Comparison Of The Major Carbapenems

Comparison of the major Comparison of the major CarbapenemsCarbapenems

Imipenem/cilastatin Imipenem/cilastatin

versusversus

MeropenemMeropenem

Is Meropenem superior to Imipenem/cilastatin?Is Meropenem superior to Imipenem/cilastatin?

NONOClinical experienceClinical experience indicates that indicates that

Meropenem is therapeutically Meropenem is therapeutically equivalent to Imipenem/cilastatinequivalent to Imipenem/cilastatin

Gauau J et al, Clin Microbiol Infect Dis 1997; 16: 789-96, Chang DC et al, Ann J Surg 1997; 174: 284-90Colardyn F et al, J Antimicrob Chemother 1996; 38: 523-37

Current text-book teachingCurrent text-book teaching also also indicates that Meropenem is indicates that Meropenem is therapeutically equivalent to therapeutically equivalent to

Imipenem/cilastatinImipenem/cilastatin

Ref: Principles and Practice of Infectious Diseases, Ref: Principles and Practice of Infectious Diseases, 66thth Edition, Philadelphia, Elsevier; 2005: 311-8 Edition, Philadelphia, Elsevier; 2005: 311-8

Meta-analysis of 27 randomized, controlled clinical trails comparing Meta-analysis of 27 randomized, controlled clinical trails comparing Meropenem with Imipenem/cilastatin at an equal dose on a gram-Meropenem with Imipenem/cilastatin at an equal dose on a gram-to-gram basis, with the same dosing regimento-gram basis, with the same dosing regimen

Meropenem did not provide any additional mortality-benefit Meropenem did not provide any additional mortality-benefit compared to Imipenem/cilastatincompared to Imipenem/cilastatin

Both carbapenems are equally effective in eradicating pathogens Both carbapenems are equally effective in eradicating pathogens on a gram-to-gram basison a gram-to-gram basis

Edwards SJ et al, Curr Med Res Opin 2005; 21(5):785-794

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

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

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.

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 -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 -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.

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

CarbapenemCarbapenem Frequency of selection Frequency of selection of Carbapenem-of Carbapenem-

resistant P. aeruginosaresistant P. aeruginosa

MeropenemMeropenem 1010-7-7 per cell per generation per cell per generation

Imipenem / cilastatinImipenem / cilastatin 1010-9-9 per cell per generationper cell per generation

Sakyo S et al, J Antibiot (Tokyo). 2006 Apr;59(4):220-8

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 for Imipenem/cilastatin 1g tid and Meropenem 1g tid, irrespective of MIC & bacterial load differencestid, irrespective 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)

Similar degree of bacterial reduction noted with Similar degree of bacterial reduction noted with higher inocula (10higher inocula (1077 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)

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

CarbapenemCarbapenem Resistance rate against Ps. Resistance rate against Ps. aeruginosa in burns aeruginosa in burns

infectioninfection

Imipenem / cilastatinImipenem / cilastatin 28.6%28.6%

MeropenemMeropenem 30.0%30.0%

Japoni A et al, Burns 2006; 32: 343-347

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

CarbapenemCarbapenem Resistance rate against Resistance rate against Acinetobacter baumaniiAcinetobacter baumanii

Imipenem / cilastatinImipenem / cilastatin 70%70%

MeropenemMeropenem 80%80%

Canduela MJ et al, J Antimocrob Chemother 2006; 57: 1220-1222

Does Acinetobacter spp. exhibit similar Does Acinetobacter spp. exhibit similar susceptibilities to both Carbapenems?susceptibilities to both Carbapenems?

NONODiscordant Carbapenem Discordant Carbapenem

susceptibilities are a reality!susceptibilities are a reality!

A strain that is susceptible to A strain that is susceptible to Imipenem/cilastatin is not always susceptible Imipenem/cilastatin is not always susceptible

to Meropenem. Treatment failures with to Meropenem. Treatment failures with Meropenem and switchover to Meropenem and switchover to

Imipenem/cilastatin have been documentedImipenem/cilastatin have been documented

Lesho E et al, Clin Infect Dis 2005; 41: 758-9

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

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

CarbapenemCarbapenem Overall Incidence of Overall Incidence of ResistanceResistance


Imipenem/cilastatinImipenem/cilastatin 17.32%17.32%

Gupta E et al, Indian J Med Res 2006 July; 124: 95-98

Indian data on Carbapenem resistanceIndian data on Carbapenem resistance

Gupta E et al, Indian J Med Res 2006 July; 124: 95-98

OrganismOrganism MEM resistanceMEM resistance IMI resistanceIMI resistance

Pseudomonas Pseudomonas spp.spp.

37.6%37.6% 30.0%30.0%

Acinetobacter Acinetobacter spp.spp.

34.7%34.7% 27.2%27.2%

E. coliE. coli 3.5%3.5% 2.1%2.1%

Klebsiella spp.Klebsiella spp. 6.9%6.9% 4.3%4.3%

Overall Imipenem/cilastatin showed better activity Overall Imipenem/cilastatin showed better activity than Meropenemthan Meropenem

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*

CarbapenemCarbapenem Bactericidal Bactericidal activityactivity

Imipenem / Imipenem / cilastatincilastatin

99.96%99.96%


CarbapenemCarbapenem Probability Probability 40% T>MIC40% T>MIC

Imipenem / Imipenem / cilastatincilastatin

99.96%99.96%


Kiffer CRV et al, Int J Antimicrob Agents 2006 (Epub ahead of print)

* Clinically significant

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

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): 435-437www.astrazenecaindia.com/Products/Meronem%20Abridged.pdf

* Kindly note that Acute Necrotizing Pancreatitis is not a labelled indication forZienam® and data presented above is completely based on published clinical evidence

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


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 Prophylactic Imipenem/cilastatin therapy Imipenem/cilastatin therapy resulted in significant resulted in significant reduction in infected reduction in infected necrosis, sepsis and necrosis, sepsis and mortalitymortality

Comparative study with Comparative study with Meropenem shows that Meropenem shows that septic complications, septic complications, indications for surgery or indications for surgery or mortality were lower with mortality were lower with Imipenem/cilastatin therapy Imipenem/cilastatin therapy than with Meropenemthan with Meropenem

Nordback I et al, J Gastrointest Surg 2001; 5: 113-118 ; Manes G et al, Pancreas 2003; 27: 379-383Heinrich S et al, Ann Surg 2006; 243: 154-168


11.40%

13.60%

10.00% 11.00% 12.00% 13.00% 14.00%

Imipenem/cilastatin

Meropenem

Sepsis, Surgery, Mortality (%)

Sepsis, Surgery, Mortality (%)

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

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 -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

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): 329-43Mosdell GM et al, Ann Surg 1991; 214: 543-549

Montravers P et al, Clin Infect Dis 1996; 23: 486-494

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): 329-43Lowe MN et al, Drugs 2000; 60: 619-646

Early empiric Carbapenem therapyEarly empiric Carbapenem therapy in Intra-abdominal Infections in Intra-abdominal Infections

The carbapenems are most appropriate for use as early empiric The carbapenems are most appropriate for use as early empiric therapy in IAI patients at high risk of death, re-infarction, re-therapy in IAI patients at high risk of death, re-infarction, re-operation, or exposure to MDR nosocomial gram-negative bacteriaoperation, or exposure to MDR nosocomial gram-negative bacteria

Tellado JM et al, Surgical Infections 2005; 6(3): 329-43

Clinical conditions where Carbapenem therapy may be appropriateClinical conditions where Carbapenem therapy may be appropriate

Empiric therapy for nosocomial IAI originated >48hr of hospital admission, either in Empiric therapy for nosocomial IAI originated >48hr of hospital admission, either in surgical ward or surgical ICUsurgical ward or surgical ICU

Empiric treatment for persistent infection after failure of non-carbapenem therapyEmpiric treatment for persistent infection after failure of non-carbapenem therapy

Intra-abdominal superinfection in tertiary peritonitisIntra-abdominal superinfection in tertiary peritonitis

Empiric treatment of IAI of any origin associated with sepsisEmpiric treatment of IAI of any origin associated with sepsis

Empiric treatment of suspected or confirmed IAI of any origin or degree of severity in Empiric treatment of suspected or confirmed IAI of any origin or degree of severity in immunosupressed or transplant recepient patientsimmunosupressed or transplant recepient patients

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

Thank youThank you

Comparison Of The Major Carbapenems

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