Comparison of the major Carbapenems Imipenem/cilastatin  versus Meropenem
Is Meropenem superior to Imipenem/cilastatin? <ul><li>NO </li></ul>Clinical experience  indicates that Meropenem is therap...
<ul><li>Meta-analysis of 27 randomized, controlled clinical trails comparing Meropenem with Imipenem/cilastatin at an equa...
But...... <ul><li>1.5 g/day of Imipenem/cilastatin is shown to be equivalent to 3.0 g/day Meropenem in clinical and bacter...
And...... <ul><li>Treatment of intra-abdominal infections with Imipenem/cilastatin is shown to be more effective and less ...
Multiple mechanisms of resistance in MDR P. aeruginosa <ul><li>Carbapenems are still the drugs of choice for treating noso...
Multiple mechanisms of resistance in MDR P. aeruginosa <ul><li>Interplay of efflux pump activation, reduced permeability (...
Potency of Carbapenems for prevention of Carbapenem-resistant P. aeruginosa <ul><li>Meropenem selected Carbapenem-resistan...
In vivo efficacy against  P. aeruginosa expressing efflux pump <ul><li>Terminal bacterial elimination similar between Imip...
<ul><li>Similar degree of bacterial reduction noted with higher inocula (10 7  CFU/thigh) for the carbapenems </li></ul><u...
Infection in Burns patients <ul><li>P. aeruginosa plays a prominent role in serious infections in burns patients contribut...
Activity against Acinetobacter spp. <ul><li>Carbapenems are considered the drugs of choice for treating serious infections...
Does Acinetobacter spp. exhibit similar susceptibilities to both Carbapenems? <ul><li>NO </li></ul>Discordant Carbapenem s...
Activity against Acinetobacter spp. <ul><li>Loss of CarO and Omp25 influx proteins have been identified as major resistanc...
Indian data on Carbapenem resistance <ul><li>Incidence of Meropenem resistance higher than that of Imipenem/cilastatin acr...
Indian data on Carbapenem resistance <ul><li>Overall Imipenem/cilastatin showed better activity than Meropenem </li></ul>G...
PD profiling against ESBL producers <ul><li>Comparable bactericidal activity against ESBL producing E. coli & Klebsiella s...
Activity against CTX-M type ESBLs (capable of hospital outbreaks) <ul><li>The plasmids (genes) encoding CTX-M1 (outbreak) ...
Acute Necrotizing Pancreatitis (ANP)* <ul><li>Imipenem/cilastatin is the antibiotic of choice for preventing infections of...
Imipenem/cilastatin in ANP* <ul><li>Carbapenem therapy for proven infection of Acute Pancreatitis: Incidence of septic com...
Imipenem/cilastatin in ANP* <ul><li>Prophylactic Imipenem/cilastatin therapy resulted in significant reduction in infected...
Meropenem in Acute Pancreatitis*: Questions that remain unanswered? <ul><li>What should be the timing of early antibiotic ...
Carbapenems in Febrile Neutropenia <ul><li>A meta-analysis of 33 randomized controlled trials comparing Carbapenems and ot...
Carbapenems in Intra-abdominal Infections <ul><li>Intra-abdominal infections are usually polymicrobial in nature </li></ul...
Carbapenems in Intra-abdominal Infections <ul><li>A meta-analysis of 15 clinical trials that evaluated Imipenem/cilastatin...
Early empiric Carbapenem therapy  in Intra-abdominal Infections <ul><li>The carbapenems are most appropriate for use as ea...
Carbapenems: Myths and Reality <ul><li>Inspite of expensiveness of Carbapenems, pharmacoeconomic studies have demonstrated...
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Comparison Of The Major Carbapenems

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Comparison Of The Major Carbapenems

  1. 1. Comparison of the major Carbapenems Imipenem/cilastatin versus Meropenem
  2. 2. Is Meropenem superior to Imipenem/cilastatin? <ul><li>NO </li></ul>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. 3. <ul><li>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 </li></ul><ul><li>Meropenem did not provide any additional mortality-benefit compared to Imipenem/cilastatin </li></ul><ul><li>Both carbapenems are equally effective in eradicating pathogens on a gram-to-gram basis </li></ul>Edwards SJ et al, Curr Med Res Opin 2005; 21(5):785-794
  4. 4. But...... <ul><li>1.5 g/day of Imipenem/cilastatin is shown to be equivalent to 3.0 g/day Meropenem in clinical and bacteriological outcome, as well as in incidence of side effects </li></ul><ul><li>Ref: Basoli A et al, Scand J Infect Dis. 1997;29(5):503-8 </li></ul>
  5. 5. And...... <ul><li>Treatment of intra-abdominal infections with Imipenem/cilastatin is shown to be more effective and less costly than Meropenem </li></ul><ul><li>Ref: Attanasio E et al, Dig Surg 2000; 17: 164-172 </li></ul>
  6. 6. Multiple mechanisms of resistance in MDR P. aeruginosa <ul><li>Carbapenems are still the drugs of choice for treating nosocomial infections due to P. aeruginosa </li></ul><ul><li>Development of carbapenem resistance severely hampers therapy </li></ul><ul><li>Understanding the mechanisms leading to carbapenem resistance in clinical isolates are important in the development of new antimicrobial strategies </li></ul>Quale J et al, Antimicrob Agents Chemother 2006 May; 50(5): 1633-1641.
  7. 7. Multiple mechanisms of resistance in MDR P. aeruginosa <ul><li>Interplay of efflux pump activation, reduced permeability (loss of oprD) and AmpC  -Lactamase hyper production noted </li></ul><ul><li>The efflux pump MexAB-OprM is constitutively expressed by all strains of P. aeruginosa </li></ul><ul><li>Hydrophobic side chain of Meropenem makes it susceptible to efflux activity of not only MexAB-OprM but also MexCD-OprJ & MexXY-OprM </li></ul><ul><li>Imipenem/cilastatin is spared of the above effect </li></ul><ul><li>Strains expressing oprD and AmpC  -Lactamase have shown elevated MICs to Meropenem compared to Imipenem/cilastatin </li></ul>Quale J et al, Antimicrob Agents Chemother 2006 May; 50(5): 1633-1641.
  8. 8. Potency of Carbapenems for prevention of Carbapenem-resistant P. aeruginosa <ul><li>Meropenem selected Carbapenem-resistant mutants of P. aeruginosa at a higher frequency than that of Imipenem/cilastatin </li></ul>Sakyo S et al, J Antibiot (Tokyo). 2006 Apr;59(4):220-8 10 -9 per cell per generation Imipenem / cilastatin 10 -7 per cell per generation Meropenem Frequency of selection of Carbapenem-resistant P. aeruginosa Carbapenem
  9. 9. In vivo efficacy against P. aeruginosa expressing efflux pump <ul><li>Terminal bacterial elimination similar between Imipenem/cilastatin and Meropenem </li></ul><ul><li>Both Imipenem/cilastatin and Meropenem produce similar bacteriostatic effects at 20-30% T>MIC* </li></ul><ul><li>The magnitude of kill (bactericidal activity) is similar for Imipenem/cilastatin 1g tid and Meropenem 1g tid, irrespective of MIC & bacterial load differences </li></ul>* %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. 10. <ul><li>Similar degree of bacterial reduction noted with higher inocula (10 7 CFU/thigh) for the carbapenems </li></ul><ul><li>Upregulation of MexA-MexB-OprM efflux pump results in reduced susceptibility only to Meropenem and not to Imipenem/cilastatin </li></ul><ul><li>No differences found between Imipenem/cilastatin and Meropenem in their ability to select for resistance </li></ul>In vivo efficacy against P. aeruginosa expressing efflux pump Ong CT et al, Diagn Microbiol Infect Dis 2006 (Epub ahead of print)
  11. 11. Infection in Burns patients <ul><li>P. aeruginosa plays a prominent role in serious infections in burns patients contributing substantially to burn morbidity and mortality </li></ul><ul><li>A 25-year review revealed that P. aeruginosa is the causative agent of bacteremia in burns contributing to 77% mortality </li></ul><ul><li>Imipenem/cilastatin and Meropenem were the most active in-vitro agents against these bugs </li></ul><ul><li>Imipenem/cilastatin demonstrated lower resistance rates than Meropenem </li></ul>Japoni A et al, Burns 2006; 32: 343-347 30.0% Meropenem 28.6% Imipenem / cilastatin Resistance rate against Ps. aeruginosa in burns infection Carbapenem
  12. 12. Activity against Acinetobacter spp. <ul><li>Carbapenems are considered the drugs of choice for treating serious infections caused by Acinetobacter baumanii </li></ul><ul><li>Progressive antimicrobial resistance in Acinetobacter is a cause of concern </li></ul><ul><li>Imipenem/cilastatin demonstrates lower MICs and lower resistance rates than Meropenem against Acinetobacter baumanii </li></ul>Canduela MJ et al, J Antimocrob Chemother 2006; 57: 1220-1222 80% Meropenem 70% Imipenem / cilastatin Resistance rate against Acinetobacter baumanii Carbapenem
  13. 13. Does Acinetobacter spp. exhibit similar susceptibilities to both Carbapenems? <ul><li>NO </li></ul>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. 14. Activity against Acinetobacter spp. <ul><li>Loss of CarO and Omp25 influx proteins have been identified as major resistance mechanisms in Acinetobacter baumanii strains </li></ul><ul><li>CarO shows slight cationic selectivity </li></ul><ul><li>Imipenem/cilastatin and Meropenem are zwitterionic (no net electric charge) </li></ul><ul><li>No specific binding sites found for Imipenem/cilastatin in CarO, which may explain higher activity & lower resistance of imipenem/cilastatin against this bug compared to Meropenem </li></ul>Siroy A et al, Antimicrob Agents Chemother 2005 Dec; 49(12): 4876-4883
  15. 15. Indian data on Carbapenem resistance <ul><li>Incidence of Meropenem resistance higher than that of Imipenem/cilastatin across clinically significant nosocomial pathogens </li></ul>Gupta E et al, Indian J Med Res 2006 July; 124: 95-98 17.32% Imipenem/cilastatin 22.16% Meropenem Overall Incidence of Resistance Carbapenem
  16. 16. Indian data on Carbapenem resistance <ul><li>Overall Imipenem/cilastatin showed better activity than Meropenem </li></ul>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 resistance MEM resistance Organism
  17. 17. PD profiling against ESBL producers <ul><li>Comparable bactericidal activity against ESBL producing E. coli & Klebsiella spp. </li></ul><ul><li>Probability of attaining 40% T>MIC (and hence Time of exposure and Bactericidal activity) marginally superior with Imipenem/cilastatin compared to Meropenem* </li></ul>Kiffer CRV et al, Int J Antimicrob Agents 2006 (Epub ahead of print) * Clinically significant 99.90% Meropenem 99.96% Imipenem / cilastatin Bactericidal activity Carbapenem 99.88% Meropenem 99.96% Imipenem / cilastatin Probability 40% T>MIC Carbapenem
  18. 18. Activity against CTX-M type ESBLs (capable of hospital outbreaks) <ul><li>The plasmids (genes) encoding CTX-M1 (outbreak) type ESBLs in E. coli raised the MICs of Meropenem but not Imipenem/cilastatin </li></ul><ul><li>This was seen even in the Carbapenem resistant strains producing CTX-M1 type ESBL </li></ul>Mena A et al, J Clin Microbiol 2006 Aug; 44(8): 2831-2837
  19. 19. Acute Necrotizing Pancreatitis (ANP)* <ul><li>Imipenem/cilastatin is the antibiotic of choice for preventing infections of pancreatic necrosis </li></ul><ul><li>Meropenem is not approved for the treatment of Acute Necrotizing Pancreatitis </li></ul><ul><li>Published data emphasizes that further studies are required to determine optimal doses of Meropenem in patients with Acute Pancreatitis </li></ul>Pezzilli 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. 20. Imipenem/cilastatin in ANP* <ul><li>Carbapenem therapy for proven infection of Acute Pancreatitis: Incidence of septic complications, indications for surgery and mortality, lower with Imipenem/cilastatin compared to Meropenem </li></ul><ul><li>Role of antibiotic prophylaxis in Acute Pancreatitis is debatable </li></ul><ul><li>Imipenem/cilastatin therapy has also been shown to prevent the need for surgery in 64% patients with infected necrosis </li></ul>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. 21. Imipenem/cilastatin in ANP* <ul><li>Prophylactic Imipenem/cilastatin therapy resulted in significant reduction in infected necrosis, sepsis and mortality </li></ul><ul><li>Comparative study with Meropenem shows that septic complications, indications for surgery or mortality were lower with Imipenem/cilastatin therapy than with Meropenem </li></ul>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
  22. 22. Meropenem in Acute Pancreatitis*: Questions that remain unanswered? <ul><li>What should be the timing of early antibiotic treatment (with Meropenem)? </li></ul><ul><li>What are the resistant strains selected by Meropenem? </li></ul><ul><li>Which are the nosocomial infections and fungal superinfections resulting from this new treatment (Meropenem)? </li></ul>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. 23. Carbapenems in Febrile Neutropenia <ul><li>A meta-analysis of 33 randomized controlled trials comparing Carbapenems and other  -Lactams for therapy of febrile neutropenia done </li></ul><ul><li>Conclusions: Both Imipenem/cilastatin and Meropenem considered suitable agents for monotherapy in febrile neutropenia </li></ul><ul><li>Both Carbapenems produced comparable results, associated with the least treatment failure and need for therapy modification </li></ul><ul><li>However, the dosage of Imipenem/cilastatin was 500mg q6h whereas that of Meropenem was 1gm tid </li></ul><ul><li>Imipenem/cilastatin may hence have a pharmacoeconomic advantage </li></ul>Paul M et al, J Antimicrob Chemother 2006; 57: 176-189
  24. 24. Carbapenems in Intra-abdominal Infections <ul><li>Intra-abdominal infections are usually polymicrobial in nature </li></ul><ul><li>Gram-positive bacteria cause about 32% of these infections </li></ul><ul><li>Imipenem/cilastatin has a superior (4 times) in-vitro activity than Meropenem against Gram-positive pathogens such as enterococci and staphylococci </li></ul><ul><li>The PK/PD of both carbapenems are similar against most Gram-negative bacteria </li></ul>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. 25. Carbapenems in Intra-abdominal Infections <ul><li>A meta-analysis of 15 clinical trials that evaluated Imipenem/cilastatin or Meropenem compared with other antibiotics was done </li></ul><ul><li>Imipenem/cilastatin 1.5-2 gm/day produced a similar % clinical response as that of Meropenem 3 gm/day </li></ul><ul><li>Incidence of adverse events as noted from the meta-analysis were also similar between the two carbapenems </li></ul>Tellado JM et al, Surgical Infections 2005; 6(3): 329-43 Lowe MN et al, Drugs 2000; 60: 619-646
  26. 26. Early empiric Carbapenem therapy in Intra-abdominal Infections <ul><li>The carbapenems are most appropriate for use as early empiric therapy in IAI patients at high risk of death, re-infarction, re-operation, or exposure to MDR nosocomial gram-negative bacteria </li></ul>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. 27. Carbapenems: Myths and Reality <ul><li>Inspite of expensiveness of Carbapenems, pharmacoeconomic studies have demonstrated the advantages of these drugs over a number of cheaper conventional antibiotics </li></ul><ul><li>Since inadequate empirical antimicrobial therapy is associated with significantly higher mortality in serious infections, Carbapenems are no longer considered second-line antimicrobials </li></ul><ul><li>The main ways to improve use of Carbapenems is: </li></ul><ul><li>- De escalation therapy </li></ul><ul><li>- Optimal dosing of Carbapenems </li></ul>Bereznyakov IG, Kharkov Medical Academy of Post Graduate Education, Kharkov, Ukraine
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