Ertapenem versus Piperacillin/Tazobactam Ertapenem versus Piperacillin/Tazobactam for Diabetic Foot Infections (SIDESTEP): for Diabetic Foot Infections (SIDESTEP): Prospective, Randomized, Controlled, Prospective, Randomized, Controlled, Double-blinded, Multi-center trialDouble-blinded, Multi-center trial

Reviewed by: Todd S. Reese, MBAReviewed by: Todd S. Reese, MBA

MWU PharmD candidate, 2007MWU PharmD candidate, 2007

April, 2007April, 2007

Prepared for:

Del E. Webb Memorial Hospital Pharmacy

Ertapenem is a Ertapenem is a carbapenem carbapenem antibiotic sold by antibiotic sold by Merck as “Merck as “InvanzInvanz.”.”

Mechanism of action: Mechanism of action: It inhibits the It inhibits the formation of formation of bacterial cell walls, bacterial cell walls, thus causing cell thus causing cell death. death.

Susceptible Organisms:

Aerobic and facultative gram-positive microorganisms:

Staphylococcus aureus (methicillin susceptible isolates only)Streptococcus agalactiaeStreptococcus pneumoniae (penicillin susceptible isolates only)Streptococcus pyogenesNote: Methicillin-resistant staphylococci and Enterococcus spp. are resistant to ertapenem.

Aerobic and facultative gram-negative microorganisms:

Escherichia coliHaemophilus influenzae (Beta-lactamase negative isolates only)Klebsiella pneumoniaeMoraxella catarrhalisProteus mirabilis

Anaerobic microorganisms:

Bacteroides fragilisBacteroides distasonisBacteroides ovatusBacteroides thetaiotaomicronBacteroides uniformisClostridium clostridioformeEubacterium lentumPeptostreptococcus speciesPorphyromonas asaccharolyticaPrevotella bivia

BackgroundBackground• Foot infections in patients with diabetes are not only Foot infections in patients with diabetes are not only

common but difficult to treat. Foot infections and common but difficult to treat. Foot infections and ulcerations are the MOST FREQUENT cause for ulcerations are the MOST FREQUENT cause for hospitalization in the United States. Outside of the United hospitalization in the United States. Outside of the United States, they are the leading cause of lower-extremity States, they are the leading cause of lower-extremity amputations.amputations.

• Treatment and prevention of foot ulcerations in patients Treatment and prevention of foot ulcerations in patients with diabetes is well-understood, yet 3.7% of people with with diabetes is well-understood, yet 3.7% of people with diabetes still have problems with foot ulcerations despite diabetes still have problems with foot ulcerations despite the accessibility of general medical and foot care.the accessibility of general medical and foot care.

• Since infections of this kind often spread to soft tissues Since infections of this kind often spread to soft tissues and bone, guidelines suggest that success is dependent and bone, guidelines suggest that success is dependent on proper wound care, early surgical interventions, and on proper wound care, early surgical interventions, and antibiotic therapy that is appropriateantibiotic therapy that is appropriate..

More BackgroundMore Background

• The authors, aware that antibiotics are The authors, aware that antibiotics are quite effective for diabetic foot quite effective for diabetic foot infections, are also aware that “most of infections, are also aware that “most of the clinical trials done to assess them the clinical trials done to assess them were of poor design and included only were of poor design and included only small numbers of patients.”small numbers of patients.”

• This study was meant to change that…This study was meant to change that…

About the studyAbout the study

• The study began in 2001 and took three years to meet the target The study began in 2001 and took three years to meet the target enrollment of 600 patients which would make it the largest study enrollment of 600 patients which would make it the largest study of diabetic foot infections. of diabetic foot infections.

• The original idea was to compare two parenteral antibiotic agents The original idea was to compare two parenteral antibiotic agents (Invanz and Zosyn) given for a minimum of five days to all (Invanz and Zosyn) given for a minimum of five days to all patients. patients.

• Patients in either group could be appropriately switched oral Patients in either group could be appropriately switched oral therapy with amoxicillin/clavulanate for a maximum total of 28 therapy with amoxicillin/clavulanate for a maximum total of 28 days of antibiotic therapy if necessary.days of antibiotic therapy if necessary.

• Enrollment included 586 patients with diabetic foot infections Enrollment included 586 patients with diabetic foot infections classified as moderate to severe infections and required classified as moderate to severe infections and required intravenous antibiotic therapy. intravenous antibiotic therapy.

• Ultimately 445 patients would be assessed at the end of IV Ultimately 445 patients would be assessed at the end of IV therapy, the primary endpoint. therapy, the primary endpoint. – 226 received ertapenem226 received ertapenem– 219 received piperacillin/tazobactam. 219 received piperacillin/tazobactam. – All were similar by all parameters at baselineAll were similar by all parameters at baseline

ResultsResults

Dr. Lipsky:Dr. Lipsky:

• ““When examining various groups at When examining various groups at different endpoints, we found that the different endpoints, we found that the clinical, microbiological and safety clinical, microbiological and safety outcomes were all outcomes were all statistically statistically comparablecomparable in patients who received in patients who received ertapenem as in those who got ertapenem as in those who got piperacillin/tazobactam. These outcomes piperacillin/tazobactam. These outcomes demonstrated that demonstrated that ertapenem is a ertapenem is a useful antibiotic for treating diabetic useful antibiotic for treating diabetic foot infectionsfoot infections as the outcomes were as the outcomes were similar to one of the most widely used similar to one of the most widely used agents for this indication.”agents for this indication.”

Conclusion of the authors:Conclusion of the authors:

• ““Clinical and microbiological outcomes Clinical and microbiological outcomes for patients treated with ertapenem for patients treated with ertapenem were were equivalentequivalent to those for patients to those for patients treated with piperacillin/tazobactam, treated with piperacillin/tazobactam, suggesting that this once-daily suggesting that this once-daily antibiotic should be considered for antibiotic should be considered for parenteral therapy of diabetic foot parenteral therapy of diabetic foot infections, when deemed appropriate.” infections, when deemed appropriate.”

Strengths of the StudyStrengths of the Study

• Large number of enrolleesLarge number of enrollees

• Multi-center study designMulti-center study design

• Newly-adopted foot infection Newly-adopted foot infection classification guidelinesclassification guidelines

Weaknesses of the StudyWeaknesses of the Study

• Mildly-infected patients excludedMildly-infected patients excluded• Patients with osteomyelitis were excluded Patients with osteomyelitis were excluded

unless resectedunless resected• Study investigators varied in terms of Study investigators varied in terms of

medical backgroundmedical background• Most patients received some form of oral Most patients received some form of oral

antibioticsantibiotics• Researchers received payment (and own Researchers received payment (and own

stock) in Merck, the stock) in Merck, the sourcesource of funds for of funds for the studythe study

Strengths of ErtapenemStrengths of Ertapenem

• As safe and effective as ZosynAs safe and effective as Zosyn

• ONCE-a-DAY dosingONCE-a-DAY dosing

• Lower sodium content Lower sodium content – (137 mg [~6 mEq] per gram of (137 mg [~6 mEq] per gram of

ertapenem ertapenem

Weaknesses of ErtapenemWeaknesses of Ertapenem

• Limited coverage for EntercocciLimited coverage for Entercocci

• Limited coverage Limited coverage for for PseudomonasPseudomonas

• NO coverage NO coverage for MRSA for MRSA

Ertapenem is a Ertapenem is a carbapenem carbapenem antibiotic sold by antibiotic sold by Merck as “Merck as “InvanzInvanz.”.”

Mechanism of action: Mechanism of action: It inhibits the It inhibits the formation of formation of bacterial cell walls, bacterial cell walls, thus causing cell thus causing cell death. death.

Susceptible Organisms:

Aerobic and facultative gram-positive microorganisms:

Staphylococcus aureus (methicillin susceptible isolates only)Streptococcus agalactiaeStreptococcus pneumoniae (penicillin susceptible isolates only)Streptococcus pyogenes

Note: Methicillin-resistant staphylococci and Enterococcus spp. are resistant to ertapenem.

Aerobic and facultative gram-negative microorganisms:

Escherichia coliHaemophilus influenzae (Beta-lactamase negative isolates only)Klebsiella pneumoniaeMoraxella catarrhalisProteus mirabilis

Anaerobic microorganisms:

Bacteroides fragilisBacteroides distasonisBacteroides ovatusBacteroides thetaiotaomicronBacteroides uniformisClostridium clostridioformeEubacterium lentumPeptostreptococcus speciesPorphyromonas asaccharolyticaPrevotella bivia

No coverage for MRSA?No coverage for MRSA?

• The NEJM, in 2006, reported “MRSA is The NEJM, in 2006, reported “MRSA is the most common identifiable cause the most common identifiable cause of skin and soft-tissue infections of skin and soft-tissue infections among patients presenting to among patients presenting to emergency departments in 11 U.S. emergency departments in 11 U.S. cities.” cities.”

New EnglandNew EnglandJournal of Medicine:Journal of Medicine:

New EnglandNew EnglandJournal of Medicine:Journal of Medicine:

• “ “When antimicrobial therapy is When antimicrobial therapy is indicated for the treatment of skin indicated for the treatment of skin and soft-tissue infections, clinicians and soft-tissue infections, clinicians should consider obtaining cultures should consider obtaining cultures and modifying empirical therapy to and modifying empirical therapy to provide MRSA coverage.”provide MRSA coverage.”

My ConclusionsMy Conclusions

• This is a fair study, but the fact it was This is a fair study, but the fact it was funded by the manufacturers of the drug funded by the manufacturers of the drug makes it highly suspicious.makes it highly suspicious.

• MRSA is an issue at Del Webb Memorial, MRSA is an issue at Del Webb Memorial, therefore the P&T committee may therefore the P&T committee may certainly consider Invanz for the certainly consider Invanz for the formulary, but any patient presenting with formulary, but any patient presenting with a diabetic foot ulceration should receive a diabetic foot ulceration should receive an antibiotic with MRSA coverage.an antibiotic with MRSA coverage.

Works Consulted:Works Consulted:

• http://www.podiatrytoday.com/article/5441http://www.podiatrytoday.com/article/5441• http://www.podiatrytoday.com/article/3464http://www.podiatrytoday.com/article/3464• http://www.healthology.com/main/http://www.healthology.com/main/

article_print.aspx?content_id=3670article_print.aspx?content_id=3670• http://www.merck.com/product/usa/pi_circulars/i/http://www.merck.com/product/usa/pi_circulars/i/

invanz/invanz_pi.pdfinvanz/invanz_pi.pdf• http://www.medscape.com/viewarticle/539090http://www.medscape.com/viewarticle/539090• http://www.mayoclinicproceedings.com/http://www.mayoclinicproceedings.com/

inside.asp?AID=3063inside.asp?AID=3063• http://www.yourlawyer.com/articles/read/12084http://www.yourlawyer.com/articles/read/12084