Comparison Of The Major Carbapenems

1. Comparison of the major Comparison of the major
CarbapenemsCarbapenems
Imipenem/cilastatin Imipenem/cilastatin
versusversus
MeropenemMeropenem

2. Is Meropenem superior to Imipenem/cilastatin?Is Meropenem superior to Imipenem/cilastatin?
NONO
Clinical experience indicates that
Meropenem is therapeutically
equivalent to Imipenem/cilastatin
Gauau J et al, Clin Microbiol Infect Dis 1997; 16: 789-96, Chang DC et al, Ann J Surg 1997; 174: 284-90
Colardyn F et al, J Antimicrob Chemother 1996; 38: 523-37
Current text-book teaching also
indicates that Meropenem is
therapeutically equivalent to
Imipenem/cilastatin
Ref: Principles and Practice of Infectious Diseases,
6
th
Edition, Philadelphia, Elsevier; 2005: 311-8

3. Meta-analysis of 27 randomized, controlled clinical trails
comparing Meropenem with Imipenem/cilastatin at an equal dose
on a gram-to-gram basis, with the same dosing regimen
Meropenem did not provide any additional mortality-benefit
compared to Imipenem/cilastatin
Both carbapenems are equally effective in eradicating pathogens
on a gram-to-gram basis
Edwards SJ et al, Curr Med Res Opin 2005; 21(5):785-794

4. But......But......
1.5 g/day of Imipenem/cilastatin is shown 1.5 g/day of Imipenem/cilastatin is shown
to be equivalent to 3.0 g/day Meropenem to be equivalent to 3.0 g/day Meropenem
in clinical and bacteriological outcome, as in clinical and bacteriological outcome, as
well as in incidence of side effectswell as in incidence of side effects
Ref: Basoli A et al, Scand J Infect Dis. 1997;29(5):503-8Ref: Basoli A et al, Scand J Infect Dis. 1997;29(5):503-8

5. And......And......
Treatment of intra-abdominal infections with Treatment of intra-abdominal infections with
Imipenem/cilastatin is shown to be more effective Imipenem/cilastatin is shown to be more effective
and less costly than Meropenemand less costly than Meropenem
Ref: Attanasio E et al, Dig Surg 2000; 17: 164-172Ref: Attanasio E et al, Dig Surg 2000; 17: 164-172

6. Multiple mechanisms of resistance Multiple mechanisms of resistance
in MDR P. aeruginosain MDR P. aeruginosa
Carbapenems are still the drugs of choice for Carbapenems are still the drugs of choice for
treating nosocomial infections due to P. treating nosocomial infections due to P.
aeruginosaaeruginosa
Development of carbapenem resistance Development of carbapenem resistance
severely hampers therapyseverely hampers therapy
Understanding the mechanisms leading to Understanding the mechanisms leading to
carbapenem resistance in clinical isolates are carbapenem resistance in clinical isolates are
important in the development of new important in the development of new
antimicrobial strategiesantimicrobial strategies
Quale J et al, Antimicrob Agents Chemother 2006 May; 50(5): 1633-1641.

7. Multiple mechanisms of resistance Multiple mechanisms of resistance
in MDR P. aeruginosain MDR P. aeruginosa
Interplay of efflux pump activation, reduced permeability Interplay of efflux pump activation, reduced permeability
(loss of oprD) and AmpC (loss of oprD) and AmpC bb-Lactamase hyper production -Lactamase hyper production
notednoted
The efflux pump MexAB-OprM is constitutively The efflux pump MexAB-OprM is constitutively
expressed by all strains of P. aeruginosaexpressed by all strains of P. aeruginosa
Hydrophobic side chain of Meropenem makes it Hydrophobic side chain of Meropenem makes it
susceptible to efflux activity of not only MexAB-OprM but susceptible to efflux activity of not only MexAB-OprM but
also MexCD-OprJ & MexXY-OprMalso MexCD-OprJ & MexXY-OprM
Imipenem/cilastatin is spared of the above effectImipenem/cilastatin is spared of the above effect
Strains expressing oprD and AmpC Strains expressing oprD and AmpC bb-Lactamase have -Lactamase have
shown elevated MICs to Meropenem compared to shown elevated MICs to Meropenem compared to
Imipenem/cilastatinImipenem/cilastatin
Quale J et al, Antimicrob Agents Chemother 2006 May; 50(5): 1633-1641.

8. Potency of Carbapenems for prevention of Potency of Carbapenems for prevention of
Carbapenem-resistant P. aeruginosaCarbapenem-resistant P. aeruginosa
Meropenem selected Carbapenem-resistant Meropenem selected Carbapenem-resistant
mutants of P. aeruginosa at a higher frequency mutants of P. aeruginosa at a higher frequency
than that of Imipenem/cilastatinthan that of Imipenem/cilastatin
10
-9
per cell per generationImipenem / cilastatin
10
-7
per cell per generationMeropenem
Frequency of selection
of Carbapenem-
resistant P. aeruginosa
Carbapenem
Sakyo S et al, J Antibiot (Tokyo). 2006 Apr;59(4):220-8

9. In vivo efficacy against In vivo efficacy against
P. aeruginosa expressing efflux pumpP. aeruginosa expressing efflux pump
Terminal bacterial elimination similar between Terminal bacterial elimination similar between
Imipenem/cilastatin and MeropenemImipenem/cilastatin and Meropenem
Both Imipenem/cilastatin and Meropenem produce Both Imipenem/cilastatin and Meropenem produce
similar bacteriostatic effects at 20-30% T>MIC*similar bacteriostatic effects at 20-30% T>MIC*
The magnitude of kill (bactericidal activity) is similar The magnitude of kill (bactericidal activity) is similar
for Imipenem/cilastatin 1g tid and Meropenem 1g tid, for Imipenem/cilastatin 1g tid and Meropenem 1g tid,
irrespective of MIC & bacterial load differencesirrespective of MIC & bacterial load differences
* %T>MIC is an established pharmacodynamic measure of antimicrobial efficacy. It is
The total duration of time for which the concentration of the antibiotic remains above MIC
Ong CT et al, Diagn Microbiol Infect Dis 2006 (Epub ahead of print)

10. Similar degree of bacterial reduction noted with Similar degree of bacterial reduction noted with
higher inocula (10higher inocula (10
77
CFU/thigh) for the carbapenems CFU/thigh) for the carbapenems
Upregulation of MexA-MexB-OprM efflux pump Upregulation of MexA-MexB-OprM efflux pump
results in reduced susceptibility only to Meropenem results in reduced susceptibility only to Meropenem
and not to Imipenem/cilastatinand not to Imipenem/cilastatin
No differences found between Imipenem/cilastatin No differences found between Imipenem/cilastatin
and Meropenem in their ability to select for and Meropenem in their ability to select for
resistanceresistance
In vivo efficacy against In vivo efficacy against
P. aeruginosa expressing efflux pumpP. aeruginosa expressing efflux pump
Ong CT et al, Diagn Microbiol Infect Dis 2006 (Epub ahead of print)

11. Infection in Burns patientsInfection in Burns patients
P. aeruginosa plays a prominent role in serious infections in burns P. aeruginosa plays a prominent role in serious infections in burns
patients contributing substantially to burn morbidity and mortalitypatients contributing substantially to burn morbidity and mortality
A 25-year review revealed that P. aeruginosa is the causative A 25-year review revealed that P. aeruginosa is the causative
agent of bacteremia in burns contributing to 77% mortalityagent of bacteremia in burns contributing to 77% mortality
Imipenem/cilastatin and Meropenem were the most active in-vitro Imipenem/cilastatin and Meropenem were the most active in-vitro
agents against these bugsagents against these bugs
Imipenem/cilastatin demonstrated lower resistance rates than Imipenem/cilastatin demonstrated lower resistance rates than
Meropenem Meropenem
30.0%Meropenem
28.6%Imipenem / cilastatin
Resistance rate against Ps.
aeruginosa in burns
infection
Carbapenem
Japoni A et al, Burns 2006; 32: 343-347

12. Activity against Acinetobacter spp.Activity against Acinetobacter spp.
Carbapenems are considered the drugs of choice for Carbapenems are considered the drugs of choice for
treating serious infections caused by Acinetobacter treating serious infections caused by Acinetobacter
baumaniibaumanii
Progressive antimicrobial resistance in Acinetobacter is a Progressive antimicrobial resistance in Acinetobacter is a
cause of concerncause of concern
Imipenem/cilastatin demonstrates lower MICs and lower Imipenem/cilastatin demonstrates lower MICs and lower
resistance rates than Meropenem against Acinetobacter resistance rates than Meropenem against Acinetobacter
baumaniibaumanii
80%Meropenem
70%Imipenem / cilastatin
Resistance rate against
Acinetobacter baumanii
Carbapenem
Canduela MJ et al, J Antimocrob Chemother 2006; 57: 1220-1222

13. Does Acinetobacter spp. exhibit similar Does Acinetobacter spp. exhibit similar
susceptibilities to both Carbapenems?susceptibilities to both Carbapenems?
NONO
Discordant Carbapenem
susceptibilities are a reality!
A strain that is susceptible to
Imipenem/cilastatin is not always susceptible
to Meropenem. Treatment failures with
Meropenem and switchover to
Imipenem/cilastatin have been documented
Lesho E et al, Clin Infect Dis 2005; 41: 758-9

14. Activity against Acinetobacter spp.Activity against Acinetobacter spp.
Loss of CarO and Omp25 influx proteins have Loss of CarO and Omp25 influx proteins have
been identified as major resistance mechanisms been identified as major resistance mechanisms
in Acinetobacter baumanii strainsin Acinetobacter baumanii strains
CarO shows slight cationic selectivityCarO shows slight cationic selectivity
Imipenem/cilastatin and Meropenem are Imipenem/cilastatin and Meropenem are
zwitterionic (no net electric charge)zwitterionic (no net electric charge)
No specific binding sites found for No specific binding sites found for
Imipenem/cilastatin in CarO, which may explain Imipenem/cilastatin in CarO, which may explain
higher activity & lower resistance of higher activity & lower resistance of
imipenem/cilastatin against this bug compared to imipenem/cilastatin against this bug compared to
MeropenemMeropenem
Siroy A et al, Antimicrob Agents Chemother 2005 Dec; 49(12): 4876-4883

15. Indian data on Carbapenem resistanceIndian data on Carbapenem resistance
Incidence of Meropenem resistance Incidence of Meropenem resistance
higher than that of Imipenem/cilastatin higher than that of Imipenem/cilastatin
across clinically significant nosocomial across clinically significant nosocomial
pathogenspathogens
17.32%Imipenem/cilastatin
22.16%Meropenem
Overall Incidence of
Resistance
Carbapenem
Gupta E et al, Indian J Med Res 2006 July; 124: 95-98

16. Indian data on Carbapenem resistanceIndian data on Carbapenem resistance
Gupta E et al, Indian J Med Res 2006 July; 124: 95-98
4.3%6.9%Klebsiella spp.
2.1%3.5%E. coli
27.2%34.7%Acinetobacter
spp.
30.0%37.6%Pseudomonas
spp.
IMI resistanceMEM resistanceOrganism
Overall Imipenem/cilastatin showed better activity Overall Imipenem/cilastatin showed better activity
than Meropenemthan Meropenem

17. PD profiling against ESBL producersPD profiling against ESBL producers
Comparable bactericidal Comparable bactericidal
activity against ESBL activity against ESBL
producing E. coli & producing E. coli &
Klebsiella spp.Klebsiella spp.
Probability of attaining 40% Probability of attaining 40%
T>MIC (and hence Time of T>MIC (and hence Time of
exposure and Bactericidal exposure and Bactericidal
activity) marginally superior activity) marginally superior
with Imipenem/cilastatin with Imipenem/cilastatin
compared to Meropenem*compared to Meropenem*
99.90%Meropenem
99.96%Imipenem /
cilastatin
Bactericidal
activity
Carbapenem
99.88%Meropenem
99.96%Imipenem /
cilastatin
Probability
40% T>MIC
Carbapenem
Kiffer CRV et al, Int J Antimicrob Agents 2006 (Epub ahead of print)
* Clinically significant

18. Activity against CTX-M type ESBLsActivity against CTX-M type ESBLs
(capable of hospital outbreaks)(capable of hospital outbreaks)
The plasmids (genes) encoding CTX-M1 The plasmids (genes) encoding CTX-M1
(outbreak) type ESBLs in E. coli raised the MICs (outbreak) type ESBLs in E. coli raised the MICs
of Meropenem but not Imipenem/cilastatinof Meropenem but not Imipenem/cilastatin
This was seen even in the Carbapenem This was seen even in the Carbapenem
resistant strains producing CTX-M1 type ESBLresistant strains producing CTX-M1 type ESBL
Mena A et al, J Clin Microbiol 2006 Aug; 44(8): 2831-2837

19. Acute Necrotizing Pancreatitis (ANP)*Acute Necrotizing Pancreatitis (ANP)*
Imipenem/cilastatin is the antibiotic of choice Imipenem/cilastatin is the antibiotic of choice
for preventing infections of pancreatic necrosisfor preventing infections of pancreatic necrosis
Meropenem is not approved for the treatment Meropenem is not approved for the treatment
of Acute Necrotizing Pancreatitisof Acute Necrotizing Pancreatitis
Published data emphasizes that further studies Published data emphasizes that further studies
are required to determine optimal doses of are required to determine optimal doses of
Meropenem in patients with Acute PancreatitisMeropenem in patients with Acute Pancreatitis
Pezzilli R, JOP. J Pancreas (online) 2006; 7(4): 435-437Pezzilli R, JOP. J Pancreas (online) 2006; 7(4): 435-437
www.astrazenecaindia.com/Products/Meronem%20Abridged.pdf
* Kindly note that Acute Necrotizing Pancreatitis is not a labelled indication for
Zienam® and data presented above is completely based on published clinical evidence

20. Imipenem/cilastatin in ANP*Imipenem/cilastatin in ANP*
Carbapenem therapy for proven infection of Carbapenem therapy for proven infection of
Acute Pancreatitis: Incidence of septic Acute Pancreatitis: Incidence of septic
complications, indications for surgery and complications, indications for surgery and
mortality, lower with Imipenem/cilastatin mortality, lower with Imipenem/cilastatin
compared to Meropenemcompared to Meropenem
Role of antibiotic prophylaxis in Acute Role of antibiotic prophylaxis in Acute
Pancreatitis is debatablePancreatitis is debatable
Imipenem/cilastatin therapy has also been Imipenem/cilastatin therapy has also been
shown to prevent the need for surgery in 64% shown to prevent the need for surgery in 64%
patients with infected necrosispatients with infected necrosis
Nordback I et al, J Gastrointest Surg 2001; 5: 113-118
Heinrich S et al, Ann Surg 2006; 243: 154-168
* Kindly note that Acute Necrotizing Pancreatitis is not a labelled indication for
Zienam® and data presented above is completely based on published clinical evidence

21. Imipenem/cilastatin in ANP*Imipenem/cilastatin in ANP*
Incidence of infected necrosis (%)
36.40%
10.60%
0.00%
10.00%
20.00%
30.00%
40.00%
No IMI prophylaxis IMI prophylaxis
Incidence of infected necrosis (%)
Prophylactic
Imipenem/cilastatin therapy
resulted in significant
reduction in infected
necrosis, sepsis and
mortality
Comparative study with
Meropenem shows that
septic complications,
indications for surgery or
mortality were lower with
Imipenem/cilastatin therapy
than with Meropenem
Nordback I et al, J Gastrointest Surg 2001; 5: 113-118 ; Manes G et al, Pancreas 2003; 27: 379-383
Heinrich S et al, Ann Surg 2006; 243: 154-168
* Kindly note that Acute Necrotizing Pancreatitis is not a labelled indication for
Zienam® and data presented above is completely based on published clinical evidence
11.40%
13.60%
10.00%11.00%12.00%13.00%14.00%
Imipenem/cilastatin
Meropenem
Sepsis, Surgery, Mortality (%)
Sepsis, Surgery, Mortality (%)

22. Meropenem in Acute Pancreatitis*: Meropenem in Acute Pancreatitis*:
Questions that remain unanswered?Questions that remain unanswered?
What should be the timing of early antibiotic What should be the timing of early antibiotic
treatment (with Meropenem)?treatment (with Meropenem)?
What are the resistant strains selected by What are the resistant strains selected by
Meropenem?Meropenem?
Which are the nosocomial infections and fungal Which are the nosocomial infections and fungal
superinfections resulting from this new treatment superinfections resulting from this new treatment
(Meropenem)?(Meropenem)?
Pezzilli R, JOP. J Pancreas (online) 2006; 7(4): 435-437
* Kindly note that Acute Necrotizing Pancreatitis is not a labelled indication for
Zienam® and data presented above is completely based on published clinical evidence

23. Carbapenems in Febrile NeutropeniaCarbapenems in Febrile Neutropenia
A meta-analysis of 33 randomized controlled trials A meta-analysis of 33 randomized controlled trials
comparing Carbapenems and other comparing Carbapenems and other bb-Lactams for -Lactams for
therapy of febrile neutropenia donetherapy of febrile neutropenia done
Conclusions: Both Imipenem/cilastatin and Meropenem Conclusions: Both Imipenem/cilastatin and Meropenem
considered suitable agents for monotherapy in febrile considered suitable agents for monotherapy in febrile
neutropenianeutropenia
Both Carbapenems produced comparable results, Both Carbapenems produced comparable results,
associated with the least treatment failure and need for associated with the least treatment failure and need for
therapy modificationtherapy modification
However, the dosage of Imipenem/cilastatin was 500mg However, the dosage of Imipenem/cilastatin was 500mg
q6h whereas that of Meropenem was 1gm tidq6h whereas that of Meropenem was 1gm tid
Imipenem/cilastatin may hence have a Imipenem/cilastatin may hence have a
pharmacoeconomic advantage pharmacoeconomic advantage
Paul M et al, J Antimicrob Chemother 2006; 57: 176-189

24. Carbapenems in Intra-abdominal InfectionsCarbapenems in Intra-abdominal Infections
Intra-abdominal infections are usually Intra-abdominal infections are usually
polymicrobial in naturepolymicrobial in nature
Gram-positive bacteria cause about 32% of Gram-positive bacteria cause about 32% of
these infectionsthese infections
Imipenem/cilastatin has a superior (4 times) in-Imipenem/cilastatin has a superior (4 times) in-
vitro activity than Meropenem against Gram-vitro activity than Meropenem against Gram-
positive pathogens such as enterococci and positive pathogens such as enterococci and
staphylococcistaphylococci
The PK/PD of both carbapenems are similar The PK/PD of both carbapenems are similar
against most Gram-negative bacteriaagainst most Gram-negative bacteria
Tellado JM et al, Surgical Infections 2005; 6(3): 329-43
Mosdell GM et al, Ann Surg 1991; 214: 543-549
Montravers P et al, Clin Infect Dis 1996; 23: 486-494

25. Carbapenems in Intra-abdominal InfectionsCarbapenems in Intra-abdominal Infections
A meta-analysis of 15 clinical trials that A meta-analysis of 15 clinical trials that
evaluated Imipenem/cilastatin or Meropenem evaluated Imipenem/cilastatin or Meropenem
compared with other antibiotics was donecompared with other antibiotics was done
Imipenem/cilastatin 1.5-2 gm/day produced a Imipenem/cilastatin 1.5-2 gm/day produced a
similar % clinical response as that of similar % clinical response as that of
Meropenem 3 gm/dayMeropenem 3 gm/day
Incidence of adverse events as noted from the Incidence of adverse events as noted from the
meta-analysis were also similar between the two meta-analysis were also similar between the two
carbapenems carbapenems
Tellado JM et al, Surgical Infections 2005; 6(3): 329-43
Lowe MN et al, Drugs 2000; 60: 619-646

26. Early empiric Carbapenem therapyEarly empiric Carbapenem therapy
in Intra-abdominal Infections in Intra-abdominal Infections
The carbapenems are most appropriate for use as early The carbapenems are most appropriate for use as early
empiric therapy in IAI patients at high risk of death, re-empiric therapy in IAI patients at high risk of death, re-
infarction, re-operation, or exposure to MDR nosocomial infarction, re-operation, or exposure to MDR nosocomial
gram-negative bacteriagram-negative bacteria
Tellado JM et al, Surgical Infections 2005; 6(3): 329-43
Empiric treatment of suspected or confirmed IAI of any origin or degree of severity in
immunosupressed or transplant recepient patients
Empiric treatment of IAI of any origin associated with sepsis
Intra-abdominal superinfection in tertiary peritonitis
Empiric treatment for persistent infection after failure of non-carbapenem therapy
Empiric therapy for nosocomial IAI originated >48hr of hospital admission, either in
surgical ward or surgical ICU
Clinical conditions where Carbapenem therapy may be appropriate

27. Carbapenems: Myths and RealityCarbapenems: Myths and Reality
Inspite of expensiveness of Carbapenems, Inspite of expensiveness of Carbapenems,
pharmacoeconomic studies have demonstrated the pharmacoeconomic studies have demonstrated the
advantages of these drugs over a number of cheaper advantages of these drugs over a number of cheaper
conventional antibioticsconventional antibiotics
Since inadequate empirical antimicrobial therapy is Since inadequate empirical antimicrobial therapy is
associated with significantly higher mortality in serious associated with significantly higher mortality in serious
infections, Carbapenems are no longer considered infections, Carbapenems are no longer considered
second-line antimicrobialssecond-line antimicrobials
The main ways to improve use of Carbapenems is:The main ways to improve use of Carbapenems is:
- De escalation therapy- De escalation therapy
- Optimal dosing of Carbapenems- Optimal dosing of Carbapenems
Bereznyakov IG, Kharkov Medical Academy of Post Graduate Education, Kharkov, Ukraine

28. Thank youThank you