Drug Criteria & Outcomes: Formulary evaluation of ertapenem among selected broad-spectrum antibiotics

By William T. Park, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University

Drugs

  • Ertapenem (Invanz)
  • Ampicillin/sulbactam (Unasyn)
  • Piperacillin/tazobactam (Zosyn)
  • Ticarcillin/clavulanate (Timentin)
  • Imipenem/cilastatin (Primaxin)
  • Cefotaxime (Claforan) + metronidazole (Flagyl)

Background

The broad-spectrum agents evaluated in this study, with the exception of metronidazole, belong to the general class of beta-lactams. By inhibiting the penicillin-binding proteins, these antibiotics interfere with cell wall synthesis, resulting in cell death. Ertapenem belongs to a subcategory of beta-lactams called the carbapenems. Imipenem also belongs to the carbapenems and is combined with cilastatin, which prevents renal metabolism of imipenem. In addition, the three penicillins in this evaluation are combined with additional agents called beta-lactamase inhibitors, which help further extend their spectrum of activity.

The third-generation cephalosporin in this review, cefotaxime, is combined with metronidazole, a nitroimidazole, which exerts its effect by interfering with the DNA of anaerobic pathogens.

Pharmacokinetics

Ertapenem has a long half-life and is the only antibiotic in this evaluation that is dosed once daily. Ertapenem is also the only antibiotic in this evaluation that is highly bound to human plasma proteins (85% to 95%). This could become an issue in conjunction with certain medications that are highly protein-bound or certain disease states that result in decreased plasma proteins (dehydration, burns, etc.). A higher-than-expected concentration of ertapenem could be observed in these situations.

Ertapenem is safe to use in pregnancy (see Table 1), and the significance of its distribution into breast milk is unknown. The majority of ertapenem is renally excreted, and dose adjustments are necessary for patients who have renal impairment.

Indications and antibacterial activity

Table 2, gives a summary of the in vitro activity of the selected antibiotics in this evaluation. Two notable differences between the antibiotics are Pseudomonas coverage and Enterococcus coverage. Ertapenem, like ampicillin and ceftriaxone+metronidazole, is not effective against Pseudomonas. Only ampicillin/sulbactam, piperacillin/tazobactam, and imipenem/cilastatin are effective against Enterococcus faecalis. Similar activity exists among the antibiotics in regards to gram-negative coverage. The anaerobic coverage is also generally similar with exception to C. difficile, which is not covered by ertapenem, piperacillin/tazobactam, and ticarcillin/clavulanate.

Table 3, compares the FDA-approved indications for the selected antibiotics. Along with ampicillin/sulbactam, ertapenem has the least number of FDA-approved indications. However, ertapenem’s indications are for complicated infections. Among lower respiratory infections, ertapenem is only indicated for community-acquired pneumonia. Indications selected for cefotaxime + metronidazole represent FDA-approved indications.

Contraindications/precautions

  • General

A contraindication that all antibiotics have in common is either known hypersensitivity to a particular antibiotic or known hypersensitivity to the specific class of which the antibiotic is a member. This is the only contraindication to the antibiotics in this evaluation, with the exception of metronidazole. An additional contraindication to metronidazole is use in the first trimester of pregnancy.

All beta-lactams have resulted in serious and occasionally fatal hypersensitivity reactions. The allergy history of patients should be taken into account when selecting a medication.

Pseudomembranous colitis has been reported with all of the antibiotics in this evaluation, with the exception of metronidazole. It is recommended that this diagnosis be considered in patients presenting with diarrhea after antibiotic use. Severity may range from mild to life-threatening, and appropriate therapy should be initiated if pseudomembranous colitis occurs.

Prolonged use of antibiotics also can result in superinfections. If overgrowth of nonsusceptible organisms results from antibiotic use, appropriate measures should be taken immediately.

  • Specific

Focal tremors, myoclonic activity, and seizures have been reported with use of ertapenem, imipenem/cilastatin, and metronidazole. The incidence of seizures for ertapenem and imipenem/cilastatin is less than 1%. An increased risk for these central nervous system disturbances is present for patients with impaired renal function and/or a seizure history. Dose adjustments are indicated in the case of impaired renal function. If seizure history is present, avoid ertapenem, metronidazole, and imipenem/cilastatin when possible.

Ampicillin/sulbactam should be avoided in patients with mononucleosis due to a higher reported incidence of rash in these patients. Ticarcillin/clavulanate can result in hypokalemia in patients with fluid electrolyte imbalances, and caution should be taken with these patients. A potentially life-threatening arrhythmia was reported in six patients who received a rapid (<60 seconds) bolus injection of cefotaxime. This adverse event occurred outside the labeled instructions for dosage and administration for cefotaxime.

Drug interactions

Ertapenem has the most favorable drug interaction profile of the antibiotics in this evaluation (see Table 4), but clinical experience with this drug is much more limited. An interaction with probenecid was shared by all of the antibiotics. The interaction between metronidazole and alcohol, including alcohol preparations, should always be considered when prescribing cefotaxime + metronidazole.

Clinical Data

1. Solomkin JS, Choc KA, Christou NV, et al. A prospective, randomized, blinded study of ertapenem vs. piperacillin/tazobactam for intraabdominal infection. Surg Infect 2001; 2(1):3.

Study purpose: To compare the efficacy of ertapenem and piperacillin/tazobactam in complicated intra-abdominal infections.

Study design: Randomized, triple-blind (sponsor-blinded), prospective trial.

Study patients and procedure:

  • 65 patients stratified based on primary diagnosis and disease severity.
  • Randomized to receive one of two regimens daily for five to 14 days:

— ertapenem, 1 g IV QD;

— piperacillin/tazobactam, 3.375 g IV q6h.

  • The two treatment groups were similar with respect to baseline characteristics.
  • Anatomic sites of infection included appendix, biliary-cholecystitis, colon, small bowel, and stomach/duodenum.
  • Infection processes included single or multiple abscesses, localized or generalized peritonitis, and perforated viscus.

Results:

  • Type of infections: 83% had facultative or aerobic gram-negative rods, 68% had anaerobic gram-negative rods, and 84% had polymicrobic infections.
  • Adverse event rates were similar between the two treatment groups.
  • At four to six weeks after intervention, the combined clinical and microbiologic success rates were 83.6% for ertapenem and 80.4% for piperacillin/tazobactam.

Conclusion: Ertapenem is efficacious in the treatment of a range of intra-abdominal infections and is generally well-tolerated.

2. Graham D, Lucasti C, Malafaia O, et al. A multicenter, randomized, double-blind study of ertapenem vs. piperacillin/tazobactam in complicated skin and skin structure infections. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago: Dec. 16, 2001; L-1483.

Study purpose: To evaluate the efficacy of ertapenem and piperacillin/tazobactam in complicated skin and structure infections.

Study design: Multicenter, randomized, double-blind.

Study patients and procedure:

  • 540 were randomized to receive on of the following regimens for seven to 14 days:

— ertapenem 1 g IV QD;

— piperacillin/tazobactam 3.375 g IV q6h;

  1. Patients were stratified into two groups based on disease severity.
  2. Baseline disease characteristics were similar between the two groups.
  3. Infections included lower-extremity infections, cutaneous abscess, deep soft-tissue abscess, perineal cellulitis/abscess, complicated cellulitis, post-traumatic wound infections, and surgical site infections.

Results:

  • Type of infection: 22% of the infections were severe, 33.5% of the infections had more than one baseline pathogen, and 39% of the polymicrobial infections included mixed aerobic and anaerobic pathogens.
  • The clinical success rates at 10-21 days after intervention were 83.9% for ertapenem and 85.3% for piperacillin/tazobactam.

Conclusion: Ertapenem has microbiological activity and clinical response rates comparable to piperacillin/tazobactam in the treatment of patients with polymicrobial wound infections.

3. Roy S, Higareda I, Angel-Muller E, et al. Results of a Phase III randomized, double-blind study of ertapenem vs. piperacillin/tazobactam for acute pelvic infection in women. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago: Dec. 16, 2001; 888.

Study purpose: To evaluate the efficacy of ertapenem in the treatment of acute pelvic infections.

Study design: Randomized, double-blind.

Study patients and procedure:

  • Two treatment groups were randomized to receive one of the following therapies:

— ertapenem 1 g IV QD;

— piperacillin/tazobactam 3.375 g IV q6h.

  • The two treatment groups were stratified into two groups based upon clinical diagnosis.
  • Patients with pelvic inflammatory disease, tubo-ovarian abscess, or postoperative abdominal wall infections were excluded.

Results:

  • A total of 316 patients were evaluated clinically at two to four weeks post-treatment.
  • The most common pathogens isolated were E. coli and anaerobes.
  • The most common infection was endomyometritis (75% of patients).
  • The clinical success rates for ertapenem and piperacillin/tazobactam were 93.9% and 91.5%, respectively.
  • Adverse drug events occurred in both groups at the same rate.

Conclusion: Ertapenem and piperacillin/ tazobactam have equal efficacy in the treatment of acute pelvic infections. Ertapenem was well-tolerated in this study.

CAP: Two randomized, double-blind, multicenter clinical trials evaluating ertapenem (1 g IV QD) and ceftriaxone (1 g IV QD) were conducted. A total of 866 patients were enrolled between the two trials. The two studies allowed for switch to an oral option of amoxicillin/clavulanate for a total of 10 to 14 days of treatment. The clinical success rates in the first study were 92.3% for ertapenem and 91.0% for ceftriaxone at seven to 14 days after therapy. The clinical success rates in the second trial were 91% for ertapenem and 91.8% for ceftriaxone at seven to 14 days after treatment.

Urinary tract infections (complicated): Two randomized, double-blind studies evaluating the efficacy of ertapenem in the treatment of complicated urinary tract infections have been conducted. The two treatment arms of both studies were ertapenem 1 g IV QD and ceftriaxone 1 g IV QD for a total of 10 to 14 days. A total of 850 patients were enrolled between the two studies. An optional switch to oral ciprofloxacin 500 mg BID was available. The microbiological success rates were 89.5% for ertapenem and 91.1% for ceftriaxone.

In summary, ertapenem compared favorably in efficacy and safety for the above indications with piperacillin/tazobactam and ceftriaxone +/- metronidazole. (See summary of ertapenem clinical studies in Table 5.) All trials were randomized, double-blind studies consisting of patients with similar baseline characteristics. A large number of patients were included in some of the trials, which helped to improve statistical analysis and reveal side effects. Certain trials only had abstracts available, and further evaluation of these trials would be optimal.

Adverse events

The adverse effects are summarized in Table 6. Caution must be taken when comparing the percentages of the adverse effects among the different antibiotics. Since clinical trials directly evaluating all the antibiotics are not available, the percentages cannot be directly compared. However, trials do exist evaluating ertapenem and piperacillin/tazobactam. Therefore, the percentages between these two antibiotics can be directly compared.

The types of adverse events are somewhat similar among the antibiotics. Diarrhea, nausea, and complications at injection site were the most common types of events reported.

Cost

The daily cost of ertapenem to Huntsville (AL) Hospital is $36.39. This is much less than the usual regimens of imipenem/cilastatin, piperacillin/ tazobactam, and ticarcillin/clavulanate. In cases where ertapenem could be used instead of the above three drugs, significant cost savings could be realized. With ampicillin/sulbactam and the cefotaxime/metronidazole combination, the cost differences compared to ertapenem are much less, and common daily regimens of both ampicillin/sulbactam and the cefotaxime/metronidazole combination may actually cost less than ertapenem. (See Table 7 and Table 8)

Summary and recommendations

When comparing ertapenem with the selected broad-spectrum antibiotics in this evaluation, both potential advantages and disadvantages of ertapenem are revealed. Once-daily dosing and relatively low cost are two attractive advantages of ertapenem. The coverage of the antibiotics varies. None of the antibiotics’ coverage includes MRSA. Ertapenem is limited in its coverage with respect to Pseudomonas aeruginosa, Enterococcus, or Clostridium difficile. Ertapenem’s indications are also more limited than the other antibiotics’ indications.

Because there is much variability among ertapenem and the other broad-spectrum agents, it is unlikely that ertapenem will replace any of the other antibiotics. Ertapenem is relatively new, and there is less clinical experience with it than with the other agents. Additional clinical trials, more resistance surveillance data, and further delineation of the drug safety profile are needed. However, a protocol could be developed that would utilize the advantages of ertapenem to benefit patients. Ticarcillin/clavulanate, piperacillin/tazobactam, and imipenem/cilastatin all have a higher cost per day than ertapenem. If ertapenem could be used in the place of these three antibiotics for infections with similar susceptibility in approved indications, then potential cost savings could occur.

Recommendations

A protocol should be developed that would allow ertapenem to be used in place of ticarcillin/clavulanate, piperacillin/tazobactam, or imipenem/cilastatin using the following criteria:

— Susceptibility of infection among the antibiotics is similar.

— Patient’s history does not contraindicate ertapenem’s use.

— Ertapenem use is projected to be equally safe as the medication for which it is substituted.

— Ertapenem usage offers cost reduction and/or convenience in administration.

Resources

  • Ampicillin/sulbactam (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.
  • Cefotaxime (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.
  • Ertapenem. In: Patient Package Insert. Whitehouse Station, NJ: Merck; 2001.
  • Gilbert DN, ed. The Sanford Guide to Antimicrobial Therapy 2001. Hyde Park, VT: Antimicrobial Therapy; 2001:52-5.
  • Hall C. Pharmacy buyer, Huntsville Hospital System Pharmacy. March 2002.
  • Imipenem/cilastatin (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.
  • Metronidazole (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.
  • Piperacillin/tazobactam (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.
  • Ticarcillin/clavulanate (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.

The following drugs recently received final approval from the Food and Drug Administration (FDA):

  • Tegaserod maleate (Zelnorm tablets) by Novartis Pharmaceuticals Corp. The FDA has approved tegaserod maleate (Zelnorm tablets) for short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation. This drug is the first medication approved for this treatment. The safety and effectiveness of tegaserod maleate in men have not been established.

Tegaserod maleate increases the movement of stools through the bowels. Tegaserod maleate does not cure IBS, nor does it treat diarrhea-predominant IBS. Zelnorm reduces pain and discomfort in the abdominal area, and reduces bloating and constipation. For more information about the approval, see www.fda.gov/bbs/topics/ANSWERS/2002/ANS01160.html.

  • Darbepoetin alfa (Aranesp) by Amgen. The FDA has approved darbepoetin alfa (Aranesp) for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies. Aranesp is a recombinant erythropoietic protein that requires fewer injections than existing treatment.
  • Levothyroxine sodium tablets, USP (Synthroid) by Abbott Laboratories. The FDA has approved the synthetic thyroid hormone replacement therapy, levothyroxine sodium tablets USP (Synthroid), for thyroid disease management, as replacement or supplemental therapy for hypothyroidism and pituitary thyroid stimulating hormone suppression.