Brand Name:  Doribax

Generic Name:  doripenem

Manufacturer:  Ortho-McNeil Pharmaceutical, Inc. ⁽⁷⁾

Drug Class:  Carbapenem antibiotic

Uses: 

Labeled:   

            -complicated intra-abdominal infections ⁽³⁾

            -complicated urinary tract infections ⁽³⁾

            -nosocomial pneumonia, including ventilator-associated pneumonia ⁽⁷⁾

            Unlabeled:

                        -mixed aerobic-anaerobic diabetic foot infections ⁽⁹⁾

Mechanism of Action:  “Inhibits bacterial cell wall synthesis by binding to several of the penicillin-binding proteins, which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis; bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.”⁽⁵⁾

Pharmacokinetics:

Metabolism:  Doripenem is not a CYP 450 substrate and is not metabolized in the liver. ^{(5, 6)}  The primary route of metabolism is by dihydropeptidase-I which metabolizes doripenem to the inactive metabolite dorapenem-M1.  ^{(5, 6)}

Elimination:  Doripenem is excreted mainly by the renal route (70% unchanged). ^{(5, 7)}

Efficacy: 

A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare Safety and Efficacy of Intravenous Doripenem and Levofloxacin in Complicated Lower Urinary Tract Infection or Pyelonephritis (JNJ-38 174942; DORI-05 CR005404) Date study initiated: 21 Dec. 2003; Date study completed: 23 Mar 2006. Clinicaltrials.gov. Accessed on July 17^th 2008.

Study Design:  Phase 3, multicenter, prospective, randomized, double-blind

Description of Study:  The study involved 753 patients randomized to receive either doripenem (377 pts) 500 mg every 8 hours as a 1 hour IV infusion, or levofloxacin (376 pts) 250 mg every 24 hours as a 1 hour IV infusion.  The primary outcome measure of this study is the microbiological response at the test-of-cure (TOC) visit 6-9 days after the completion of a 10 day trial of doripenem in patients with complicated UTI.  The secondary outcome measures include the clinical response at the TOC visit, and the safety of doripenem in patients with complicated UTI.  Doripenem was proven to be non-inferior to levofloxacin in microbiological cure rate (82.1% doripenem vs 83.4% levofloxacin).  79.2% of doripenem patients and 78.2% of levofloxacin patients were determined to be microbiologically cured.  Clinical cure rate was 95.1% and 90.2% for doripenem and levofloxacin, respectively.  Doripenem was established non inferior to levofloxacin for treatment of clinical symptoms of cUTI (complicated lower UTI and pyelonephritis).  Doripenem is effective against major causative pathogens of cUTI including E. coli, Klebsiella pneumoniae, and Proteus mirabilis; however, doripenem was not superior to levofloxacin in E. coli eradication.  

Limitations:  It was not noted as to why some patients were not included in each of the separate analyses of the study (i.e. dropout, adverse effects, treatment failure, etc.).  Also, some of the levofloxacin group was switched to oral therapy if deemed necessary which may be less effective than IV levofloxacin, and may not directly compare to IV doripenem.  The power was not reported.

Conclusion:  Doripenem is microbiologically and clinically effective in the treatment of cUTI, complicated pyelonephritis, and patients with concurrent bacteremia.  Doripenem is non inferior compared to levofloxacin, and is effective against common uropathogens including E. coli, K. pneumoniae, and P. mirabilis.

Chastre, Jean.  Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia:  A multicenter, randomized study.  Crit Care Med.  2008; 36(4):1089-1096.

Study Design:  Phase 3, multicenter, prospective, randomized, open-label (with in-house blinding)

Description of Study:  The study randomized 531 patients to receive either doripenem (264 pts) 500 mg every 8 hours for a four hour IV infusion, or imipenem (267 pts) 500 mg every 6 hours for a 30 minute IV infusion or 1000 mg every 8 hours for a 60 minute IV infusion.  Concomitant amikacin and vancomycin therapy was permitted for P. aeroginosa and MRSA infections, respectively.  The duration of treatment was 7 to 14 days of IV study drug therapy only.  The primary outcome measure was to compare the clinical response rate of IV doripenem versus IV imipenem at the test-of-cure visit (TOC) 7 to 14 days after the completion of the IV study drug therapy.  The secondary outcome measures included:  microbiological response per subject, emergence of study drug-resistant Pseudomonas aeruginosa, per pathogen microbiological outcome rate and clinical cure rate, all-cause mortality rate at 28 days post therapy initiation, and safety profile comparison.  The clinical response rates at the TOC visit were 68.3% and 64.8% for doripenem and imipenem, respectively.  The microbiological response rates were 73.3% for doripenem and 67.3% for imipenem.  18% of doripenem subjects showed resistance to P. aeroginosa compared to 56% of imipenem subjects.  The clinical cure rate was 69.0% for doripenem and 64.5% for imipenem.  No difference between the two treatment arms was found for all-cause mortality.  The safety profiles of each drug were similar. 

Limitations:  It was not noted how many patients also received either vancomycin or amikacin in addition to the doripenem or imipenem.  Also, the individual results of imipenem 500 mg versus 1000 mg were not noted and/or compared to the doripenem regimen.  Small sample size resulted in non-statistically significant results.  The power was not reported.  Open label design may have altered the results. 

Conclusion:  Doripenem is not inferior to imipenem in the treatment of ventilator associated pneumonia.  The clinical and microbiological success rates for P. aeruginosa infections were double in the doripenem group compared to the imipenem group.  Doripenem was also the favorable option for Klebsiella sp. and E. coli.  Although statistically significant results were not present, doripenem may have more clinical significance compared to imipenem when treating VAP.  More research is needed to confirm clinical significance. 

A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare the Safety and Efficacy of Intravenous Doripenem with that of Meropenem in Complicated Intra-abdominal Infections (JNJ-38 174942; DORI-08 CR005389) Date study initiated: 03 May 2004; Date study completed:  27 March 2006.  Clinicaltrials.gov. Accessed on July 17^th 2008.

Study Design:  Phase 3, multicenter, prospective, randomized, double-blind, double-dummy

Description of Study:  The study randomized 486 patients to receive either doripenem (249 pts) 500 mg every 8 hours as a 1 hour IV infusion, or meropenem 1 gram every 8 hours as 3 to 5 minute IV bolus.  After greater than or equal to 9 doses of study drug therapy, and if the patients temperature and WBC count were decreasing relative to baseline values (if increased at baseline), cIAI signs and/or symptoms were absent/improved relative to those at baseline, and normal bowel function had returned, then the patient was switched to oral amoxicillin/clavulanate 875/125 mg twice daily.  The duration of treatment was between 5 and 14 days (IV only or IV plus oral).  The primary outcome measure was to compare the clinical response of doripenem versus meropenem in hospitalized patients with complicated intra-abdominal infections (cIAI) at the test-of-cure (TOC) visit (4 to 6 weeks after the completion of study drug therapy).  The secondary outcome measures included: comparing microbiological response at the TOC visit, and the safety profile of doripenem with that of meropenem.  The clinical cure rates at TOC (21-60 days post therapy) and at any time up to 60 days after the last dose of study drug therapy were similar in both treatment arms.  Doripenem was effective against major causative pathogens of cIAI including:  E. coli, K. pneumoniae, P. aeruginosa, S. intermedius, B. caccae, B. thetaiotaomicron, B. fragilis, and B. uniformis.  For anaerobic pathogens (gram positive and negative), doripenem was favorable at 84% eradication or presumed eradication compared to 79% with meropenem. 

Limitations:  It was not noted how many patients were switched to oral therapy with amoxicillin/clavulanate.  The power was not reported. 

Conclusion:  Doripenem is clinically effective in the treatment of patients with cIAI and therapeutically non inferior to meropenem.  Doripenem is effective against the major pathogens associated with cIAI.

Contraindications:

            -Allergy to B-lactams ⁽⁶⁾

            -Serious hypersensitivity to other carbapenem antibiotics ⁽⁶⁾

Precautions:

-For patients with a history of seizures, head or brain injury, subarachnoid hemorrhages, cerebrovascular accidents, or a history of epilepsy, doripenem may result in seizures. ⁽⁸⁾

            -Hypersensitivity/allergy to beta lactam antibiotics. ⁽⁵⁾

-Fungal or bacterial superinfections may result with prolonged use of doripenem. ⁽⁵⁾

-Dosage adjustment may be necessary for patients with renal impairment:  As renal function decreased, serum half-life increased from 1 to 5 hours (severe renal impairment) to up to 9 hours (end-stage renal failure). ^{(5, 7)}

-Doripenem reduces valproic acid concentrations and may result in breakthrough sezuires. ⁽⁵⁾

-Probenecid can increase doripenem concentrations, thus concomitant use is not recommended. ⁽⁶⁾

Adverse Effects:

            -Headache, 4-16% ^{(2, 5, 7)}

            -Nausea, 4-12% ^{(2, 5, 7, 8)}

            -Diarrhea, 6-11% ^{(2, 5, 7, 8)}

            -Rash, 1-5% ^{(2, 5, 8)}

            -Injection site phlebitis, 4-8% ^{(2, 5, 7)}

            -Hepatic enzyme increase, 1-2% ^{(6, 8)}

            -Fungal infection, oral candiasis, 1% ^{(5, 8)}

Drug Interactions:

-Valproic Acid:  carbapenems can decrease serum concentrations of valproic acid resulting in loss of seizure control.  Monitor valproic acid concentration frequently. ^{(2, 5, 6)}

-Probenecid:  doripenem serum concentrations increase due to interference of tubular secretion by Probenecid.  Concomitant administration is not recommended. ^{(2, 5, 6)}

-Typhoid vaccine: Antibiotics may decrease effectiveness of the Ty21a live, attenuated typhoid vaccine; delay vaccination for >24 hours after administration of antibiotic. ⁽⁵⁾

Dosing/Administration:

Usual dose:  For bacterial strains with MIC’s less than 2 micrograms/mL, 500 mg every 8 hours administered over 1 hour would be effective. ^{(2, 7)}  Less susceptible strains would need to be treated with longer infusions. ⁽⁷⁾  A course of 5 to 14 days is necessary for complicated intraabdominal infection, and 10 to 14 days for complicated urinary tract infection or pyelonephritis. ⁽⁵⁾

Geriatric dose:  see Usual dose.  Monitor renal function due to the possibility for the need of a dosage adjustment. ⁽⁵⁾

Pediatric dose:  Safety and efficacy has not been established in pediatrics. ⁽⁶⁾

Renal impairment dose:  Cl_cr 30-50 mL/minute: 250 mg every 8 hours ⁽⁵⁾

 Cl_cr 11-29 mL/minute: 250 mg every 12 hours ⁽⁵⁾

Hemodialysis: Dialyzable (approximately 52% of dose removed during 4-hour session in ESRD patients) ⁽⁵⁾

Hepatic impairment dose:  No dosage adjustment necessary. ⁽¹⁰⁾

Use in Special Circumstances:

Pregnancy category:  B ⁽⁶⁾

Breastfeeding:  It is unknown whether or not doripenem is excreted into breast milk. ⁽⁶⁾

Conclusion:

The FDA approved uses for doripenem include:  complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial or ventilator associated pneumonia.   Based on in vitro activity, doripenem has a major role in multi-drug resistant gram negative bacteria, including P. aeruginosa. Doripenem has a unique 1-beta-methyl side chain with a sulfamoylaminomethyl group which allows for beta-lactamase stability and resistance to inactivation by renal dihydropeptidases. Doripenem exhibits activity against 15 to 20% of the strains resistant to imipenem and almost 40% of the strains resistant to ceftazidime, cefepime, and aztreonam. The longer stability at room temperature seen with doripenem compared to other carbapenems, allows for 4 hour extended infusions when necessary (i.e. less susceptible strains that require higher MIC’s). Carbapenem antibiotics have been known to increase the risk of seizures due to their affinity for the GABA receptors; however, an advantage of doripenem is that it has a lower affinity for GABA, thus a lesser risk for seizure activity. Doripenem has a very broad spectrum of activity including:  gram-positive, gram-negative, and anaerobic pathogens; but doripenem is not active against oxacillin-resistant staphylococci, E. faecium, and S. maltophilia.  Doripenem was effective against major causative pathogens of cIAI including:  E. coli, K. pneumoniae, P. aeruginosa, S. intermedius, B. caccae, B. thetaiotaomicron, B. fragilis, and B. uniformis. Doripenem is microbiologically and clinically effective in the treatment of cUTI, complicated pyelonephritis, and patients with concurrent bacteremia. Doripenem is non inferior compared to levofloxacin, and is effective against common uropathogens including E. coli, K. pneumoniae, and P. mirabilis. Doripenem is not inferior to imipenem in the treatment of ventilator associated pneumonia. The clinical and microbiological success rates for P. aeruginosa infections were double in the doripenem group compared to the imipenem group. Doripenem was also the favorable option for Klebsiella sp. and E. coli. In addition, an in vitro study that isolated aerobes and anaerobes from diabetic foot infections suggests that doripenem is a promising agent for the treatment of diabetic foot infections. Overall, this drug should be reserved for the use in seriously ill patients with a polymicrobial infection, a multiple drug resistant gram negative infection, or for those who have Pseudomonas.

Recommended References:

1. Bhavnani, Sujata M.  Use of Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Phase 2 and 3 Dosing Strategies for Doripenem.  Antimicrob. Agents Chemother. 2005 Sept;49(9):3944-3947.
2. Medical Letter. Doripenem (Doribax)-A New Parenteral Carbapenem.  Obstetrics &Gynecology. 2008 May;111(5):1206-1207.
3. ADIS R&D Profile. Doripenem S 4661.  Drugs R&D. 2003;4(6):363-365.
4. Jones, Ronald N.  Activities of Doripenem (S-4661) against Drug-Resistant Clinical Pathogens.  Antimicrob. Agents Chemothr.  2004 Aug.;48(8):3136-3140. 
5. Lexi-Comp Online. Doripenem.  Accessed July 16^th 2008.
6. Micromedex. DrugDex. Doripenem. Accessed July 16^th 2008.
7. Giamarellou, H.  Current Therapies for Psuedomonas Aeruginosa.  Crit Care Clin. 2008;24:261-278.
8. Chastre, Jean.  Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia:  A multicenter, randomized study.  Crit Care Med.  2008;36(4):1089-1096.
9. Goldstein, EJC.  In Vitro Activities of Doripenem and Six Comparator Drugs against 423 Aerobic and Anaerobic Bacterial Isolates form Infected Diabetic Foot Wounds.  Antimicrob. Agents Chemothr. 2008 Feb;52(2):761-766.
10. Clinical Pharmacology. Doripenem. Accessed July 16^th 2008.
11. A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare the Safety and Efficacy of Intravenous Doripenem with that of Meropenem in Complicated Intra-abdominal Infections (JNJ-38 174942; DORI-08 CR005389) Date study initiated: 03 May 2004; Date study completed:  27 March 2006.  Clinicaltrials.gov. Accessed on July 17^th 2008.
12. A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare Safety and Efficacy of Intravenous Doripenem and Levofloxacin in Complicated Lower Urinary Tract Infection or Pyelonephritis (JNJ-38 174942; DORI-05 CR005404) Date study initiated: 21 Dec. 2003; Date study completed: 23 Mar 2006. Clinicaltrials.gov. Accessed on July 17^th 2008.

Prepared by:  Marcella Hoyland, Doctor of Pharmacy Candidate.