Pharmacology Update: A Novel Once-a-Day Carbapenem
A Novel Once-a-Day Carbapenem
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Merck has received FDA approval for ertapenem (InvanzTM), a once-daily parenteral carbapenem. It has a broad spectrum of activity as shown in Table 1. Its spectrum is similiar to that of imipenem, but with lesser activity against Pseudomonas aeruginosa. In clinical studies, it has been evaluated against ceftriaxone (RocefinTM) and piperacillin/tazobactam (ZosynTM) and has shown comparable efficacy and side-effect profiles.
Clinical Studies
In complicated intra-abdominal infections, ertapenem (1 g IV every 24 hours) was compared to piperacillin/ tazobactam (3.375 g IV every 6 hours) for 5-14 days. A total of 665 patients were enrolled and the combined clinical and microbiologic success rates in the microbiologically evaluable population at 4-6 weeks post-therapy were 83.6% (163/195) for ertapenem and 80.4% (152/189) for piperacillin/tazobactam.
In complicated skin and skin structure infections, ertapenem (1 g IV every 24 hours) was compared to piperacillin/tazobactam (3.375 g IV every 6 hours) for 7-14 days. A total of 540 patients were enrolled and the clinical success rates at 10-21 days post-therapy were 83.9% (141/168) for ertapenem and 85.3% (145/170) for piperacillin/tazobactam.
In community-acquired pneumonia, 2 studies were performed, comparing ertapenem (1 g IV every 24 hours) to ceftriaxone (1 g IV every 24 hours). A total of 866 patients were enrolled and both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of 10-14 days of combined IV and oral treatment. In the first study, success rates at 7-14 days post-therapy were 92.3% (168/182) for ertapenem and 91.0% (183/201) for ceftriaxone. In the second study, the success rates at 7-14 days post-therapy were 91% (91/100) for ertapenem and 91.8% (45/49) for ceftriaxone.
In complicated urinary tract infections including pyelonephritis, 2 studies were performed, comparing ertapenem (1 g IV every 24 hours) to ceftriaxone (1 g IV every 24 hours). A total of 850 patients were enrolled and both regimens allowed the option to switch to oral ciprofloxacin (500 mg twice daily) for a total of 10-14 days of combined IV and oral treatment. The microbiological success rates of the combined studies at 5-9 days post-therapy were 89.5% (229/256) for ertapenem and 91.1% (204/224) for ceftriaxone.
In acute pelvic infections, ertapenem (1 g IV every 24 hours) was compared to piperacillin/tazobactam (3.375 g IV every 6 hours) for 3-10 days. A total of 412 patients, including 250 patients with obstetric/postpartum infections and 45 patients with septic abortion, were enrolled and the clinical success rates at 2-4 weeks posttherapy were 93.9% (153/163) for ertapenem and 91.5% (140/153) for piperacillin/tazobactam.
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Based upon pharmacokinetic and preclinical studies, ertapenem can be dosed once daily due to its half-life of 4 hours and plasma clearance of 1.8 L/h. Recommended dosing of ertapenem is 1 gram daily for up to 14 days intravenously or 7 days intramuscularly. Ertapenem is eliminated primarily by the kidneys with 80% recovered in urine (38% unchanged and 37% as ring-opened metabolite) and 10% in feces. Therefore, dosage adjustments are only necessary in renal impairment when the CLCR is < 30 mL/min/1.73m2. In those patients, the dosage should be 0.5 grams every 24 hours. Also, since 30% of ertapenem is removed during hemodialysis, a supplemental dose of 150 mg is recommended if ertapenem is administered within 6 hours prior to hemodialysis.
Precautions
Ertapenem has not been thoroughly tested in pregnant women or pediatric patients and is, therefore, not recommended for them. Because ertapenem is excreted in breast milk, the normal benefit/risk ratio must be taken into consideration before prescribing in women who are breast-feeding.
Preparation and Administration
Ertapenem can be given as a 30-minute intravenous infusion in normal saline (incompatible with dextrose solutions) or injected intramuscularly after reconstitution with 1% lidocaine for injection. Stability of the intravenous solution is similar to other carbapenems—6 hours at room temperature or 24 hours refrigerated. It is recommended that intramuscular solutions be used within 1 hour after preparation.
FDA-Approved Indications
Ertapenem is indicated for the treatment of adult patients with the following moderate-to-severe infections caused by susceptible strains of the designated microorganisms:
• Complicated intra-abdominal infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis;
• Complicated skin and skin structure infections due to Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pyogenes, E coli, or Peptostreptococcus spp.;
• Community-acquired pneumonia due to Streptococcus pneumoniae (penicillin-susceptible strains only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative strains only), or Moraxella catarrhalis;
• Complicated urinary tract infections including pyelonephritis due to E coli including cases with concurrent bacteremia, or Klebsiella pneumoniae;
• Acute pelvic infections including postpartum endomyometritis, septic abortion, and postsurgical gynecologic infections due to Streptococcus agalactiae, E coli, B fragilis, Porphyromonas asaccharolytica, Peptostreptococcus spp., or Prevotalla bivia.
Comment by Thomas G. Schleis, MS, RPh
We have been involved in a number of clinical studies with ertapenem and our experience has been favorable. Side effects were minimal and similar to the comparator drugs. Efficacy, as summarized above, paralleled our clinical experience. One caution is that, while compared to ceftriaxone in some studies, ertapenem is broader spectrum and may not be appropriate in all indications where ceftriaxone is used. Additionally, whether wide use of ertapenem may result in the development of resistant strains of bacteria has not been fully evaluated. As with any new antimicrobial, the development of resistant bacterial strains will need to be closely monitored. Also, as we have seen in the past, unforeseen side effects may be revealed after large numbers of patients are treated. This will also have to be watched carefully after ertapenem becomes available.
Despite the obvious concerns with any new antimicrobial, ertapenem gives us another once-daily antibiotic that will be extremely useful in the outpatient setting. Pricing has not been set yet, but one would expect it to be comparable to the comparator drugs. According to Merck, the drug will be available the first quarter of 2002.
Dr. Schleis, Director of Pharmacy Services, Infections Limited, Tacoma, WA, is Associate Editor of Infectious Disease Alert.
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