0.5

8

64

64

64

2

128

16

>128

K. pneumoniae 5196

TEM-10 1.2106

1.2107

0.06

0.5

≤0.03

1

0.5

1

2

>128

>128

>128

4

128

128

>128

MIC=minimum inhibitory concentration; ERT=ertapenem; MER=meropenem; IMI=imipenem; CRX=ceftriaxone; CFZ=ceftazidime; CPM=cefepime; AZT=aztreonam

Adapted from Kohler J et al Antimicrob Agents Chemother 1999;43:1170–1176.

Slide 28

In VitroIn Vitro Effect of Inoculum Size on MIC ( Effect of Inoculum Size on MIC (µµg/ml) g/ml) of ESBL-Producing Gram-Negative Strainsof ESBL-Producing Gram-Negative Strains

Increase in MIC*

AntibioticESBL-producing

KlebsiellaESBL-negative

Klebsiella

Ertapenem 1- to 8-fold 1- to 4-fold

Imipenem 1- to 32-fold 1- to 16-fold

Ceftazidime 1- to 8-fold (44/50 resistant)

<1- to 32-fold

Cefepime 4- to 128-fold 1- to 32-fold

Piperacillin All (50/50) resistant 4- to 32-fold

Piperacillin/tazobactam 2-fold to 128-fold

(38/50 resistant)

8- to 16-fold

*Fold increase with higher (106 CFU/spot) vs. lower (104 CFU/spot) inoculum density

Adapted from Livermore DM et al Antimicrob Agents Chemother 2001;45:2831–2837.

Slide 29

Ertapenem: Minimal Risk for Resistance Selection

• Minimal resistance selection among P. aeruginosa• Minimal risk for resistance selection among Enterobacteriaceae

– Confirmed in two separate bowel colonization studies– Carbapenem-resistant Enterobacteriaceae remain low after

20 years of imipenem use, including in the hospital setting– Carbapenems remain drugs of choice for infections caused

by ESBL-producing Enterobacteriaceae

Adapted from Livermore DM et al J Antimicrob Chemother 2005;55:306–311; DiNubile MJ et al Eur J Clin Microbiol Infect Dis 2005;24:443–449; Wenzel RP et al Antimicrob Agents Chemother 2003;47:3089–3098; Karlowsky JA et al Antimicrob Agents Chemother 2003;47:1672–1680; Livermore DM Ann Med 2003;35:226–234; Jacoby GA, Munoz-Price LS N Engl J Med 2005;352:380–391.

Slide 30

Ertapenem Has Minimal Selectivity for Ertapenem Has Minimal Selectivity for Imipenem-Resistant Imipenem-Resistant P. aeruginosa P. aeruginosa Mutants Mutants

Under Clinical ConditionsUnder Clinical Conditions

• Pharmacodynamics do not favor the selection of imipenem-resistant P. aeruginosa– “Selective concentration pertains only very briefly in vivo, militating

against selection in the patient”—Livermore DM et al

• Ertapenem aimed at community-acquired infections where P. aeruginosa is not a likely pathogen– No or minimal selection demonstrated in a subanalysis of two

OASIS trials

• Analogous to ceftriaxone, which has not been blamed for selecting ceftazidime-resistant P. aeruginosa in clinical setting

OASIS=Optimizing Intra-Abdominal Surgery with INVANZ™ Studies

Adapted from Livermore DM et al J Antimicrob Chemother 2005;55:306–311; DiNubile MJ et al Eur J Clin Microbiol Infect Dis 2005;24:443–449.

Slide 31

Ertapenem: Minimal Risk of Resistance Ertapenem: Minimal Risk of Resistance Development in OASIS I SubanalysisDevelopment in OASIS I Subanalysis

Adapted from DiNubile MF et al Eur J Clin Microbiol Infect Dis 2005;24:443–449.

Ertapenem Piperacillin/tazobactam

Per

cen

t

BaselineEnd of therapy2 weeks post therapy

0

2

4

14

0%

6

8

% Resistant % ESBL producers % Resistant

10

12

(n=162) (n=155) (n=133) (n=133)(n=155)(n=162) (n=160) (n=156) (n=133) (n=133)(n=156)(n=160)

0.6% 0% 0%0.6% 0.8% 0.6% 0.6% 0.8%

12.2%

4.5%

2.6%

% ESBL producers

Slide 32

Ertapenem: Minimal Risk of Resistance Ertapenem: Minimal Risk of Resistance Development in OASIS II SubanalysisDevelopment in OASIS II Subanalysis

Adapted from DiNubile MF et al Eur J Clin Microbiol Infect Dis 2005;24:443–449.

Ertapenem Ceftriaxone/metronidazole

Per

cen

t

BaselineEnd of therapy2 weeks post therapy

0

25

0.5%

5

10

% Resistant % Resistant

15

20

(n=201) (n=196) (n=182) (n=182)(n=196)(n=201) (n=195) (n=193) (n=174) (n=174)(n=193)(n=195)

0.5% 0% 0%

4.0%

2.2% 2.6% 2.1%

17.2%17.1%

22.4%

9.3%

% ESBL producers % ESBL producers

Slide 33

Lower Emergence of Resistance Among Enterobacteriaceae with Ertapenem vs.

Piperacillin/Tazobactam

Ertapenem(n=122)

Piperacillin/tazobactam(n=122)

*p=0.008 vs. baseline and p=0.007 vs. ertapenem

Adapted from DiNubile M et al Antimicrob Agents Chemother 2005;49:3217–3221.

Per

cen

t

BaselineEnd of therapy

0

1

2

3

4

10

0%

5

6

7

0% 0% 0% 0% 0%

0.8%

% Resistant % ESBL producers % Resistant % ESBL producers

8

9

7.4%*

Slide 34

Ertapenem Shares the Properties Ertapenem Shares the Properties of Carbapenemsof Carbapenems

• Broad spectrum of activity (gram-positive, gram-negative, anaerobes), including multidrug-resistant S. pneumoniae and gram-negative Enterobacteriaceae

• Rapidly bactericidal

• High stability to hydrolysis by plasmidic or chromosomal beta-lactamases (ESBL, ampC enzymes)– Resistance to carbapenem in Enterobacteriaceae remains rare– Minimal inoculum effect

• Minimal risk for resistance selection in Enterobacteriaceae

Adapted from Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542; Livermore DM et al Antimicrob Agents Chemother 2001;45:2831–2837; Livermore DM et al J Antimicrob Chemother 2005;52:331–344; Maglio D et al Antimicrob Agents Chemother 2005;49:276–280; Kohler J et al Antimicrob Agents Chemother 1999;43:1170–1176.

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Slide 36

Clinical Efficacy of ErtapenemClinical Efficacy of Ertapenem

Complicated intra-abdominal infections

Acute pelvic infections

Community-acquired pneumonia

Complicated urinary tract infections

Complicated skin and skin-structure infections

Diabetic foot infections without osteomyelitis

Slide 37

Complicated Intra-Abdominal Infections: Complicated Intra-Abdominal Infections: Ertapenem vs. Ceftriaxone/MetronidazoleErtapenem vs. Ceftriaxone/Metronidazole

Adapted from Yellin AE et al Int J Antimicrob Agents 2002;20:165–173.

• Study design: prospective, multicenter, randomized, double-blind trial

• Patients: 114 hospitalized adults with mild to moderate intra-abdominal infections requiring surgery

• Therapy: ertapenem 1 g once daily vs. ceftriaxone 2 g once daily plus metronidazole 500 mg every eight hours

• Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic assessments at test of cure four to six weeks after completion of therapy

Slide 38

Complicated Intra-Abdominal Infections: Clinical Efficacy vs. Ceftriaxone/Metronidazole

Adapted from Yellin AE et al Int J Antimicrob Agents 2002;20:165–173.

Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic responses at test-of-cure evaluation

Ertapenem1 g once daily

Ceftriaxone 2 g once daily/metronidazole 500 mg every 8 hours

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

84%(26/31)

85%(35/41)

Slide 39

Complicated Intra-Abdominal Infections: Complicated Intra-Abdominal Infections: Ertapenem vs. Ceftriaxone/Metronidazole (OASIS II)Ertapenem vs. Ceftriaxone/Metronidazole (OASIS II)

• Study design: prospective, multicenter, randomized, open-label trial (OASIS II)

• Patients: 450 hospitalized adults with intra-abdominal infections requiring surgery

• Therapy: ertapenem 1 g once daily vs. ceftriaxone 2 g in one or two daily doses plus metronidazole 30 mg/kg

per day in two to four divided doses

• Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic assessments at test of cure two weeks after completion of study therapy

Adapted from Navarro N et al Int J Surg 2005;3:25–34.

Slide 40

Complicated Intra-Abdominal Infections: Clinical Efficacy vs. Ceftriaxone/Metronidazole in OASIS II

Adapted from Navarro NS et al Int J Surg 2005;3:25–34.



Ceftriaxone 2 g (1 or 2 daily doses)/

metronidazole 30 mg/kg per day (2–4 divided doses)

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

97%(143/146)

97%(146/151)

Slide 41

Complicated Intra-Abdominal Infections: Complicated Intra-Abdominal Infections: Ertapenem vs. Piperacillin/TazobactamErtapenem vs. Piperacillin/Tazobactam


• Patients: hospitalized adults with intra-abdominal infections requiring surgery

• Therapy: ertapenem 1 g once daily vs. piperacillin/tazobactam 3.375 g every six hours

• Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic assessments at test of cure four to six weeks after completion of therapy

Adapted from Solomkin JS et al Ann Surg 2003;237:235–245.

Slide 42

Complicated Intra-Abdominal Infections: Clinical Efficacy vs. Piperacillin/TazobactamPiperacillin/Tazobactam

Adapted from Solomkin JS et al Ann Surg 2003;237:235–245.

Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic responses


Piperacillin/tazobactam3.375 g every 6 hours

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

87%(176/203) 81%

(157/193)

Slide 43

Complicated Intra-Abdominal Infections: Complicated Intra-Abdominal Infections: Ertapenem vs. Piperacillin/Tazobactam (OASIS I)Ertapenem vs. Piperacillin/Tazobactam (OASIS I)

• Study design: prospective, multicenter, randomized, open-label trial (OASIS I)


• Therapy: ertapenem 1 g once daily vs. piperacillin/tazobactam 3.375 g every six hours or 4.5 g every eight hours

• Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic assessments at test of cure two weeks after completion of therapy

Adapted from Dela Pena AS et al. Presented at the 14th ECCMID, May 1–4, 2004. Poster 1686.

Slide 44

Complicated Intra-Abdominal Infections: Clinical Efficacy vs. Piperacillin/Tazobactam (OASIS I)Piperacillin/Tazobactam (OASIS I)


Adapted from Dela Pena AS et al. Presented at the 14th ECCMID, May 1–4, 2004. Poster 1686.


Piperacillin/tazobactam3.375 g every 6 hours or

4.5 g every 8 hours

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

90%(107/119)

94%(107/114)

Slide 45

Moderate to Severe Acute Pelvic Infections: Moderate to Severe Acute Pelvic Infections: Ertapenem vs. Piperacillin/TazobactamErtapenem vs. Piperacillin/Tazobactam

• Study design: prospective, multicenter, randomized, open-label trial



• Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic assessments at test of cure two to four weeks after completion of therapy

Adapted from Roy S et al Infect Dis Obstet Gynecol 2004;11:27–37.

Slide 46

Moderate to Severe Acute Pelvic Infections: Moderate to Severe Acute Pelvic Infections: Clinical Efficacy vs. Piperacillin/Tazobactam Clinical Efficacy vs. Piperacillin/Tazobactam

Adapted from Roy S et al Infect Dis Obstet Gynecol 2004;11:27–37.

Primary study endpoint: proportion of clinically evaluable patients considered cured at test-of-cure evaluation


Piperacillin/tazobactam3.375 g every 6 hours

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

94%(153/163)

92%(140/153)

Slide 47

Serious Community-Acquired Pneumonia: Serious Community-Acquired Pneumonia: Ertapenem vs. CeftriaxoneErtapenem vs. Ceftriaxone


• Patients: 364 hospitalized adults with serious community-acquired pneumonia

• Therapy: ertapenem 1 g IV once daily vs. ceftriaxone 1 g IV once daily

• Primary study endpoint: clinical response rate in clinically evaluable patients at test of cure seven to 14 days after completion of therapy

Adapted from Vetter N et al Clin Ther 2002;24:1770–1785.

Slide 48

Serious Community-Acquired Pneumonia: Serious Community-Acquired Pneumonia: Clinical Efficacy vs. CeftriaxoneClinical Efficacy vs. Ceftriaxone

Adapted from Vetter N et al Clin Ther 2002;24:1770–1785.


Ertapenem1 g IV once daily

Ceftriaxone 1 g IV once daily

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

92%(n=182)

94%(n=93)

Slide 49

Community-Acquired Pneumonia: Community-Acquired Pneumonia: Ertapenem vs. CeftriaxoneErtapenem vs. Ceftriaxone


• Patients: 502 adults with serious community-acquired pneumonia

• Therapy: ertapenem 1 g once daily vs. ceftriaxone 1 g once daily

• Primary study endpoint: proportion of clinically evaluable patients with favorable clinical response at test of cure seven to 14 days after completion of therapy

Adapted from Ortiz-Ruiz G et al Clin Infect Dis 2002;34:1076–1083.

Slide 50

Community-Acquired Pneumonia: Community-Acquired Pneumonia: Clinical Efficacy vs. CeftriaxoneClinical Efficacy vs. Ceftriaxone

Adapted from Ortiz-Ruiz G et al Clin Infect Dis 2002;34:1076–1083.

Primary study endpoint: proportion of clinically evaluable patients with favorable clinical response at test of cure seven to 14 days after completion of therapy


Ceftriaxone 1 g once daily

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

92%(168/182)

91%(183/201)

Slide 51

• Study design: combined analysis of two prospective, multicenter, randomized, double-blind trials

• Patients: 866 hospitalized adults with serious community-acquired pneumonia requiring parenteral antimicrobial therapy


• Primary study endpoint: clinical response (cure) in clinically evaluable patients at test-of-cure evaluation seven to 14 days after completion of therapy

Studies of Community-Acquired Pneumonia: Ertapenem vs. Ceftriaxone

Adapted from Ortiz-Ruiz G et al J Antimicrob Chemother 2004;53(suppl S2):ii59–ii66.

Slide 52

Efficacy of Ertapenem in Community-Acquired Pneumonia

End of IV therapy(approximately 5.2 days)

Test-of-cure assessment(primary endpoint;

1–2 weeks post therapy)

Su

cces

s ra

te (

%)

Ertapenem 1 g once a dayCeftriaxone 1 g once a day

0

20

40

60

80

100

95%(n=363)

94%(n=293)

92%(n=364)

92%(n=294)

IV=intravenous

Adapted from Ortiz-Ruiz G et al J Antimicrob Chemother 2004;53(suppl S2):ii59–ii66.

Slide 53

Efficacy of Ertapenem in Elderly Patients with Community-Acquired Pneumonia

Adapted from Chan C et al. Presented at the Third Forum on Respiratory Tract Infections, Monte Carlo, Monaco, February 5–7, 2004.

<65 years 65 years

Res

po

nse

rat

e (%

)

Ertapenem 1 g once a dayCeftriaxone 1 g once a day

82

84

90

92

94

96

91%(197/217)

93%(159/171)

88

86

94%(138/147)

90%(111/123)

94%(63/67)

87%(55/63)

75 years

Slide 54

Complicated Urinary Tract Infections: Complicated Urinary Tract Infections: Ertapenem vs. CeftriaxoneErtapenem vs. Ceftriaxone


• Patients: 592 adults with complicated urinary tract infections


• Primary study endpoint: bacterial eradication in microbiologically evaluable patients at test-of-cure evaluation five to nine days after completion of therapy

Adapted from Tomera KM et al Antimicrob Agents Chemother 2002;46:2895–2900.

Slide 55

Complicated Urinary Tract Infections: Complicated Urinary Tract Infections: Clinical Efficacy vs. CeftriaxoneClinical Efficacy vs. Ceftriaxone

Primary study endpoint: bacterial eradication in microbiologically evaluable patients at test-of-cure evaluation five to nine days post therapy


Ceftriaxone 1 gonce daily

Pro

po

rtio

n o

f p

atie

nts

0

20

40

60

80

100

92%(146/159)

93%(159/171)

Adapted from Tomera KM et al Antimicrob Agents Chemother 2002;46:2895–2900.

Slide 56

Study of Complicated Skin and Skin-Structure Infection:

Ertapenem vs. Piperacillin/Tazobactam


• Patients: 540 adults with complicated skin/soft-tissue infections


• Primary study endpoint: favorable clinical response at discontinuation of IV therapy

Adapted from Graham DR et al Clin Infect Dis 2002;34:1460–1468.

Slide 57

Clinical Efficacy of Ertapenem in Complicated Clinical Efficacy of Ertapenem in Complicated Skin and Skin-Structure InfectionSkin and Skin-Structure Infection

End of IV therapy(approximately 9.5 days)

Final assessment(test of cure, primary endpoint;

10–21 days post therapy)

Res

po

nse

(%

)

Ertapenem 1 g once a dayPiperacillin/tazobactam 3.375 g every six hours

0

20

40

60

80

100

87%(160/185)

88%(152/173) 82%

(n=185)

84%(n=174)

Adapted from Graham DR et al Clin Infect Dis 2002;34:1460–1468.

Slide 58

Study of Diabetic Foot Infection (SIDESTEP): Ertapenem vs. Piperacillin/Tazobactam


• Patients: 586 adults with diabetic foot infections without osteomyelitis


• Primary study endpoint: favorable clinical response at discontinuation of IV therapy

SIDESTEP=Study of Infections in Diabetic Feet Comparing Efficacy, Safety, and Tolerability of Ertapenem versus Piperacillin/Tazobactam

Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.

Slide 59

Study of Diabetic Foot Infection (SIDESTEP): Clinical Efficacy vs. Piperacillin/Tazobactam

End of IV therapy(primary endpoint)

Final assessment(secondary endpoint; 10 days post therapy)

Res

po

nse

(%

)

Ertapenem 1 g once a dayPiperacillin/tazobactam 3.375 g every six hours

0

20

40

60

80

100

94%(213/226)

92%(202/219) 87%

(180/206) 82%(162/196)

Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.

Slide 60

Clinical Adverse Experiences* Profile

*Drug related; **Combined data from trials vs. piperacillin/tazobactam and ceftriaxone

Adapted from Teppler H et al J Antimicrob Chemother 2004;53(suppl S2):ii75–ii81.

Ertapenem phase II–III clinical trial program

1% in ertapenem treatment groups

Ertapenem 1 g

(n=802)**


3.375 g(n=774)

Ertapenem 1 g

(n=1152)

Ceftriaxone 1 or 2 g (n=942)

SystemicDiarrheaNauseaHeadacheVomitingPruritusRashAbdominal painVaginitis

5.0%2.5%1.9%0.9%1.2%1.1%0.7%0.9%

7.0%3.4%1.2%1.7%1.2%1.8%0.5%0.7%

5.6%3.4%2.3%1.3%0.5%1.1%1.0%2.9%

5.9%3.3%2.3%1.2%1.0%0.6%1.3%3.5%

LocalInfused-vein complicationsPhlebitis/thrombophlebitis

4.5%1.6%

5.5%1.3%

3.2%1.0%

4.6%1.5%

Slide 61

Laboratory Adverse ExperiencesLaboratory Adverse Experiences** Profile Profile

ALT=alanine transaminase; AST=aspartate transaminase

*Drug related

Adapted from Teppler H et al J Antimicrob Chemother 2004;53(suppl S2):ii75–ii81.

1% in ertapenem treatment groups

Ertapenem 1 g

(n=766)


3.375 g(n=755)

Ertapenem 1 g

(n=1122)

Ceftriaxone 1 or 2 g (n=920)

Increased ALT 5.0% 4.4% 6.5% 5.1%

Increased AST 4.9% 4.5% 5.3% 4.3%

Increased alkaline phosphatase 4.4% 4.0% 2.7% 1.5%

Increased platelets 3.2% 4.6% 2.1% 0.9%

Ertapenem phase II–III clinical trial program

Slide 62

Proven Efficacy of Ertapenem in Five Clinical Settings

• Clinical efficacy shown in clinical studies of– Complicated intra-abdominal infection– Acute pelvic infection– Community-acquired pneumonia– Complicated urinary tract infection– Complicated skin and skin-structure infection including

diabetic foot infections without osteomyelitis

• Dose: 1 g once daily*

*500 mg daily for patients with creatinine clearance ≤30 ml/min/1.73 m2 including those on hemodialysis

Slide 63

Clinical Efficacy of Ertapenem Clinical Efficacy of Ertapenem in Pediatric Patients in Pediatric Patients in Five Clinicalin Five Clinical SettingsSettings

Slide 64

Efficacy of Ertapenem vs. Ceftriaxone in Pediatric Patients: Evaluable Per-Protocol Analysis*

Skin/soft-tissueinfection**

Community-acquired pneumonia**

Res

po

nse

(%

)

Ertapenem 15 mg/kg twice daily (3 mo–12 yr); 1 g once daily (13–17 yr)Ceftriaxone 50 mg/kg per day in 2 doses (3 mo–12 yr); 50 mg/kg per day in 1 dose (13–17 yr)

40

50

80

90

100

96%(64/67)

100%(26/26)

70

60

Urinary tract infection***

96%(74/77)

96%(27/28)

87%(40/46)

90%(18/20)

*Of randomized, multicenter, double-blind clinical trials; **Clinical success rate; ***Microbiologic success rate

Slide 65

Efficacy of Ertapenem vs. Ticarcillin/Clavulanate in Pediatric Patients:

Evaluable Per-Protocol Analysis*

Acute pelvic infection Intra-abdominal infection

Res

po

nse

(%

)

Ertapenem 15 mg/kg twice daily (3 mo–12 yr);1 g once daily (13–17 yr)Ticarcillin/clavulanate 50 mg/kg 4–6 times daily (<60 kg);3 g daily in 4–6 divided doses (60 kg)

0

20

40

60

80

100

100%(23/23)

100%(4/4)

84%(36/43)

64%(7/11)

*Of randomized, multicenter, double-blind clinical trials

Slide 66

Tolerability Profile of Ertapenem in Randomized Clinical Trials of Pediatric Patients

Drug-related clinical adverse events in 1% of patients

ErtapenemN=384

CeftriaxoneN=100

Ticarcillin/clavulanate

N=24

Diarrhea 5.5% 10.0% 4.2%

Vomiting 1.6% 2.0% 0

Rash 1.3% 1.0% 4.2%

Infusion-site erythema 2.6% 2.0% 0

Infusion-site pain 5.5% 1.0% 12.5%

Infusion-site phlebitis 1.8% 3.0% 0

Infusion-site swelling 1.0% 0 0

Slide 67

Excellent Efficacy of Ertapenem in Pediatric Patients in Five Clinical Settings

• In pediatric patients (3 mo–17 yr)– Complicated intra-abdominal infection– Skin and skin-structure infection– Community-acquired pneumonia– Complicated urinary tract infection– Acute pelvic infection

• Dosage: 15 mg/kg every 12 hr (3 mo–12 yr);1 g once daily (13–17 yr)

Slide 68




Slide 69

2003 IDSA Guidelines on 2003 IDSA Guidelines on Empiric Therapy for Complicated IAIsEmpiric Therapy for Complicated IAIs

IDSA=Infectious Diseases Society of America; IAIs=intra-abdominal infections

Adapted from Solomkin JS et al Clin Infect Dis 2003;37:997–1005.

Type of therapyAgents for mild to moderate

infectionsAgents for high-severity

infections

Single agent

Beta-lactam/beta-lactamase inhibitor combinations

Ampicillin/sulbactamTicarcillin/clavulanic acid


Carbapenems Ertapenem Imipenem/cilastatinMeropenem

Combination regimens

Cephalosporin-based Cefazolin or cefuroxime + metronidazole

3rd/4th generation agents

Fluoroquinolone-based Ciprofloxacin, levofloxacin, moxifloxacin, or gatifloxacin,

each + metronidazole

Ciprofloxacin + metronidazole

Monobactam-based Aztreonam + metronidazole

Slide 70

2002 SIS Guidelines on 2002 SIS Guidelines on Empiric Therapy for Complicated IAIsEmpiric Therapy for Complicated IAIs

Type of therapy ClassLower-risk patientswithout risk factors*

Higher-risk patientswith risk factors*

Single agent Beta-lactam/beta-lactamase

inhibitor

Ampicillin/sulbactamTicarcillin/

clavulanate


Carbapenem Ertapenem Imipenem, meropenem

Combination regimen

Cephalosporin-based

Cefazolin or cefuroxime + metronidazole

3rd/4th generation cephalosporin + metronidazole

Fluoroquinolone-based

Ciprofloxacin + metronidazole

Aminoglycoside-based

Aminoglycoside + anti-anaerobe

Aminoglycoside+anti-anaerobe

Monobactam-based Aztreonam + clindamycin Aztreonam + clindamycin

*Risk factors for increased postoperative mortality/treatment failure

SIS=Surgical Infection Society

Adapted from Mazuski JE et al Surg Infect 2002;3:175–233.

Slide 71

Selected IDSA Guidelines on Empiric Therapy Selected IDSA Guidelines on Empiric Therapy for Diabetic Foot Infections, for Diabetic Foot Infections, Based on Clinical SeverityBased on Clinical Severity

Type of therapy Class Moderate Severe

Single agent Carbapenem Ertapenem Imipenem/cilastatin

Beta-lactam/beta-lactamase

inhibitor

Ampicillin/sulbactamAmoxicillin/clavulanateTicarcillin/clavulanate



Cephalosporins CefoxitinCeftriaxone

Fluoroquinolones Levofloxacin or ciprofloxacin with

clindamycin

Levofloxacin or ciprofloxacin with

clindamycin

Adapted from Lipsky BA et al Clin Infect Dis 2004;39:885–910.

Slide 72

IDSA Guidelines on Empiric Therapy for IDSA Guidelines on Empiric Therapy for Community-Acquired Pneumonia: Community-Acquired Pneumonia:

Appropriate Use of Antipseudomonal AgentAppropriate Use of Antipseudomonal Agent

• Ertapenem is a recommended nonpseudomonal beta-lactam antibiotic for hospitalized patients who are not at risk for Pseudomonas infection

• Risk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent antibiotic therapy or stay in hospital (especially in the ICU)

Adapted from Mandell LA et al Clin Infect Dis 2003;37:1405–1433.

Slide 73

Conclusions: Ertapenem Is an Effective and Appropriate Antibiotic for Hospitalized Patients with Moderate to

Severe Infections Originating in the Community

• Excellent activity against common gram-positive and gram-negative aerobic and anaerobic pathogens

• Excellent clinical efficacy in all approved indications*

• Effective nonpseudomonal carbapenem in treating serious infections in which multidrug-resistant, ESBL-producing Enterobacteriaceae are suspected

• Excellent tolerability profile, with minimal drug–drug interaction

• Low risk for resistance selection compared to other classes of antimicrobials

• One gram, one dose, once-a-day IV or IM**

IM=intramuscular

*Complicated intra-abdominal infections, complicated skin and skin-structure infections, community-acquired pneumonia, complicated urinary tract infections, acute pelvic infections, bacterial septicemia; **500 mg daily for patients with creatinine clearance ≤30 ml/min/1.73 m2 including those on hemodialysis

Adapted from Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542; Teppler H et al J Antimicrob Chemother 2004;53(suppl S2):ii75–ii81; Livermore DM et al J Antimicrob Chemother 2005;55:306–311.

Slide 74

Ertapenem Is Appropriate for Treating Hospitalized Patients with Moderate to Severe Polymicrobial

Infections Originating in the Community

• Pseudomonal coverage is not required in most community-acquired infections– Spares the use of antipseudomonal antibiotics, thus reducing

antibiotic pressure on selecting multidrug-resistant P. aeruginosa

• Spares the use of antipseudomonal carbapenem in treating hospitalized patients with community-acquired multidrug-resistant Enterobacteriaceae– Reduces the antibiotic pressure on selecting carbapenem-

resistant Pseudomonas

Adapted from Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542; Livermore DM et al J Antimicrob Chemother 2005;55:306–311.

Slide 75

Bibliography

• Please see notes for references

Slide 76

Bibliography (continued)


Slide 77

Bibliography (continued)


Slide 78

Ertapenem: An Antibiotic for Ambulatory Patients Hospitalized with Moderate to Severe Infections

Before prescribing, please consult the manufacturers’ prescribing information.

Merck does not recommend the use of any product in any different manner than as described

in the prescribing information.

Copyright © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA.

All rights reserved. 3-07 IVZ 2005-W-226381-SS Printed in USA

VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com

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Slide 1 Ertapenem: An Antibiotic for Ambulatory Patients Hospitalized with Moderate to Severe Infections 2005 Clinical Update