Summary
Abstract
Ertapenem, a carbapenem antibacterial, has in vitro activity against many Gramnegative (including Enterobacteriaceae) and Gram-positive aerobic and anaerobic bacteria that are commonly associated with various infections.
Once-daily parenteral (intravenous or intramuscular) ertapenem 1g was as effective as comparator antimicrobial agents (piperacillin/tazobactam or ceftriax-one ± metronidazole) in patients with bacterial infections in randomised, double-blind, multicentre clinical trials. Response rates with ertapenem were 84% and 87% (combined microbiological and clinical) in patients with complicated intra-abdominal infections (CIAI), 82% (clinical) in patients with complicated skin and skin structure infections (CSSSI), 86% and 92% (microbiological) in patients with complicated urinary tract infections (CUTI), 92% (clinical) in patients with community-acquired pneumonia (CAP) associated with typical pathogens and 94% (clinical) in patients with acute pelvic infection. Respective response rates were statistically equivalent to those with comparators (81–94%). The efficacy of ertapenem was equivalent to that of piperacillin/tazobactam in patients infected with Enterobacteriaceae or anaerobes and to ceftriaxone in patients infected with Enterobacteriaceae.
Ertapenem was generally well tolerated by patients with bacterial infections, with most adverse events being mild to moderate in severity. The most common ertapenem-associated adverse events were diarrhoea, infused vein complication, nausea, headache, vaginitis in females, phlebitis and/or thrombophlebitis and vomiting.
Conclusion: Ertapenem is a broad-spectrum parenteral antibiotic with activity against many Gram-negative (including Enterobacteriaceae) and Gram-positive aerobic and anaerobic bacteria and is suitable for once-daily administration. Ertapenem has a role in the treatment of CAP associated with typical respiratory pathogens and is of particular value in the treatment of polymicrobial infections (such as CIAI, CSSSI, CUTI and acute pelvic infections), especially where Enterobacteriaceae and anaerobic bacteria are involved.
Antibacterial Activity
Ertapenem is active against many Enterobacteriaceae (including extended-spectrum and AmpC β-lactamase-producing isolates), common Gram-negative respiratory tract pathogens (including Moraxella catarrhalis and Haemophilus influenzae), but has negligible activity against nonfermenting aerobes (e.g. Pseudomonas aeruginosa and Acinetobacter baumanni).
Ertapenem is active against most Gram-positive bacteria (including penicillin-susceptible and -resistant Streptococcus pneumoniae and methicillin/oxacillin-susceptible Staphylococcus aureus), but not Enterococcus spp. (E. faecalis and E. faecium) and methicillin/oxacillin-resistant S. aureus.
Ertapenem is active against a wide range of clinical isolates of Gram-negative (Bacteroides spp., Prevotella spp., and Porphyromonas spp., including β-lactamase-producing strains) and Gram-positive (e.g. Peptostreptococcus spp. and Clostridium spp.) anaerobes. However, ertapenem has limited activity against Lactobacillus spp. and varying activity against Bilophila wadsworthia.
Ertapenem shows a positive post-antibiotic effect (PAE) against Gram-positive isolates (S. pneumoniae, S. aureus), but limited (E. cloacae), none (H. influenzae) or negative (Escherichia coli) PAE against Gram-negative isolates.
Ertapenem is bactericidal against many common pathogens; the antibacterial activity of ertapenem is time-dependent.
Ertapenem is stable to most of the β-lactamases produced by Gram-negative bacteria; however, ertapenem is susceptible to the metallo-β-lactamases produced by some Enterobacteriaceae. Alterations in penicillin binding protein account for the resistance of methicillin/oxacillin-resistant Staphylococcus spp. and Enterococcus spp. to ertapenem. Reduced permeability as a result of porin deficiency may have contributed to resistance in a K. pneumoniae isolate.
Pharmacokinetic Properties
After administration of a single dose of ertapenem 1g, mean maximum total plasma concentrations were 164.6 mg/L at the end of a 30-minute intravenous (IV) infusion and 70.6 mg/L after a single intramuscular (IM) injection; mean area under the plasma concentration time curve (AUC) were 597.4 (IV) and 524.9 (IM) mg · h/L. Following IM administration of ertapenem 1 g/day, maximum drug plasma concentration was reached after 2 hours.
Plasma protein binding is approximately 95% for plasma concentrations <100 mg/L and approximately 82–85% for concentrations of ≈300 mg/L. Mean volume of distribution at steady state is approximately 8L.
Ertapenem exhibits good skin-blister fluid penetration. After multiple doses of ertapenem 1 g/day, the mean ratio of AUC for ertapenem in blister fluid to AUC in plasma was 0.61.
The major metabolite of ertapenem is a ring-opened derivative formed by hydrolysis of the β-lactam ring.
Ertapenem is primarily eliminated by the kidneys. The mean plasma elimination half-life (t1/2) of a single dose of IV or IM ertapenem 1g was ≈4 hours. The mean apparent plasma clearance of a single 30-minute infusion of ertapenem 1g was 1.7 L/h (28 mL/min).
The AUC and t1/2 of ertapenem in patients with renal impairment were increased compared with those of healthy volunteers. For patients with impaired renal function given a single 1g dose of ertapenem, t1/2 values were 4–14 hours and AUC values increased by 7–192% depending on the extent of renal impairment.
Therapeutic Efficacy
In patients with complicated intra-abdominal infections (CIAI), complicated skin and skin structure infections (CSSSI), complicated urinary tract infection (CUTI), community-acquired pneumonia (CAP) and acute pelvic infections, parenteral ertapenem 1 g/day was as effective as parenteral administration of comparator antimicrobial agents (piperacillin/tazobactam 3.375g every 6 hours, ceftriaxone 1 g/day, ceftriaxone 2 g/day plus metronidazole 500mg every 8 hours) in randomised, double-blind, multicentre clinical trials. The duration of treatment (parenteral plus optional oral therapy, if permitted) was generally 3–14 days for CIAI, 7–14 days for CSSSI, 10–14 days for CUTI and CAP and 2–12 days for acute pelvic infections.
In microbiologically evaluable patients with CIAI, 84% and 87% of ertapenem, 81% of piperacillin/tazobactam and 85% of ceftriaxone plus metronidazole recipients achieved favourable combined clinical and microbiological responses at the test of cure (TOC) visit (28–42 days after completion of therapy); statistical equivalence between ertapenem and the comparator treatment was established.
In patients with CSSSI, treatment with ertapenem or piperacillin/tazobactam resulted in statistically equivalent clinical response (82% and 84% ) and microbiological response (both 83%) rates at the time of TOC (10–21 days after completion of therapy) in a well designed trial. Clinical response rates were similar in patients with different types or severities of infection.
In patients with CUTI, the microbiological response rates were statistically equivalent in parenteral ertapenem (86% and 92%) and parenteral ceftriaxone (85% and 93%) recipients in a two well designed study at TOC assessment (5–9 days after completion of therapy).
Clinical and microbiological response rates were high (>90%) and statistically equivalent in ertapenem and ceftriaxone recipients in two well designed trials in patients with CAP at TOC (7–14 days after completion of therapy). S. pneumoniae, M. catarrhalis, H. influenzae and S. aureus were the most commonly isolated pathogens. In microbiologically evaluable patients infected with S. pneumoniae (the most common pathogen), similar clinical and microbiological response rates occurred with ertapenem for both penicillin-susceptible and penicillin-nonsusceptible infections.
In women with acute pelvic infections (obstetric and gynaecological postoperative infections), clinical responses rates at TOC (14–28 days after completion of therapy) were 94% with ertapenem and 92% with piperacillin/tazobactam in clinically evaluable patients in a well designed study. Statistical equivalence between the groups was established.
In a combined subgroup analysis of 1167 patients with infections caused by Enterobacteriaceae from seven randomised, double-blind trials, ertapenem was as effective as piperacillin/tazobactam (CIAI, CSSSI and acute pelvic infection) or ceftriaxone (CUTI and CAP). Similarly, in a combined subgroup analysis of 296 evaluable patients with infections involving anaerobic bacteria from three randomised, double-blind trials (CIAI, CSSSI and acute pelvic infections), ertapenem was as effective as piperacillin/tazobactam (overall response rates 89.3% vs 85.9%).
Tolerability
Most adverse events associated with parenteral ertapenem 1 g/day in patients with bacterial infections were mild to moderate in severity. In a pooled analysis of clinical trials, discontinuation due to adverse experiences occurred in 1.3% of ertapenem recipients. The most common ertapenem-associated adverse events during therapy plus the 14-day follow-up period were diarrhoea (5%), infused vein complication (5%) and nausea (3%). The incidence of adverse experiences was similar in recipients of ertapenem and its comparator (piperacillin/tazobactam or ceftriaxone). scizure was reported in 0.5% of ertapenem recipients, 0.3% in piperacillin/tazobactam recipients and in none of the ceftriaxone recipients. Drug-related laboratory adverse events included increases in alanine transferase (5%), aspartate transferase (5%), serum alkaline phosphatase (4%) and platelet count (3%).
Dosage and Administration
In the US, ertapenem is indicated for the treatment of adult patients with CIAI, CSSSI, CAP, CUTI and acute pelvic infections (including postpartum endomyometritis, septic abortion and post surgical gynaecological infections) caused by susceptible strains of causative organisms.
In Europe, ertapenem is indicated for CIAI, CAP and acute gynaecological infections, caused by susceptible strains of causative organisms.
Ertapenem 1g is administered once daily by intravenous infusion (over 30 minutes) for up to 14 days, or by intramuscular injection for up to 7 days (in patients for which intramuscular therapy is appropriate). When clinically indicated, a switch to an appropriate oral antibacterial agent may be implemented if clinical improvement has occurred.
Patients with advanced renal impairment and end-stage renal insufficiency should receive reduced ertapenem dosages.
No dosage adjustment recommendations have been made based on age or gender or for patients with impaired hepatic function.