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PubMed2004

Safety and tolerability of ertapenem.

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 > or = 65 years and > or = 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.

Adult↗

PubMed2002

A prospective, randomized, double-blind multicenter comparison of parenteral ertapenem and ceftriaxone for the treatment of hospitalized adults with community-acquired pneumonia.

BACKGROUND: Ertapenem is a once-daily parenteral beta-lactam licensed in the United States in November 2001 and in Europe in May 2002. OBJECTIVE: This study compared the efficacy and safety profiles of ertapenem with those of ceftriaxone for the treatment of hospitalized adult patients with serious community-acquired pneumonia (CAP) requiring parenteral therapy. METHODS: In this prospective, double-blind (with sponsor blinding), multicenter study, adult patients with CAP were stratified by Pneumonia Severity Index (< or = 3 or > 3) and age (< or = 65 or > 65 years) and randomized (2:1) to receive IV or intramuscular (IM) ertapenem 1 g once daily or IV or IM ceftriaxone 1 g once daily. Investigators could switch patients to an oral antimicrobial agent if clinical improvement was shown after at least 3 days of parenteral therapy. RESULTS: A total of 364 patients were randomized to treatment: 239 to the ertapenem group and 125 to the ceftriaxone group. Three patients in the ertapenem group and 2 in the ceftriaxone group did not receive study therapy. Of the treated patients, 77.1% (182/236) of patients in the ertapenem group and 75.6% (93/123) in the ceftriaxone group were clinically evaluable. Among clinically evaluable patients, the mean (SD) durations of parenteral and total (parenteral plus optional oral) therapy were 5.5 (2.6) and 11.5 (2.7) days for ertapenem and 5.6 (2.8) and 11.7 (3.0) days for ceftriaxone, respectively. Streptococcus pneumoniae was the most frequently isolated pathogen in both treatment groups. Cure rates were 92.2% for clinically evaluable patients in the ertapenem group and 93.6% for those in the ceftriaxone group (95% CI for the difference, adjusted for stratum, -8.6 to 5.7), fulfilling the criteria for statistical equivalence. At completion of parenteral therapy, 94.7% of patients in the ertapenem group and 95.8% in the ceftriaxone group showed clinical improvement. Infused vein complications (ertapenem, 3.4% [8/236]; ceftriaxone, 7.3% [9/123]) and elevated transaminase levels (ertapenem, 6.3% [13/207]; ceftriaxone, 7.1% [8/113]) were the most common adverse events in both groups. CONCLUSIONS: In this study of hospitalized adult patients, ertapenem therapy, with an oral switch option, was as effective as ceftriaxone with the same oral switch option for treatment of CAP requiring initial parenteral therapy. The overall safety profiles of the 2 drugs were comparable.

Aged↗

PubMed2001

In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia.

Ertapenem (MK-0826, L-749,345) is a 1-beta-methyl carbapenem with a long serum half-life. Its in vitro activity was determined by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone, and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the family Enterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC(90)s) of < or =1 microg/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci, and anaerobes, but its MIC(90)s for these groups remained < or =0.5 microg/ml. Acinetobacter spp. and Pseudomonas aeruginosa were also much less susceptible to ertapenem than imipenem, and most Enterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of > or =16 microg/ml, was seen in only 3 of 1,611 strains of the family Enterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1 Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of < or =2 microg/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were as high as 2 microg/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 microg/ml and one required an MIC of 4 microg/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 microg/ml. These streptococci also had diminished susceptibilities to other beta-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results in good agreement with those of the broth microdilution method for ertapenem.

Anti-Bacterial Agents↗

PubMed2002

Safety and local tolerability of intramuscularly administered ertapenem diluted in lidocaine: a prospective, randomized, double-blind study versus intramuscular ceftriaxone.

BACKGROUND: Ertapenem is a new, structurally unique, parenteral beta-lactam antimicrobial agent that can be administered once daily. OBJECTIVE: This study compared the local tolerability of ertapenem 1 g once a day administered intramuscularly (IM) versus IM ceftriaxone, with both drugs reconstituted in lidocaine. METHODS: In this prospective, double-blind, multicenter study, adult patients with lower respiratory tract infection, skin infection, or urinary tract infection requiring initial parenteral therapy were randomly assigned in a 3:1 ratio to treatment with IM ertapenem 1 g once daily or IM ceftriaxone 1 g once daily. Although study drugs were administered by unmasked personnel, the patients, investigators, and the sponsor medical reviewer were blinded. Patients who improved clinically could be switched to oral amoxicillin-clavulanate after at least 2 days of IM therapy. Tolerability and safety analyses were carried out for the treated population, and efficacy analyses were performed for the modified intent-to-treat population. RESULTS: A total of 117 patients were randomized. The 87 patients in the ertapenem group and 30 in the ceftriaxone group received IM therapy for a mean duration of 4.1 and 3.8 days, respectively. During treatment, 35.6% (31/87) of patients treated with ertapenem and 43.3% (13/30) of those treated with ceftriaxone experienced > or =1 symptom at the local injection site; the most common symptom was tenderness, followed by pain. Symptoms were moderate to severe in only 1 patient (1.1%) in the ertapenem group and 3 patients (10.0%) in the ceftriaxone group. Clinical drug-related adverse events were reported during IM therapy in 14 patients (16.1%) in the ertapenem group and 5 patients (16.7%) in the ceftriaxone group. Mean +/- SD creatine kinase concentrations, measured in all patients, were 204.8+/-234.8 U/L at the end of IM ertapenem therapy and 382.9+/-721.1 U/L at the end of IM ceftriaxone therapy; at follow-up, values had returned to normal or had decreased in all cases. CONCLUSIONS: Ertapenem 1 g (reconstituted in lidocaine) administered once daily IM was generally well tolerated. The tolerability and safety profiles of IM ertapenem therapy in this study were comparable to those of IM ceftriaxone therapy.

Aged↗

PubMed2006

Ertapenem versus cefotetan prophylaxis in elective colorectal surgery.

BACKGROUND: Ertapenem, a long-acting carbapenem, may be an alternative to the recommended prophylactic antibiotic cefotetan. METHODS: In this randomized, double-blind trial, we assessed the efficacy and safety of antibiotic prophylaxis with ertapenem, as compared with cefotetan, in patients undergoing elective colorectal surgery. A successful outcome was defined as the absence of surgical-site infection, anastomotic leakage, or antibiotic use 4 weeks postoperatively. All adverse events were collected until 14 days after the administration of antibiotic prophylaxis. RESULTS: Of the 1002 patients randomly assigned to study groups, 901 (451 in the ertapenem group and 450 in the cefotetan group) qualified for the modified intention-to-treat analysis, and 672 (338 in the ertapenem group and 334 in the cefotetan group) were included in the per-protocol analysis. After adjustment for strata, in the modified intention-to-treat analysis, the rate of overall prophylactic failure was 40.2% in the ertapenem group and 50.9% in the cefotetan group (absolute difference, -10.7%; 95% confidence interval [CI], -17.1 to -4.2); in the per-protocol analysis, the failure rate was 28.0% in the ertapenem group and 42.8% in the cefotetan group (absolute difference, -14.8%; 95% CI, -21.9 to -7.5). Both analyses fulfilled statistical criteria for the superiority of ertapenem. In the modified intention-to-treat analysis, the most common reason for failure of prophylaxis in both groups was surgical-site infection: 17.1% in the ertapenem group and 26.2% in the cefotetan group (absolute difference, -9.1; 95% CI, -14.4 to -3.7). In the treated population, the overall incidence of Clostridium difficile infection was 1.7% in the ertapenem group and 0.6% in the cefotetan group (P=0.22). CONCLUSIONS: Ertapenem is more effective than cefotetan in the prevention of surgical-site infection in patients undergoing elective colorectal surgery but may be associated with an increase in C. difficile infection. (ClinicalTrials.gov number, NCT00090272 [ClinicalTrials.gov].).

Adult↗

PubMed2004

In vitro activity of ertapenem against selected respiratory pathogens.

OBJECTIVES: The in vitro activity of ertapenem was evaluated in comparison to 21 selected agents against a large collection of recently isolated respiratory tract pathogens including: 180 Streptococcus pneumoniae, 100 Streptococcus pyogenes, 70 Haemophilus influenzae, 70 Moraxella catarrhalis, 100 methicillin-susceptible Staphylococcus aureus and 30 Klebsiella pneumoniae. Additional in vitro tests (time-kill curves with ertapenem alone and in combination with four other agents) for S. pneumoniae were carried out. METHODS: MIC determinations and time-kill curves were carried out following the procedures suggested by the NCCLS. RESULTS: According to NCCLS susceptibility breakpoints, ertapenem was comparable to the most potent compounds tested for all pathogens studied. Ertapenem was 100% active against penicillin-susceptible and -intermediate S. pneumoniae and against 60% of penicillin-resistant strains. Time-kill tests at 4x MIC confirmed a pronounced bactericidal potency of ertapenem against these organisms. Interactions of ertapenem with several other agents against pneumococci resulted in clear synergic interactions (98.4%). Indifference was extremely rare and antagonism was not observed. All S. pyogenes strains tested were inhibited by ertapenem, irrespective of their macrolide resistance phenotypes. Ertapenem was also fully active against H. influenzae (100% susceptible) and M. catarrhalis (MIC90 0.015-0.03 mg/L) even when capable of synthesizing beta-lactamases. Methicillin-susceptible S. aureus and K. pneumoniae, including extended-spectrum beta-lactamase-producing strains, were 100% susceptible to ertapenem. CONCLUSIONS: Our results indicate that ertapenem has a suitable spectrum of activity against organisms encountered in community-acquired bacterial respiratory tract infections.

Bacteria↗

PubMed2006

Pharmacodynamic activity of ertapenem versus penicillin-susceptible and penicillin-non-susceptible Streptococcus pneumoniae using an in vitro model.

BACKGROUND: Ertapenem is a novel carbapenem with activity against both penicillin-susceptible (MIC < or = 0.06 mg/L) and penicillin-non-susceptible (MIC > or = 0.12 mg/L) Streptococcus pneumoniae. This study assessed the pharmacodynamic activity of ertapenem against penicillin-susceptible and penicillin-non-susceptible S. pneumoniae using an in vitro pharmacodynamic model. METHODS: Fifteen S. pneumoniae strains including 3 penicillin-susceptible and 12 penicillin-non-susceptible [4 penicillin-intermediate (MIC 0.12-1 mg/L) and 8 penicillin-resistant (MIC > or = 2 mg/L); with different resistance phenotypes including erythromycin-resistant (MIC > or = 1 mg/L), ciprofloxacin-resistant (MIC > or = 4 mg/L) and doxycycline-resistant (MIC > or = 8 mg/L)] were studied. The in vitro pharmacodynamic model was inoculated with 1 x 10(6) cfu/mL and ertapenem was dosed once daily at 0 and 24 h to simulate f (free) Cmax and t(1/2) obtained after a standard 1 g intravenous once daily dose in healthy volunteers (fCmax 15 mg/L, t(1/2) 4 h). Sampling was performed for 48 h to assess viable growth. RESULTS: Ertapenem T(> MIC) > or = 80% (ertapenem MICs < or = 0.5 mg/L) resulted in bactericidal (> or = 3 log10 killing) activity at 12, 24 and 48 h with complete eradication of penicillin-susceptible and penicillin-non-susceptible S. pneumoniae from the model with no regrowth over the 48 h study period. Ertapenem T(> MIC) < or = 63% (ertapenem MIC > or = 1 mg/L) resulted in bactericidal activity at 12 h with regrowth at 24 and 48 h. The observed MICs for S. pneumoniae of ertapenem studied in the in vitro model did not change during the 48 h period, even for strains where regrowth occurred. CONCLUSIONS: Ertapenem is bactericidal against both penicillin-susceptible and penicillin-non-susceptible S. pneumoniae (ertapenem MICs < or = 0.5 mg/L) when simulating free drug after 1 g intravenous once daily dosing.

Anti-Bacterial Agents↗

PubMed2002

Pharmacokinetics of ertapenem in healthy young volunteers.

Ertapenem (INVANZ) is a new once-a-day parenteral beta-lactam antimicrobial shown to be effective as a single agent for treatment of various community-acquired and mixed infections. The single- and multiple-dose pharmacokinetics of ertapenem at doses up to 3 g were examined in healthy young men and women volunteers. Plasma and urine samples collected were analyzed using reversed-phase high-performance liquid chromatography with UV detection. Ertapenem is highly bound to plasma protein. The protein binding changes from approximately 95% bound at concentrations of <50 micro g/ml to approximately 92% bound at concentrations of 150 micro g/ml (concentration at the end of a 30-min infusion following the 1-g dose). The nonlinear protein binding of ertapenem resulted in a slightly less than dose proportional increase in the area under the curve from 0 h to infinity (AUC(0- infinity )) of total ertapenem. The single-dose AUC(0- infinity ) of unbound ertapenem was nearly dose proportional over the dose range of 0.5 to 2 g. The mean concentration of ertapenem in plasma ranged from approximately 145 to 175 micro g/ml at the end of a 30-min infusion, from approximately 30 to 34 micro g/ml at 6 h, and from approximately 9 to 11 micro g/ml at 12 h. The mean plasma t(1/2) ranged from 3.8 to 4.4 h. About 45% of the plasma clearance (CL(P)) was via renal clearance. The remainder of the CL(P) was primarily via the formation of the beta-lactam ring-opened metabolite that was excreted in urine. There were no clinically significant differences between the pharmacokinetics of ertapenem in men and women. Ertapenem does not accumulate after multiple once-daily dosing.

Adult↗

PubMed2006

Pharmacokinetics and lung concentrations of ertapenem in patients with ventilator-associated pneumonia.

OBJECTIVE: We conducted a prospective, open-label study to determine the steady-state serum and epithelial lining fluid (ELF) concentrations of unbound ertapenem administered once daily to critically ill patients with early-onset ventilator-associated pneumonia (VAP). DESIGN AND SETTING: Prospective, open-label study in an intensive care unit and research ward in a university hospital. PATIENTS: Fifteen patients with VAP received 1-h intravenous infusions of 1 g ertapenem once daily. INTERVENTIONS: After 2 days of therapy the steady-state serum and ELF concentrations of free ertapenem were determined by high-performance liquid chromatography. MEASUREMENTS AND RESULTS: The median (interquartile range) free ertapenem peak (C(max)), intermediate (C(12)), and trough (C(min)) concentrations (mg/l) 1, 12, and 24 h after the end of infusion were 30.3 (27.1-37.8), 4.8 (3.9-6.4), and 0.8 (0.5-1.2) in serum and 9.4 (8.0-10.7), 2.0 (1.1-2.5), and 0.3 (0.2-0.4) in ELF, respectively, showing a median free ertapenem percentage penetration in ELF of approx. 30%. The median (interquartile range) serum area under concentration-time curve of free ertapenem during the observational period was 226.7 mg h(-1) l(-1) (202.2-263.9). CONCLUSION: Our study shows satisfactory results, with unbound ertapenem concentrations both in serum and ELF exceeding the MIC(90) values of most of the causative pathogens encountered in early-onset VAP during 50-100% time. This suggests that 1 g intravenous ertapenem administered once daily should be effective during the treatment of early-onset VAP in critically ill patients with no known risk factors for multidrug-resistant pathogens.

Aged↗

PubMed2002

Use of surrogate antimicrobial agents to predict susceptibility to ertapenem.

Broth or agar dilution susceptibility test results for Enterobacteriaceae (11,775 strains), anaerobes (2888 strains), staphylococci (2206 strains), Haemophilus spp. (840 strains), group A streptococci (280 strains), group B streptococci (269 strains), Streptococcus pneumoniae (709 strains), and 160 other streptococci were analyzed to identify surrogate antimicrobial agents to predict susceptibility to ertapenem. Ertapenem MIC interpretive categories approved by the United States FDA were compared to those of imipenem, oxacillin (staphylococci), or penicillin (streptococci). Ertapenem resistance was rare (1.2%) among 8187 consecutively collected clinical isolates of Enterobacteriaceae, including a large proportion of isolates from intensive care units. Absolute categorical agreement between ertapenem and imipenem, and very major (false susceptible) and major errors (false resistant) using imipenem to predict ertapenem results were 97.2%, 0.9%, and 0.4%, respectively, for Enterobacteriaceae (10,992 strains tested against both drugs) and 99.0%, 0.2%, and 0% for anaerobes. All Haemophilus spp., groups A and B streptococci, penicillin-susceptible and -intermediate S. pneumoniae, and other penicillin-susceptible streptococci were susceptible to ertapenem. All oxacillin-susceptible Staphylococcus aureus were ertapenem susceptible, except 1 that was intermediate. Surrogate antimicrobial agents that can be used to reliably predict ertapenem susceptibility by MIC tests are imipenem for Enterobacteriaceae and anaerobes, oxacillin for staphylococci, and penicillin for streptococci.

Anti-Bacterial Agents↗

PubMed2002

Ertapenem monotherapy versus combination therapy with ceftriaxone plus metronidazole for treatment of complicated intra-abdominal infections in adults.

The efficacy and safety of intravenous (IV) ertapenem, 1 and 1.5 g once a day, for treatment of adults with complicated intra-abdominal infection were compared with those of IV ceftriaxone 2 g once a day plus IV metronidazole 500 mg every 8 h. After at least 3 days of IV therapy and satisfactory clinical response, patients could be switched to oral ciprofloxacin plus metronidazole. Fifty-nine patients were randomized to receive ertapenem 1 g and 51 to receive ertapenem 1.5 g; 55 patients were randomized to each comparator group. At the test of cure, 4-6 weeks post therapy, in the 1 g cohort, 84% (26/31) of patients treated with ertapenem and 85% (35/41) with comparator therapy had a favourable clinical and microbiological assessment. Success rates in the 1.5 g cohort were 83% (22/29) and 77% (24/31) in the ertapenem and comparator groups, respectively. Drug-related adverse events were generally similar in both treatment groups. Ertapenem 1 or 1.5 g once a day followed by optional oral therapy appeared similar to combined therapy with ceftriaxone plus metronidazole with the same optional oral switch for treatment of complicated intra-abdominal infections in adults. Although not compared directly in a randomized fashion, the efficacy and safety profiles of ertapenem 1 and 1.5 g appeared comparable. Ertapenem was generally well tolerated and had an overall safety profile similar to ceftriaxone plus metronidazole.

Abdomen↗

PubMed2004

Stability and compatibility of reconstituted ertapenem with commonly used i.v. infusion and coinfusion solutions.

PURPOSE: The stability of ertapenem sodium in various commonly used i.v. infusion solutions and its compatibility with coinfusion solutions was studied. METHODS: Ertapenem was reconstituted with sterile water for injection and then diluted with various commercial i.v. infusion solutions to concentrations of 10 and 20 mg/mL. The solutions were stored in flexible polyvinyl chloride containers at 4 and 25 degrees C and in sterile glass vials at -20 degrees C. The drug's stability at 4 degrees C was monitored daily for up to 10 days, at 25 degrees C at appropriate hourly intervals for up to 30 hours, and at -20 degrees C. The daily for up to 14 days. Compatibility with the coinfusion solutions was monitored for up to eight hours at room temperature. Stability assays were conducted until the ertapenem concentration decreased by 10% or the corresponding degradation products exceeded the approved specifications. Ertapenem concentrations were determined by a stability-indicating high-performance liquid chromatography assay. RESULTS: Ertapenem was more stable in solutions stored at 4 degrees C versus 25 degrees C. Samples frozen at -20 degrees C showed extreme variability. Ertapenem 10 mg/mL was stable for a longer time than at the 20-mg/mL concentration. Ertapenem demonstrated the greatest stability in 0.9% and 0.225% sodium chloride solutions. CONCLUSION: Ertapenem sodium injection 10 and 20 mg/mL are relatively stable in sodium chloride injections and Ringer's solution when stored at 25 and 4 degrees C, but are unstable in mannitol and dextrose solutions. The drug can be coinfused with hetastarch, heparin sodium, and potassium chloride over several hours.

Chromatography, High Pressure Liquid↗

PubMed2003

Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial.

OBJECTIVE: To examine the clinical efficacy and safety of ertapenem, a novel beta-lactam agent with wide activity against common pathogens encountered in intraabdominal infection. SUMMARY BACKGROUND DATA: Ertapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections. METHODS This prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections. RESULTS: Six hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population). A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability. For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam. One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam. CONCLUSIONS: In this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections. Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam. A formal process for review of adequacy of source control was found to be of benefit. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.

Abdominal Abscess↗

PubMed2004

Pharmacokinetics of total and unbound ertapenem in healthy elderly subjects.

Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC(0- infinity ) of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC(0- infinity ) of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects ( approximately 5 to 11%) was generally greater than that in young adults ( approximately 5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.

Adult↗

PubMed2005

Ertapenem-associated seizures in a peritoneal dialysis patient.

OBJECTIVE: To report a case of a patient undergoing peritoneal dialysis who developed refractory seizures after 2 doses of ertapenem. CASE SUMMARY: A 56-year-old white man with end-stage renal disease requiring continuous ambulatory peritoneal dialysis experienced 5 seizures following 2 doses of ertapenem 500 mg given intravenously. The first generalized tonic-clonic seizure occurred 16 hours after the second ertapenem dose and lasted 3 minutes. Three hours after his first seizure, the patient experienced 2 more seizures 15 minutes apart, lasting 3 minutes each. After suffering a fifth seizure, the patient became apneic and pulseless and was not resuscitated, as he had previously requested a "do not resuscitate" status. DISCUSSION: Carbapenem treatment has been associated with simple partial, complex partial, and generalized tonic-clonic seizures, with generalized seizures representing the most frequently occurring type. Safety data from 7 published clinical trials of ertapenem revealed a seizure incidence of 0.18%. To our knowledge, there are no previously published reports of ertapenem neurotoxicity in patients undergoing peritoneal dialysis. Moreover, little information is available regarding the pharmacokinetics of carbapenems in end-stage renal disease. Ertapenem pharmacokinetics were not tested in any patients receiving peritoneal dialysis during published clinical trials. CONCLUSIONS: Our patient experienced 5 seizures, possibly induced by ertapenem, as validated by the Naranjo probability scale. Clinicians administering ertapenem to patients undergoing peritoneal dialysis should use caution, as clinical experience with the agent is limited and pharmacokinetic data are lacking.

Ertapenem↗

PubMed2003

Ertapenem: a review of its use in the management of bacterial infections.

UNLABELLED: Ertapenem, a carbapenem antibacterial, has in vitro activity against many Gram- negative (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 ceftriaxone +/- 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.

Animals↗

PubMed2003

[Comparative in vitro activity of ertapenem against aerobic and anaerobic bacteria].

The in vitro activity of ertapenem (MK-0826), a new carbapenem, was studied against 389 aerobic microorganisms (187 Enterobacteriaceae, 15 Aeromonas spp., 42 Staphylococcus spp., 43 Streptococcus spp., 15 Enterococcus spp., 30 Haemophilus spp., 15 Moraxella catarrhalis, 12 Neisseria gonorrhoeae, 15 Pseudomonas aeruginosa and 15 Acinetobacter spp.) and 54 anaerobic isolates (15 Clostridium spp., 12 Peptostreptococcus spp. and 27 fragilis group Bacteroides recovered from four Spanish hospitals. Ertapenem activity was compared with that of imipenem, piperacillin-tazobactam, cefoxitin, ceftriaxone, ceftazidime, cefepime, and norfloxacin. Ertapenem was the most active antibiotic against Enterobacteriaceae (MIC(90) < or =0.5 mg/l) particularly in the case of broad-spectrum, extended-spectrum and chromosomally encoded AmpC betalactamase-producing strains. Ertapenem exhibited less activity, even lower than that of imipenem, against P. aeruginosa, Acinetobacter spp. and enterococci (MIC(90) > or =16 mg/l). Ertapenem was active against methicillin-susceptible S. aureus and coagulase-negative staphylococci, beta-haemolytic streptococci, and Streptococcus pneumoniae (MIC(90) < or =1 mg/l). In the case of Haemophilus spp., M. catarrhalis and N. gonorrhoeae, ertapenem, with a MIC(90) < or =0.06 mg/l resulted the most active antibiotic tested. When considering the anaerobes, ertapenem displayed a broad spectrum of activity, similar to that of imipenem, against Clostridium spp. (MIC(90) 2 mg/l) and was slightly less active against Bacteroides fragilis (MIC(90) 0.5 mg/l). Both carbapenems were the most active among the tested compounds. Due to its activity against almost all pathogens studied, ertapenem appears to be an option for the treatment of mixed bacterial infections.

Anti-Bacterial Agents↗

PubMed2001

In vitro evaluation of ertapenem (MK-0826), a long-acting carbapenem, tested against selected resistant strains.

Ertapenem (MK-0826) is a novel, long-acting parenteral carbapenem. The purpose of this in vitro study was to test ertapenem's activity against a collection of multiply-resistant strains of gram-positive and -negative bacteria isolated from locations worldwide, and to examine its bactericidal activity and ability to act in a synergistic manner in combination with other antimicrobial agents. Ertapenem was active against a variety of gram-negative pathogens, with particular potency noted for Escherichia coli and Klebsiella pneumoniae (MIC90s < or =0.015-0.5 microg/mL) including extended spectrum beta-lactamase producing strains. Less ertapenem activity was seen against Pseudomonas aeruginosa, especially ceftazidime-resistant strains (MIC50 16 microg/mL). Except for enterococci, ertapenem was active against most gram-positive species, including beta-haemolytic streptococci (MIC90 0.03 microg/mL; 100% susceptible), viridans group streptococci (MIC90 2 microg/mL; 98.1% susceptible), and penicillin-susceptible Streptococcus pneumoniae (MIC90 < or =0.015 microg/mL; 100% susceptible). Ertapenem was also very potent against Haemophilus influenzae (MIC90 0.25 microg/mL; 100% susceptible). Bactericidal action was observed versus staphylococci, E. coli, and K. pneumoniae, and at least an additive effect was detected against the majority of the strains tested when ertapenem was combined with ciprofloxacin or gentamicin. These results from testing 902 organisms indicate that ertapenem appears to be a promising broad-spectrum carbapenem with a possible role against some emerging resistant species.

Anti-Bacterial Agents↗