The overuse of 3GC and quinolones has led to

MDR development and few options became

available
Hospitalized Patient
Multi Drug
withResistant
CommunityOrganism
Acquired Infection
Cephalosporins and
ESBL quinolones are the
Production workhorse agents

Broad Haveeffective
Fewer Proven to select
antibiotics
High Cost for resistance
Antimicrobial availableduring therapy
for treatment
Health Care System
Resistance

Select Resistant
Pathogen
High Morbidity and Mortality
 Unintended Consequences of
Antibiotic Therapy

• “ 'Collateral damage' is a term used

to refer to ecological adverse effects
of antibiotic therapy; namely, the
selection of drug-resistant organisms
and the unwanted development of
colonization or infection with
multidrug-resistant organisms.”

Paterson DL. Clin Infect Dis 2004;38(Suppl 4):S341-S345

 Important Mechanisms for
Type I β-Lactamase Production

The in vitro process

– Induction

The in vivo process

– Selection

Sanders CC, Sanders WE. J Infect Dis 1986;154:792-800

 Resistance Due to Selection

Drug
treatment

Spontaneous Mutant is Resistant Resistance

mutation selected for by clone grows becomes
occurs in the drug treatment within what clinically
absence of as sensitive used to be a manifested
drug selection strains die off sensitive during therapy
in a sensitive population
population

Sanders CC, Sanders WE. J Infect Dis 1986;154:792-800

 A Recurrent Inaccurate Phrase
in Discussions of Resistance

• “Resistance was induced.”

 The context: an antibiotic was

used, and it lead to resistance.

The correct terminology:

“Resistance was selected.”
Recent Publications confirm resistance linked
to overuse of traditional antibiotics

“…Neither third-generation cephalosporins nor quinolones appear suitable

for sustained use in hospitals as “workhorse” antibiotic therapy….”
 Increasing Antimicrobial Resistance
among Nosocomial Pathogens
3rd generation cephalosporin- Fluoroquinolone-resistant
resistant Klebsiella pneumoniae 30
Pseudomonas aeruginosa
14
25
12

Percent Resistance
Percent Resistance

10 20
8
15
6
4 10
2 5
0
0

Non-Intensive Care Unit Patients

Intensive Care Unit Patients

Source: National Nosocomial Infections Surveillance (NNIS) System

• The impact of ertapenem
on hospital ecology
The theoretical considerations

Conclusions: Whilst ertapenem can select for P. aeruginosa

mutants with cross-resistance to imipenem and ertapenem in
vitro, this selectivity should be minimal under clinical
conditions.
 Ertapenem: Minimal Risk of Resistance
Development in OASIS I Subanalysis

14
Baseline
12.2%
End of therapy
12 2 weeks post
therapy
10
Percent

6
4.5%
4
2.6%
2 0.8% 0.8%
0.6% 0.6% 0.6% 0.6%
0% 0% 0%
0
(n=162) (n=155) (n=133) (n=162) (n=155) (n=133) (n=160) (n=156) (n=133) (n=160) (n=156) (n=133)
% Resistant % ESBL producers % Resistant % ESBL producers
Ertapenem Piperacillin/tazobactam

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

 Ertapenem: Minimal Risk of Resistance
Development in OASIS II Subanalysis

25
Baseline 22.4%
End of therapy
2 weeks post
20 therapy
17.1% 17.2%

15
Percent

9.3%
10

4.0%
5 2.6%
2.2% 2.1%
0.5%
0.5% 0% 0%
0
(n=201) (n=196) (n=182) (n=201) (n=196) (n=182) (n=195) (n=193) (n=174) (n=195) (n=193) (n=174)
% Resistant % ESBL producers % Resistant % ESBL producers
Ertapenem Ceftriaxone/metronidazole

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

 Lower Emergence of Resistance Among
Enterobacteriaceae with Ertapenem vs.
Piperacillin/Tazobactam
10
9 Baseline
End of therapy 7.4%*
8
7
6
Percent

5
4
3
2
0.8%
1
0% 0% 0% 0% 0% 0%
0
% Resistant % ESBL producers % Resistant % ESBL producers
Ertapenem Piperacillin/tazobactam
(n=122) (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.
Results: Debra Goff - ICAAC abstract
2005

Organism
2002 2004 2002 2004 2002 2004 2002 2004 2002 2004
(# in 02/04)
K. pneumoniae 99 99 89 92 99 100 85 84 92 94
(484/542)
K. pneumoniae- ESBL 95 100 NT NT NT NT 23 17 14 16
(22/29)
K. oxytoca 99 98 96 89 99 98 96 92 96 97
(80/93)
E.coli 100 100 96 94* 100 100 91 83* 95 94
(979/1047)
E. coli -ESBL NT 100 NT NT NT NT NT 10 NT 14
(0/21)
E. cloacae 100 100 79 70* 89 85 81 80 89 79
(191/187)
S. marcescens 90 98* 79 84 93 96 86 86 83 93*
(138/138)
P. aeruginosa 71 71 82 83 72 74 62 55* 81 85*
(785/819)

No decrease in imipenem susceptibilities

 Ertapenem/Imipenem and ESBL Klebsiella
pneumoniae: Debra Goff - ICAAC abstract
40
2005 10

ertapenem
9
imipenem
8
30 resistance
7

% ESBL resistance
DDD/1000 pt days

20 5

3
10
2

0 0

2001 2002 2003 2004

Year
 Effect of the addition of Ertapenem to the formulary of St Johns
Health Center - Santa Monica, CA – ICAAC 2006 : Dr. Ellie Goldstein

Usage of Antibiotics with Anerobe Coverage

80

70

60

50
DDD / 1000 pt days

40

30

20

10
Shortage
Shortage
0
2002-1 2002-2 2002-3 2002-4 2003-1 2003-2 2003-3 2003-4 2004-1 2004-2 2004-3 2004-4 2005-1 2005-2 2005-3 2005-4
Quarter

Imipenem Ertapenem Pip/Tazo Clindamycin Metronidazole Cefoxitin Amp/Sulbactam

Ertapenem Ertapenem auto

added - 2002 sub - 2003
Effect of the addition of Ertapenem to the formulary of St Johns
Health Center - Santa Monica, CA – ICAAC 2006 : Dr. Ellie Goldstein

ESBLs
7%
6%
Percent of Isolates

5%
4%
3%
2%
1%
0%
2002 2003 2004 2005

E.coli ESBLs Kleb spp ESBLs

Ertapenem added Ertapenem auto sub

 Effect of the addition of Ertapenem to the formulary of St Johns
Health Center - Santa Monica, CA – ICAAC 2006 : Dr. Ellie Goldstein

E.coli

250
100%
225
200
80%
175
DDD / 1000 pt days

% Susceptible
150 60%
125
Ertapenem auto sub
100 40%
75 Ertapenem added
50 20%
25
0 0%
2 0 0 2 - 1 2 0 0 2 - 2 2 0 0 2 - 3 2 0 0 2 - 4 2 0 0 3 - 1 2 0 0 3 - 2 2 0 0 3 - 3 2 0 0 3 - 4 2 0 0 4 - 1 2 0 0 4 - 2 2 0 0 4 - 3 2 0 0 4 - 4 2 0 0 5- 1 2 0 0 5- 2 2 0 0 5- 3 2 0 0 5- 4

Quarter
Bar = Doses Line =% S
Cefazolin Levofloxacin PipTazo Gentamicin Ertapemem
Cefazolin Levofloxacin Pip/Tazo Gentamicin Ertapenem
Effect of the addition of Ertapenem to the formulary of St Johns
Health Center - Santa Monica, CA – ICAAC 2006 : Dr. Ellie Goldstein

Klebsiella pneumoniae/oxytoca

250
100%
225
200
80%
175
DDD / 1000 pt days

150

% Susceptible
60%
125 Ertapenem auto sub
100 40%
Ertapenem added
75
50 20%
25
0 0%
2 0 0 2 - 1 2 0 0 2 - 2 2 0 0 2 - 3 2 0 0 2 - 4 2 0 0 3 - 1 2 0 0 3 - 2 2 0 0 3 - 3 2 0 0 3 - 4 2 0 0 4 - 1 2 0 0 4 - 2 2 0 0 4 - 3 2 0 0 4 - 4 2 0 0 5- 1 2 0 0 5- 2 2 0 0 5- 3 2 0 0 5 - 4

Quarter Bar = Doses Line =% S

Cefazolin Levofloxacin PipTazo Gentamicin Ertapemem

Cefazolin Levofloxacin Pip/Tazo Gentamicin Ertapenem
 The introduction of ertapenem didn’t change the susceptibility patterns
of Enterobacteriaceae and even improved the susceptibility to
Pseudomonas of imipenem, levofloxacin, and cefepime.
Pseudomonas aeruginosa
250
100%

200
80%

% Susceptible
DDD / 1000 pt days

150
60%

Ertapenem auto sub

100 40%
Ertapenem added

50 20%

0 0%
2002-1 2002-2 2002-3 2002-4 2003-1 2003-2 2003-3 2003-4 2004-1 2004-2 2004-3 2004-4 2005-1 2005-2 2005-3 2005-4
Quarter
Levofloxacin PipTazo Imipenem Cefepime Tobramycin Ertapemem

Pip/Tazo Tobramycin Cefepime Imipenem Levofloxacin

 Effect of Ertapenem Utilization on Pseudomonas
aeruginosa Susceptibility to Imipenem: IDSA 2006 –
C. Crank, B. Hota, J. Segreti
• In this analysis, a significant increase in ertapenem utilization paralleled a
significant increase in percentage of PSA isolates susceptible to imipenem.
• Ertapenem use does not appear to be driving carbapenem resistance in PSA at
our institution. The study will continue to monitor PSA susceptibilities.
 The Effect of Ertapenem on Hospital Ecology: the
effect on third-generation-cephalosporin-resistance
among Enterobacteriaceae, and the effect on
carbapenem-resistance among Enterobacteriaceae
and among P. aeruginosa isolates.
Yehuda Carmeli, MD, MPH
Nine medicine wards were included.
504 months were studied.
139,185 patients admissions
540,255 patients days were included.
541,150 antibiotics DDDs
Average of 1,072 DDDs per month per ward
 Imipenem resistant P. aeruginosa.
• In multivariate analysis, each year there was a 3.8% increase in the
incidence of IMP-R-PA (p<0.001).
• Multivariate analysis showed that group 2 carbapenem (imipenem and
meropenem) use was highly associated with IMP-R-PA; for each 100
DDD given, there was a 20% increase in the incidence of IMP-R-PA
(p=0.0014).
• Group 2 carbapenems were the only significant variable associated with
increase in the proportion of imipenem-resistance (p=0.036).
• In contrast, Group 1 carbapenem (ertapenem) use was not associated
with higher incidence of IMP-R-PA (p=.88), or with increased proportion of
imipenem resistance (p=0.66).
• A weak effect of the penicillin group was found, for each 100 DDD given,
there was 1% increase in the incidence of IMP-R-PA (p=0.049).
 Third generation cephalosporin-
resistant Enterobacteriaceae
• A total of 3,562 third-generation cephalosporin
resistant Enterobacteriaceae were isolated
during the study period, with an incidence of
25.6 cases per 1,000 patients’ admissions.
• Proportion of resistant isolates varied between 4
and 48%, and averaged 21.9%.
• Analysis of the association revealed as expected
association between cephalosporin use
(p=0.029) and quinolone use (p=o.o5) and third
generation cephalosporin resistance.
 Third generation cephalosporin-
resistant Enterobacteriaceae
• The strongest association was found between use of
carbapenem (both group 2 and group1) and third
generation cephalosporin resistance (p=0.004 and p
=0.002, respectively).
• The investigators believe that this unexpected
association is actually reflection of “confounding by
indication” i.e. most of the carbapenem use is to treat
third generation cephalosporin resistant
Enterobacteriacea (mostly ESBL producers), thus
high incidence of resistance leads to high
carbapenem use
 Imipenem-resistant
Enterobacteriaceae
• Imipenem resistance in Enterobacteriaceae was
detected only rarely
• There was no clustering in time or space.
• There was no association between usage of
carbapenem (either group2 or group1) with this
resistance.
• The small number of organisms precluded statistical
analysis.
• Is it time to reconsider initial antibiotic
treatment strategies for severe urinary
tract infections in Europe? March 2007
• Until recently, most reported cases of
bacteraemia caused by multidrug-resistant
strains of Enterobacteriacae producing an
extended-spectrum β-lactamase (ESBL) in
Europe have been nosocomial in origin.
However, increasing numbers of reports of
community-acquired bacteraemia and urinary
tract infection caused by ESBL-producing
microorganisms suggest that the geographical
origin of patients should be taken into account
as a risk-factor for possible ESBL production.
Early identification of patients at high-risk of
infection with ESBL-producing microorganisms,
based on their geographical origin and travel
history, should help to optimise initial antibiotic
treatment strategies for severe urinary tract
infections in Europe.
• Ertapenem: the new carbapenem 5 years after first FDA
licensing for clinical practice – February 2007
• Ertapenem, a parenteral broad-spectrum 1-β-methyl-
carbapenem, was licensed 5 years ago for clinical
practice in the US and Europe. The substance has a
good in vitro activity against many common aerobic and
anaerobic Gram-positive and -negative bacteria. Its in
vitro activity against Enterobacteriaceae carrying plasmid-
or chromosomal-mediated β-lactamases, including
AmpC- and extended-spectrum β-lactamases, is
especially clinically significant. Advantages concerning in
vitro activity and low potential for so-called ‘collateral
damage’, and development of own resistance during
therapy, as shown in several randomized, controlled
clinical trials, make ertapenem an excellent treatment
choice for complicated aerobic and anaerobic mix
infections caused by ertapenem-sensitive bacteria. On
the other hand, due to its limited activity against
Acinetobacter spp., enterococci and Pseudomonas
aeruginosa, it is less suitable for late-onset nosocomial
infections.
• Extended-spectrum and AmpC b-
lactamases in Escherichia coli and
Klebsiella pneumoniae from a rural South
Indian tertiary care hospital- IN PRESS -
International Journal of Antimicrobial
Agents
• …. ….Overall resistances among ESBLproducing
isolates of E. coli and K. pneumoniae were,
respectively: amikacin 34% in both species;
ciprofloxacin, 55.1% and 59.5%; gentamicin,
67.2% and 42.8%; and cotrimoxazole, 72.4% and
50%. There is a paucity of information on the
documentation of simultaneous detection of
ESBLs and AmpC b-lactamases in India. A study
from India [7] reports 62% of E. coli and 73% of
Klebsiella spp. were ESBL producers, whereas
6.9% of E. coli and 6.1% of Klebsiella spp. were
plasmid mediated AmpC b-lactamase producers.
Compared with the above study, our reports
shows 53.4% of E. coli and 52.4% of K.
pneumoniae were ESBL producers, whereas 3.4%
of E. coli and 4.8% of K. pneumoniae were
plasmid-mediated AmpC b-lactamase
producers……
• Decision-Making Analysis for Selection of
Antibiotic Treatment in Intra-Abdominal
Infection Using Preference Measurements –
October 2006
• …All these data indicate that use of aminoglycosides
for patients with abdominal infection implies
subjecting these patients to an unnecessary risk that
is not compensated for by lower initial cost. The
results also indicate that the newer molecules offer
much better effectiveness and safety profiles.
Ertapenem, a carbapenem, has been classified in
group one, meaning that it does not have an effect
against Pseudomonas, has an acceptable safety
profile, and has effectiveness similar to that of other
available molecules. Piperacillin-tazobactam, a beta-
lactam/ beta-lacatamase inhibitor combination has
acceptable safety and effectiveness values.
Ampicillin-sulbactam appears to have similar
characteristics; however, the number of trials using
ampicillin-sulbactam to treat patients with intra-
abdominal infection is small. Moreover, the
prevalence of E. coli resistant to ampicillin-sulbactam
could be as high as 50%, thus compromising its
clinical effectiveness. All these circumstances and the
results of this study must be weighed against other
factors such as…..