Doripenem (Doribax): A Novel Carbapenem
Special Report
By Yvonne V. Phan, PharmD Candidate, Kristine G. Chin, PharmD Candidate, and Jessica C. Song, MA, PharmD, Yvonne V. Phan and Kristine G. Chin are PharmD Candidates at the University of the Pacific, and Jessica C. Song is PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Yvonne V. Phan, Kristine G. Chin, and Jessica C. Song report no financial relationships relevant to this field of study.
In 1985, the newly fda-approved antimicrobial agent, Primaxin® (imipenem/cilastatin), introduced a new class of drugs known as carbapenems. This new class provided benefits as well as unwanted side effects. Carbapenems work similarly to other β-lactam antibiotics, but with substantially broader-spectrum of activity and better penetration into bacterial cell walls to prevent synthesis. Carbapenems are useful in resistant bacterial infections against Gram-negative, Gram-positive, and anaerobic microorganisms. Primaxin consists of imipenem in combination with cilastatin [dehydropeptidase-1 (DHP-1) inhibitor] to reduce the risk of proximal tubule toxicity caused by imipenem metabolism. Newer carbapenems such as meropenem, ertapenem, and doripenem are stable to metabolism by DHP-1, so they are used without cilastatin. Doripenem is the newest addition to the carbapenem class of antibiotics.1
Doripenem is a semi-synthetic carbapenem antimicrobial agent used intravenously. Carbapenems, along with all β-lactam antimicrobial agents, exert their bactericidal effects by binding to penicillin-binding proteins (PBPs) and preventing the completion of transpeptidation or cross-linking of peptidoglycan strands leading to inhibition of cell wall synthesis. Each carbapenem has different binding affinities for different PBPs. Therefore, it has been noted that both meropenem and doripenem are more potent in vitro against gram-negative microorganisms, such as Pseudomonas aeruginosa, than imipenem. Doripenem was approved by the FDA on October 12, 2007, for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. An NDA (New Drug Application) was submitted and is currently under investigation for treatment of nosocomial and ventilator-associated pneumonia.1
This article will: 1) review the spectrum of activity of doripenem; 2) review the clinical efficacy of doripenem for the treatment of complicated intra-abdominal infection; 3) review the clinical efficacy of doripenem for the treatment of complicated urinary tract infection; and 4) discuss the current Phase III clinical trial of doripenem for the treatment of nosocomial and ventilator-associated pneumonia.
Spectrum of Activity
Carbapenems, in general, have a broader-spectrum of activity compared with other β-lactam antibiotics because they are stable against β-lactamases. Table 1 compares the spectrum of activity of the four carbapenems: doripenem, imipenem, meropenem, and ertapenem. All carbapenems produce in vitro MIC90 values of < 1mg/L against the most commonly isolated species of Gram-positive aerobic bacteria, including methicillin-susceptible S. aureus, penicillin intermediate and resistant isolates of S. pneumonia, but excluding Enterococcus spp. and methicillin-resistant S. aureus. In most cases, imipenem and doripenem are slightly more potent against Gram-positive aerobic bacteria compared with ertapenem and meropenem. Ertapenem has MIC90 values > 8-fold higher than other carbapenems against isolates of P. aeruginosa. Doripenem has exhibited anti-pseudomonal activity that is greater than imipenem on a weight basis and equal to or slightly greater than that of meropenem. Since all carbapenems are stable compared to most β-lactamases, they have activity against most pathogens that produce extended-spectrum β-lactamases (ESBLs), E. coli, and K. pneumoniae. This is an important observation because the presence of ESBLs can lead to resistance to and treatment failure with third-generation cephalosporins.2
Pharmacological/Other Clinical Properties of Doripenem
Table 2 provides a summary of the mechanism of action, spectrum of activity, FDA indications, pharmacokinetics, dosing/administration, adverse effects, contraindications, drug interactions, storage, and cost of doripenem (contract price at Santa Clara Valley Medical Center, San Jose, CA).
Complicated Intra-Abdominal Infections
Complicated intra-abdominal infections (cIAI) are infections that extend beyond the hollow viscus of origin into the peritoneal space, and are associated with abscess formation or peritonitis. Furthermore, resolution of these types of infections requires either operative or percutaneous intervention.3 There is a wide variety of conditions associated with cIAI, including perforated gastroduodenal ulcers, biliary tract infections, small bowel perforations, appendicitis, and diverticulitis.4 The pathogens causing cIAI vary depending on whether the infection is community-acquired or health care-associated. Empirical treatment will be dependent on the type of infection the patient presents with upon hospital admission.
According to the 2003 Infectious Diseases Society of America (IDSA) Guidelines, empiric antimicrobial agents for community-acquired intra-abdominal infections should cover enteric Gram-negative aerobic and facultative bacilli, as well as β-lactam-susceptible Gram-positive cocci. Additionally, coverage for obligate anaerobic bacilli is needed for distal small-bowel, colon-derived infections, and for more proximal perforations when obstruction is present. Narrower spectrum agents that are not commonly used for nosocomial infections are preferred over broader spectrum antimicrobials for mild-to-moderate community-acquired intra-abdominal infections. High-severity infections (higher APACHE II scores, significant cardiovascular disease, poor nutritional status, or immunosuppression) may benefit from antimicrobials with a broader spectrum of activity against facultative and aerobic Gram-negative pathogens.3 Refer to Table 3 for agents used for the treatment of community-acquired cIAI.
Health care-associated intra-abdominal infections occur as a result of complications of previous elective or emergent intra-abdominal operations, and are caused by more resistant pathogens, including Pseudomonas aeruginosa, Enterobacter spp, Proteus spp, methicillin-resistant Staphylococcus aureus, enterococci, and Candida spp. These infections often require complex multi-drug regimens, where local nosocomial resistance patterns dictate empirical treatment. Once results of microbiology workup of infected fluid is obtained, antimicrobial therapy should be adjusted accordingly.3
According to IDSA guidelines in 2003, meropenem has often been a recommended agent for high-severity complicated intra-abdominal infections due to favorable results observed in several studies. However, doripenem has since been tested to be safe and effective for the use in cIAI. In 2007, Solomkin and colleagues performed two phase III clinical trials comparing doripenem (500 mg IV q8h) to meropenem (1 g IV q8h) for the treatment of complicated intra-abdominal infections in 962 patients. There was an optional stepdown therapy in which patients could be switched to amoxicillin/clavulanate (875 mg PO BID) after nine IV doses, for a total of 5-14 days of treatment if necessary. The primary end point was a clinical response within 21 to 60 days after treatment completion. Results of the trial showed that clinical cure rates of microbiologically-evaluable patients were 84.6% for doripenem and 84.1% for meropenem (treatment difference, 0.5%; 95% CI, -5.5% to 6.4%), making doripenem non-inferior to meropenem. Based on these findings, doripenem use in cIAI may be comparable to the use of meropenem.5
Doripenem is indicated as a single agent for use in the treatment of complicated intra-abdominal infections caused by susceptible strains of E. coli, K. pneumoniae, P. aeruginosa, B. caccae, B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, S. intermedius, S. constellatus, or P. micros.6
Complicated Urinary Tract Infections
Urinary tract infections (UTIs) are amongst the most common problems managed by primary care physicians. Most UTIs are the uncomplicated cystitis type caused by Escherichia coli in otherwise healthy young women. These infections are easily managed with short-term oral antimicrobial therapy, usually without the need for follow-up urine cultures. Treatment of complicated UTI (cUTI), in contrast, is often less successful. A therapy lasting 10-14 days, with an antimicrobial agent active against a more extensive list of Gram-negative bacilli, is recommended. For serious infections, initial empirical therapy with a broad-spectrum parenteral antimicrobial agent, often followed by an oral agent to which the responsible uropathogen is susceptible, is standard therapy. Follow-up urine cultures are also an important component of management of cUTIs because bacterial eradication is difficult, and recurrence after completion of therapy is not uncommon.7
According to an analysis conducted by Wells and colleagues, the treatment of cUTIs is usually initiated empirically, before identification of the causal organism(s). In most cases of cUTI, Enterobacteriaceae accounted for the overwhelming majority of pathogens. E. coli is generally the predominant single isolate in most cases, and in North America, uropathogenic E. coli are increasingly resistant to ampicillin and trimethoprim/sulfamethoxazole, especially those strains isolated from patients who have received prior antimicrobial therapy. Patients with underlying urinary tract abnormalities are also at increased risk of infection with other Enterobacteriaceae that may be more resistant to antimicrobial agents. In the analysis, Wells et al found that Enterobacteriaceae resistant to ertapenem, a carbapenem, are uncommon. In addition, ertapenem 1g IV or IM once a day, with the option to switch to an appropriate oral antimicrobial agent after clinical improvement, was highly effective both clinically and microbiologically for the treatment of moderate-to-severe cUTI, requiring initial parenteral therapy in adults. The results of these studies demonstrate that ertapenem was excellent therapy for complicated UTIs in adults with moderate-to-severe disease. The safety and efficacy profile of ertapenem allowed for FDA approval in November 2001.1,7
Since doripenem is a carbapenem that was developed to improve upon the older carbapenems, both in its safety and efficacy profile, it was further investigated for the treatment of cUTIs. Doripenem was found to have a wider spectrum of activity than the older carbapenems or β-lactam and cephalosporin antibiotics. The possibility of doripenem for treatment against certain cUTI pathogens such as Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae was further tested. In the randomized, double-blind phase III clinical trial conducted by Naber and colleagues doripenem (500 mg IV q8h) was compared to levofloxacin (250 mg IV qd) in 753 patients with complicated urinary tract infections, including pyelonephritis. Levofloxacin is generally a drug of choice in cUTI if the patient is allergic to sulfa drugs or shows bacterial resistance to trimethoprim/sulfamethoxazole (refer to Table 4). Patients who showed a clinical improvement had the option of switching to oral levofloxacin (250 mg PO qd) after at least 3 IV doses for a total of 10 days of treatment. The primary end point was a favorable microbiological response within 6-9 days after treatment completion. Microbiologic cure rates of microbiologically evaluable patients were 82.1% and 83.4% for doripenem-treated patients and levofloxacin-treated patients, respectively (treatment difference, -1.3%, 95% CI, -8.0% to 5.5%). In conclusion of this Phase III clinical trial, the clinical efficacy and safety of doripenem was non-inferior to levofloxacin, which allows it to be a possible drug of choice for the treatment of cUTIs.8
Doripenem is indicated for the treatment of complicated urinary tract infections, including pyelonephritis caused by susceptible strains of E coli, including cases with concurrent bacteremia, K. pneumoniae, P. mirabilis, P. aeruginosa, or A. baumannii.6
Prospective Indications for Doripenem
Pseudomonas aeruginosa, a Gram-negative pathogen with increasing multi-drug resistance, is one of the leading causes of nosocomial infections.10 According to the Centers for Disease Control and Prevention (CDC), two million Americans develop hospital-acquired infections each year, and approximately 90,000 die as a result. Approximately 70% of these infections are resistant to at least one antibiotic.11
Eventually, clinicians expect doripenem to be approved for nosocomial Gram-negative infections, including ventilator-associated and nosocomial pneumonia in the near future. In studies of ventilator-associated and nosocomial pneumonia, doripenem produced a cure rate similar to that of piperacillin/tazobactam and imipenem/cilastatin, but was associated with less resistance to the pathogens involved in either clinical trial.
With an NDA submitted for use in nosocomial and ventilator-associated pneumonia (VAP), doripenem is still under investigation for FDA approval of those indications. In the meantime, two open-label, phase III clinical trials were done in which the efficacy and safety of doripenem was compared to either a β-lactam/β-lactamase inhibitor or another carbapenem. In one study done by Rea-Neto and colleagues, 448 patients with either early-onset VAP (onset of < 5 days) or nosocomial pneumonia received either doripenem (500 mg IV q8h) or piperacillin/tazobactam (4.5 g IV q6h). After 9 IV doses, patients that showed clinical improvement had the option of switching to oral levofloxacin (750 mg PO qd). The primary end point was a clinical response within 7 to 14 days after treatment completion. By the end of the trial, clinical cure rates were 81.3% and 79.8% for patients treated with doripenem and piperacillin/tazobactam, respectively (treatment difference, 1.5%; 95% CI, -9.1% to 12.1%). Resistance to doripenem among P. aeruginosa strains and K. pneumoniae strains were 4% and 0%, respectively. Resistance to piperacillin/tazobactam among P. aeruginosa strains and K. pneumoniae strains were 27% and 43%, respectively.11 Chastre and colleagues completed another trial in which 531 patients with VAP were given either doripenem (500 mg IV q8h) or imipenem/cilastatin (500 mg IV q6h to 1g IV q8h). The primary end point was a clinical response within 7-14 days after treatment completion. Findings of this trial included clinical cure rates of 68.3% and 64.8% for patients treated with doripenem or imipenem/cilastatin, respectively (treatment difference, 3.5%; 95% CI, -9.1% to 16.1%). Resistance to doripenem among P. aeruginosa strain was 5/28, while resistance to imipenem/cilastatin among P. aeruginosa strains was 14/25. For those patients with Pseudomonas aeruginosa infection, doripenem demonstrated a 65% clinical cure rate compared to a 36% clinical cure rate seen with imipenem.12
Conclusion
Doripenem is an intravenously administered carbapenem with a broad spectrum of activity against many multidrug-resistant pathogens, including aerobic or anaerobic Gram-negative and Gram-positive microorganisms. As seen in clinical trials, doripenem is fairly similar to meropenem. Both carbapenems are more active against some P. aeruginosa strains that may have become resistant to imipenem or other antibiotics. Doripenem may be beneficial in hospital settings for patients with serious infections, such as complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, that may require broad-spectrum therapy. With further clinical trials and studies, future treatment of nosocomial and ventilator-associated pneumonia with doripenem seems quite promising.
References
- Clinical Pharmacology CD-ROM. Version 2.27. 2008. Gold Standard
- Zhanel GG, et al. Comparative review of the carbapenems. Drugs. 2007;67:1027-1052.
- Solomkin JS, et al. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005.
- Goldstein EJ. Intra-abdominal anaerobic infections: bacteriology and therapeutic potential of newer antimicrobial carbapenem, fluoroquinolone, and desfluoroquinolone therapeutic agents. Clin Infect Dis. 2002;35:S106-S111.
- Solomkin J, et al. Doripenem versus meropenem with an option for oral step-down therapy in the treatment of complicated intra-abdominal infections. Presented at: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, IL.
- Doripenem (Doribax) prescribing information. Raritan, NJ: Ortho-McNeil Pharmaceutical Inc.; October 2007.
- Wells WG, et al. Treatment of complicated urinary tract infection in adults: combined analysis of two randomized, double-blind, multicentre trials comparing ertapenem and ceftriaxone followed by appropriate oral therapy. J Antimicrob Chemother. 2004;53:ii67-ii74.
- Naber K, et al. Intravenous therapy with doripenem versus levofloxacin with an option for oral step-down therapy in the treatment of complicated urinary tract infections and pyelonephritis. Int J Antimicrob Agents. 2007;29:S212. Poster P833.
- Adapted from: Infect Med 16(8):533-540, 1999. © 1999 Cliggott Publishing, Division of SCP Communications http://www.medscape.com/viewarticle/417511_3
- European Antimicrobial Resistance Surveillance System, EARSS Annual Report 2005, October 2006. L.R. Peterson and G.A. Noskin, New Technology for Detecting Multidrug-Resistance Pathogens in the Clinical Microbiology Laboratory. Em. Infect. Dis. Vol. 7. No. 2, March-April 2001.
- Rea-Neto A, et al. Efficacy and safety of intravenous doripenem vs. piperacillin/tazobactam in nosocomial pneumonia. Presented at: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, IL.
- Chastre J, et al. Efficacy and safety of doripenem versus imipenem for ventilator-associated pneumonia. Presented at: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, IL.
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