Post on 12-Jan-2016
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
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 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
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 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
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 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.
Slide 35
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 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.
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 (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
• Study design: prospective, multicenter, randomized, double-blind trial
• 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
Ertapenem1 g once daily
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)
• Patients: 370 hospitalized adults with intra-abdominal infections requiring surgery
• 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)
Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic responses at test-of-cure evaluation
Adapted from Dela Pena AS et al. Presented at the 14th ECCMID, May 1–4, 2004. Poster 1686.
Ertapenem1 g once daily
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
• Patients: 412 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 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
Ertapenem1 g once daily
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
• Study design: prospective, multicenter, randomized, double-blind trial
• 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.
Primary study endpoint: proportion of microbiologically evaluable patients with favorable clinical and microbiologic responses at test-of-cure evaluation
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
• Study design: prospective, multicenter, randomized, double-blind trial
• 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
Ertapenem1 g once daily
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
• Therapy: ertapenem 1 g IV once daily vs. ceftriaxone 1 g IV once daily
• 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
• Study design: prospective, multicenter, randomized, double-blind trial
• Patients: 592 adults with complicated urinary tract infections
• Therapy: ertapenem 1 g IV once daily vs. ceftriaxone 1 g IV once daily
• 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
Ertapenem1 g once daily
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
• Study design: prospective, multicenter, randomized, double-blind trial
• Patients: 540 adults with complicated skin/soft-tissue infections
• Therapy: ertapenem 1 g once daily vs. piperacillin/tazobactam 3.375 g every six hours
• 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
• Study design: prospective, multicenter, randomized, double-blind trial
• Patients: 586 adults with diabetic foot infections without osteomyelitis
• Therapy: ertapenem 1 g once daily vs. piperacillin/tazobactam 3.375 g every six hours
• 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)**
Piperacillin/tazobactam
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)
Piperacillin/tazobactam
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
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 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
Piperacillin/tazobactam
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
Piperacillin/tazobactam
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
Piperacillin/tazobactam
Piperacillin/tazobactam
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)
• Please see notes for references
Slide 77
Bibliography (continued)
• Please see notes for references
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