Ertapenem

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Abstract
The Group 1, 1β-methyl carbapenem ertapenem (Invanz®) is approved for parenteral use in patients with complicated intra-abdominal infection (cIAI), community-acquired pneumonia (CAP) and acute pelvic infection caused by susceptible strains of certain designated organisms in both the US and the EU. Additional approved indications in the US include complicated skin and skin structure infection (cSSSI) and complicated urinary tract infection (cUTI). Ertapenem is approved for use in adults in both the US and the EU and in paediatric patients aged ≥3 months in the US. Ertapenem has a broad spectrum of in vitro activity against Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae, Gram-positive pathogens and anaerobic pathogens. It has similar efficacy to comparator antibacterials such as piperacillin/tazobactam in cSSSI (including diabetic foot infection), cIAI and acute pelvic infection and ceftriaxone with or without metronidazole in cIAI, cUTI and CAP. The drug has also shown efficacy in the treatment of paediatric patients with complicated community-acquired bacterial infections. Ertapenem has a convenient once-daily administration schedule and is generally well tolerated. Thus, ertapenem is an important option for the empirical treatment of complicated community-acquired bacterial infections in hospitalised patients. Ertapenem demonstrated good in vitro activity against clinically relevant Enterobacteriaceae (e.g. Escherichia coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., Morganella morganii, Proteus spp. and Serratia marcescens); the minimum concentration inhibiting 90% of strains (MIC90) was generally ≤1 mg/L and susceptibility rates, where reported, were 100%. Ertapenem was active against ESBL- and AmpC-producing Enterobacteriaceae, although MIC90 values for these strains were raised. Ertapenem was also active against Haemophilus influenzae and Moraxella catarrhalis, although it had poor activity against Pseudomonas aeruginosa and Acinetobacter spp. Ertapenem had good in vitro activity against the Gram-positive pathogens Staphylococcus aureus (methicillin/oxacillin-susceptible isolates), coagulase-negative staphylococci (oxacillin-susceptible isolates), Streptococcus pneumoniae (penicillin-susceptible and -intermediate isolates), S. agalactiae and S. pyogenes, with MIC90 values of ≤0.5 mg/L and susceptibility rates, where reported, of 100%. Ertapenem lacked activity against methicillin/oxacillin-resistant staphylococci, Enterococcus faecalis and E. faecium. Ertapenem had good in vitro activity against a wide range of anaerobes, including the Bacteroides fragilis group of pathogens, Clostridium clostridioforme, C. perfringens, Eubacterium lentum, Fusobacterium spp., Peptostreptococcus spp., Porphyromonas spp. and Prevotella spp., with MIC90 values of ≤4 mg/L and, where reported, susceptibility rates of 97–100%. The ertapenem MIC90 for various pathogens remained below the mean total ertapenem plasma concentration for 24 hours and below the mean unbound ertapenem plasma concentration for ≥8 hours after a single intravenous 1g dose. Ertapenem had rapid, time-dependent bactericidal activity and a minimal inoculum effect. Ertapenem is generally stable against hydrolysis by various β-lactamases, such as penicillinases, cephalosporinases and ESBLs, although it may be affected by carbapenemases. However, it is thought that additional factors besides the presence of carbapenemases, such as impermeability, are needed for substantive carbapenem resistance to develop. It is thought unlikely that ertapenem will select for P. aeruginosa isolates with cross resistance to other carbapenems in the clinical setting. The frequency of bowel colonisation with ertapenem-resistant Enterobacteriaceae was not increased with ertapenem therapy in three clinical studies in patients with cIAI. No accumulation of ertapenem was seen at steady state following intravenous or intramuscular administration; the mean bioavailability of the drug following intramuscular administration is ≈90%. Ertapenem is highly plasma protein bound in a nonlinear concentration-dependent manner, and achieves good penetration into lung tissue and skin blister fluid following intravenous administration. The main route of elimination for ertapenem is renal and the pharmacokinetics of the drug are altered to a clinically significant extent in patients with advanced or end-stage renal impairment. The plasma elimination half-life of ertapenem (≈4 hours) allows for once-daily dosing. The efficacy of ertapenem in adults with complicated bacterial infections has been examined in large well designed trials. The efficacy of ertapenem was equivalent to that of piperacillin/tazobactam in the treatment of cSSSI with clinical cure rates of 82% and 84% in the respective treatment groups at the test-of-cure (TOC) visit. In addition, ertapenem had similar efficacy to piperacillin/tazobactam in diabetic foot infection, with favourable clinical response rates of 94% and 92% in the respective treatment groups at the discontinuation of intravenous therapy. Ertapenem had similar efficacy to piperacillin/tazobactam in three trials in patients with cIAI with clinical cure rates of 82–94% and 82–93% and combined clinical and microbiological cure rates of 87% and 81% in the corresponding treatment groups at the TOC visit. Combined clinical and microbiological cure rates of 84% and 85% were reported in ertapenem and ceftriaxone plus metronidazole recipients in a fourth trial. The efficacy of ertapenem was equivalent to that of ceftriaxone in two trials in patients with cUTI with microbiological...