Journal of Antimicrobial Chemotherapy

Solomkin, Joseph; Teppler, Hedy; Graham, Donald R.; Gesser, Richard M.; Meibohm, Anne R.; Roy, Subir; Woods, Gail L.

doi: 10.1093/jac/dkh206pmid: 15150183

The efficacy of ertapenem 1 g once a day for the treatment of polymicrobial complicated intra-abdominal, complicated skin/skin-structure and acute pelvic infections was compared with piperacillin–tazobactam 3.375 g every 6 h in a post hoc analysis of data from three large randomized double-blind trials. Of the 1558 treated patients in the three trials, no pathogen was identified in 345 (22.1%), 423 (27.2%) had a monomicrobial infection and 790 (50.7%) had a polymicrobial infection. At the test-of-cure assessment, there were no significant differences in outcome between the two treatment groups for any of the three infections. Cure rates (clinical and microbiological for intra-abdominal infection, clinical for skin/skin-structure and pelvic infections) in microbiologically evaluable patients for ertapenem and piperacillin–tazobactam, respectively, were 85.6% (154/180 evaluable patients) and 82.5% (127/154) for polymicrobial intra-abdominal infection, 80.3% (53/66) and 78.7% (48/61) for polymicrobial skin/skin-structure infection, and 95.7% (88/92) and 92.6% (88/95) for polymicrobial pelvic infection. Respective cure rates for all evaluable patients in the original trials were: 83.6% and 80.4% for intra-abdominal, 83.9% and 85.3% for skin/skin-structure, and 93.9% and 91.5% for pelvic infections. These data show that in the three trials, ertapenem 1 g once a day was highly effective for the treatment of polymicrobial infections and as effective as piperacillin–tazobactam 3.375 g every 6 h.

Ortiz-Ruiz, Guillermo; Vetter, Norbert; Isaacs, Robin; Carides, Alexandra; Woods, Gail L.; Friedland, Ian

doi: 10.1093/jac/dkh207pmid: 15150184

The efficacy and safety of ertapenem, 1 g once a day, for the treatment of community-acquired pneumonia (CAP) requiring parenteral therapy were compared with those of ceftriaxone, 1 g once a day, in 866 hospitalized adults randomized in two prospective, double-blind, multicentre studies. Patients were stratified according to Pneumonia Severity Index (≤3 or >3) or age (≤65 or >65 years). After ≥3 days of parenteral antimicrobial therapy, patients who had clinically improved could be switched to oral co-amoxiclav. The median durations of parenteral, oral and total therapy in the 658 clinically evaluable patients, of whom 88% were switched to oral therapy, were 4, 7 and 12 days, respectively, in both treatment groups. The most common pathogen was Streptococcus pneumoniae, of which 79% (143/181) were penicillin susceptible and 3.3% (6/181; three in each treatment group) were penicillin resistant. Cure rates for the two treatments were equivalent: 91.9% for ertapenem and 92.0% for ceftriaxone (95% confidence interval for the difference, adjusted for strata: –4.5 to 4.4). Cure rates in the different severity and age strata and bacterial eradication rates for both treatment groups were also similar. The most common drug-related adverse events in both treatment groups were diarrhoea and mild-to-moderate elevations in aminotransferase levels. The results of these studies demonstrate that ertapenem, 1 g once a day, was highly effective therapy for CAP in hospitalized adults with moderate-to-severe disease.

Teppler, Hedy; Gesser, Richard M.; Friedland, Ian R.; Woods, Gail L.; Meibohm, Anne; Herman, Gary; Mistry, Goutam; Isaacs, Robin

doi: 10.1093/jac/dkh209pmid: 15150186

Ertapenem is a Group 1 carbapenem that was licensed in the USA in November 2001 and in Europe in April 2002. Its safety profile has been assessed in 240 healthy volunteers participating in 12 clinical pharmacology studies and in 2046 patients enrolled in five Phase IIa and eight Phase IIb/III clinical trials. The most common drug-related adverse events (AEs) reported in trials comparing ertapenem and piperacillin–tazobactam and in trials comparing ertapenem and ceftriaxone were: diarrhoea (ertapenem versus piperacillin–tazobactam 5.0% versus 7.0%; ertapenem versus ceftriaxone 5.6% versus 5.9%); infused vein complications (ertapenem versus piperacillin–tazobactam 4.5% versus 7.9%; ertapenem versus ceftriaxone 3.2% versus 4.6%); nausea (ertapenem versus piperacillin–tazobactam 2.5% versus 3.4%; ertapenem versus ceftriaxone 3.4% versus 3.3%); and elevations in alanine aminotransferase levels (ertapenem versus piperacillin–tazobactam 8.8% versus 7.3%; ertapenem versus ceftriaxone 8.3% versus 6.9%). Most ertapenem-related AEs were reported as mild-to-moderate in intensity. Ertapenem was not associated with prolongation of the QTc interval. Local reactions of moderate-to-severe intensity at the infusion site were infrequent and occurred with similar frequency in the ertapenem and comparator treatment groups. No overall differences in safety were observed between elderly (aged ≥65 years and ≥75 years) and younger patients. Ertapenem, 1 g once a day given by intravenous infusion or intramuscular injection, was generally well tolerated and had overall safety and tolerability profiles similar to those of piperacillin–tazobactam and ceftriaxone.

Goldstein, Ellie J. C.; Snydman, David R.

doi: 10.1093/jac/dkh201pmid: 15150181

Complicated intra-abdominal infections require a combination of surgery/drainage and antimicrobial therapy that is active against both the aerobic and the anaerobic bacteria that comprise the intestinal flora. Ertapenem, a parenteral carbapenem, is highly resistant to a wide variety of β-lactamase enzymes, and has a broad spectrum of activity against bacteria associated with community-acquired infections including those of complicated intra-abdominal conditions. This article reviews the bacteriology of complicated intra-abdominal infections, their antimicrobial susceptibility, especially to anaerobes, the utility of animal models in these mixed infections, and the supportive clinical trials and in vitro susceptibility data that show ertapenem to be generally well tolerated and as effective as either piperacillin–tazobactam or ceftriaxone plus metronidazole in the therapy of complicated intra-abdominal infections.

Wells, Wilbur G.; Woods, Gail L.; Jiang, Qi; Gesser, Richard M.

doi: 10.1093/jac/dkh208pmid: 15150185

The efficacy and safety of parenteral ertapenem, a Group 1 carbapenem, 1 g once a day, for the treatment of complicated urinary tract infections (UTIs; i.e. acute pyelonephritis, UTI in men, or UTI associated with obstruction, foreign body or a urological abnormality interfering with normal voiding) in adults, were compared with those of parenteral ceftriaxone, 1 g once a day, in two similarly designed prospective, double-blind, randomized studies. In both studies, patients could be switched to an oral agent after ≥3 days of parenteral study therapy. At entry, 850 patients were stratified according to whether they had acute pyelonephritis or other complicated UTI without acute pyelonephritis. Two hundred and fifty-six patients in the ertapenem group and 224 in the ceftriaxone group were microbiologically evaluable. Ninety-six per cent of these patients were switched to oral therapy, usually ciprofloxacin; the median (range) duration of parenteral and total therapy, respectively, was 4 (2–14) days and 13 (14–18) days for ertapenem and 4 (2–14) days and 13 (3–17) days for ceftriaxone. The most common pathogens were Escherichia coli and Klebsiella pneumoniae, which accounted for 64.7% and 9.8% of isolates, respectively. At the primary efficacy endpoint 5–9 days after treatment, 229 (89.5%) patients who received ertapenem and 204 (91.1%) patients who received ceftriaxone had a favourable microbiological response (95% confidence interval, –7.4 to 4.0), indicating that outcomes in the two treatment groups were equivalent. Success rates in both treatment groups were similar when compared by stratum and severity of infection. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. In this combined analysis, ertapenem was highly effective therapy for the treatment of complicated UTIs in adults with moderate-to-severe disease.

Reeves, David; Symonds, Jane; Wilson, Peter

doi: 10.1093/jac/dkh238pmid: N/A

Hammond, Milton L.

doi: 10.1093/jac/dkh203pmid: 15150178

Ertapenem, a Group 1 carbapenem, is the most recent β-lactam antibiotic to enter clinical practice in the USA and Europe. While structurally a carbapenem, the overall molecular structure of ertapenem has been modified to focus its antibacterial spectrum on important community-acquired aerobic and anaerobic pathogens, and to increase its plasma half-life, permitting once-a-day dosing for this parenteral antibiotic. A number of chemical features are responsible for the unique properties of ertapenem. The inclusion of a trans-1-hydroxyethyl group in the structure of ertapenem enables the drug to maintain antibacterial efficacy against the vast majority of β-lactamase-producing organisms. A critical 1β-methyl substituent shields the β-lactam carbonyl group and serves to reduce dehydropeptidase (DHP)-1 catalysed hydrolysis of the β-lactam, enabling ertapenem to be administered without a DHP-1 inhibitor. A meta-substituted benzoic acid substituent increases the molecular weight and lipophilicity of the molecule, and the carboxylic acid moiety, ionized at physiological pH, results in ertapenem having a net negative charge. As a result, ertapenem is highly protein bound and has an extended half-life, permitting a once-a-day treatment regimen.

Wexler, Hannah M.

doi: 10.1093/jac/dkh204pmid: 15150179

Ertapenem is a long-acting, 1β-methyl parenteral Group 1 carbapenem antibiotic that has a broad antibacterial spectrum and once-a-day dosing supported by clinical studies. Ertapenem is active against both Gram-positive and Gram-negative bacteria, including Enterobacteriaceae, Streptococcus pneumoniae and most species of anaerobic bacteria. Isolates from a variety of infections (intra-abdominal infections, skin/soft-tissue infections, community-acquired pneumonia, pelvic infections and urinary tract infections) are inhibited by ertapenem. It has restricted activity against nosocomial pathogens such as Pseudomonas aeruginosa, Acinetobacter species, methicillin-resistant staphylococci and enterococci. Ertapenem has potent activity against the majority of anaerobic isolates from intra-abdominal infections, and against most of the aerobes isolated from these infections, with the exceptions of the nosocomial pathogens mentioned above. MIC90s for most species of Enterobacteriaceae were <1 mg/L, significantly lower than those of imipenem. MIC90s for most Bacteroides fragilis group isolates ranged from 1 to 4 mg/L, and MIC90s were species specific for Clostridium, ranging from 0.06 mg/L for Clostridium perfringens to 4 mg/L for Clostridium clostridioforme. Ertapenem was equivalent to or better than piperacillin–tazobactam in activity against most anaerobic species isolated from these infections, and was more potent than piperacillin–tazobactam and ceftriaxone against the most common skin pathogens (e.g. methicillin-susceptible Staphylococcus aureus). Ertapenem was highly active against most of the pathogens isolated from patients with community-acquired pneumonia, except for isolates of methicillin-resistant S. aureus (which are infrequent causes of community-acquired infection); these isolates were also resistant to ceftriaxone. Resistance to ertapenem is most commonly attributable to a variety of mechanisms including alterations in penicillin-binding proteins in Gram-positive organisms, and combinations of potent metallo-β-lactamase enzymes, porin protein defects and efflux pumps in Gram-negative organisms.

Nix, David E.; Majumdar, Anup K.; DiNubile, Mark J.

doi: 10.1093/jac/dkh205pmid: 15150180

Ertapenem, a Group 1 carbapenem, is a once-a-day parenteral β-lactam antibiotic recently licensed in the USA and Europe. Monotherapy with ertapenem dosed as 1 g once a day has been shown to be highly effective in clinical trials for the treatment of complicated infections of skin and skin structures, complicated intra-abdominal infections, community-acquired pneumonia, acute pelvic infections and complicated urinary tract infections. Dosing modifications have not been recommended for adults on the basis of gender, age, weight or liver disease. Presently there are no data regarding the use of ertapenem in children. Dose reductions are indicated for patients with advanced renal insufficiency. Ertapenem is neither a substrate nor an inhibitor of P-glycoprotein or cytochrome P450 enzymes; significant drug interactions between ertapenem and drugs handled by these systems are not expected.

DiNubile, Mark J.; Lipsky, Benjamin A.

doi: 10.1093/jac/dkh202pmid: 15150182

Skin and skin-structure infections are common, and range from minor pyodermas to severe necrotizing infections. Complicated infections are defined as involving abnormal skin or wounds, occurring in compromised hosts, or requiring surgical intervention. Classification schemes for these infections are varied and confusing. Distinguishing characteristics include the aetiological agent(s), clinical context and findings, depth of tissue involvement and rate of progression. The most common pathogens are aerobic Gram-positive cocci, but complicated infections frequently involve Gram-negative bacilli and anaerobic bacteria. Initial antibiotic therapy is usually empirical, and later modified by the results of stains and cultures of wound specimens. Broad-spectrum coverage is frequently needed for complicated infections. Ertapenem is a once-a-day parenteral Group 1 carbapenem antibiotic, recently licensed in the USA and Europe, which may assume an important role in treating some complicated skin and skin-structure infections. Surgical debridement is important for many complicated infections, and is the critical element in managing necrotizing fasciitis and myonecrosis.