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Ertapenem sodium is a carbapenem antibiotic.
Average plasma concentrations (mcg/mL) of ertapenem following a single 30-minute infusion of a 1 g intravenous (IV) dose and administration of a single 1 g intramuscular (IM) dose in healthy young adults are presented in Table 8.
Table 8: Plasma Concentrations of Ertapenem in Adults After
Single Dose Administration
| Average Plasma Concentrations (mcg/mL) | |||||||||
| Dose/Route | 0.5 hr | 1 hr | 2 hr | 4 hr | 6 hr | 8 hr | 12 hr | 18 hr | 24 hr |
| 1g lV* | 155 | 115 | 83 | 48 | 31 | 20 | 9 | 3 | 1 |
| 1 g IM | 33 | 53 | 67 | 57 | 40 | 27 | 13 | 4 | 2 |
| *Infused at a constant rate over 30 minutes | |||||||||
The area under the plasma concentration-time curve (AUC) of ertapenem in adults increased less-than dose-proportional based on total ertapenem concentrations over the 0.5 to 2 g dose range, whereas the AUC increased greater-than dose-proportional based on unbound ertapenem concentrations. Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding at the proposed therapeutic dose. There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults.
Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 9.
Table 9: Plasma Concentrations of Ertapenem in Pediatric Patients
After Single IV* Dose Administration
| Age Group | Dose | Average Plasma Concentrations (mcg/mL) | |||||||
| 0.5 hr | 1 hr | 2hr | 4hr | 6hr | 8hr | 12 hr | 24 hr | ||
| 3 to 23 months | |||||||||
| 15 mg/kg† | 103.8 | 57.3 | 43.6 | 23.7 | 13.5 | 8.2 | 2.5 | - | |
| 20 mg/kg† | 126.8 | 87.6 | 58.7 | 28.4 | - | 12.0 | 3.4 | 0.4 | |
| 40 mg/kg‡ | 199.1 | 144.1 | 95.7 | 58.0 | - | 20.2 | 7.7 | 0.6 | |
| 2 to 12 years | |||||||||
| 15 mg/kg† | 113.2 | 63.9 | 42.1 | 21.9 | 12.8 | 7.6 | 3.0 | - | |
| 20 mg/kg† | 147.6 | 97.6 | 63.2 | 34.5 | - | 12.3 | 4.9 | 0.5 | |
| 40 mg/kg‡ | 241.7 | 152.7 | 96.3 | 55.6 | - | 18.8 | 7.2 | 0.6 | |
| 13 to 17 years | |||||||||
| 20 mg/kg‡ | 170.4 | 98.3 | 67.8 | 40.4 | - | 16.0 | 7.0 | 1.1 | |
| 1g§ | 155.9 | 110.9 | 74.8 | - | 24.0 | - | 6.2 | - | |
| 40 mg/kg‡ | 255.0 | 188.7 | 127.9 | 76.2 | - | 31.0 | 15.3 | 2.1 | |
| *Infused at a constant rate over 30 minutes † up to a maximum dose of 1 g/day ‡ up to a maximum dose of 2 g/day § Based on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy trials |
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Ertapenem, reconstituted with 1% lidocaine HCI injection, USP (in saline without epinephrine), is almost completely absorbed following intramuscular (IM) administration at the recommended dose of 1 g. The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma concentrations (Cmax) are achieved in approximately 2.3 hours (Tmax).
Ertapenem is highly bound to human plasma proteins, primarily albumin. In healthy young adults, the protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of < 100 micrograms (mcg)/mL to approximately 85% bound at an approximate plasma concentration of 300 mcg/mL.
The apparent volume of distribution at steady state (Vss) of ertapenem in adults is approximately 0.12 liter/kg, approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.
The concentrations of ertapenem achieved in suction-induced skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 10. The ratio of AUC0-24 in skin blister fluid/AUC0-24 in plasma is 0.61.
Table 10: Concentrations (mcg/mL) of Ertapenem in Adult Skin
Blister Fluid at each Samplinq Point on the Third Day of 1-q Once Daily IV Doses
| 0.5 hr | 1 hr | 2hr | 4hr | 8hr | 12 hr | 24 hr |
| 7 | 12 | 17 | 24 | 24 | 21 | 8 |
The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) was measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3-10 days of therapy). The concentration of ertapenem in breast milk within 24 hours of the last dose of therapy in all 5 women ranged from < 0.13 (lower limit of quantitation) to 0.38 mcg/mL; peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation ( < 0.13 mcg/mL) in 1 woman.
In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring-opened derivative formed by hydrolysis of the beta-lactam ring.
Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is approximately 4 hours and the plasma clearance is approximately 1.8 L/hour. The mean plasma half-life in pediatric patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in pediatric patients 3 months to 12 years of age.
Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite.
In healthy young adults given a 1 g IV dose, the mean percentage of the administered dose excreted in urine was 17.4% during 0-2 hours postdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 hours postdose.
Total and unbound fractions of ertapenem pharmacokinetics were investigated in 26 adult subjects (31 to 80 years of age) with varying degrees of renal impairment. Following a single 1 g IV dose of ertapenem, the unbound AUC increased 1.5-fold and 2.3-fold in subjects with mild renal impairment (CLCR 60-90 mL/min/1.73 m2) and moderate renal impairment (CLCR 31-59 mL/min/1.73 m2), respectively, compared with healthy young subjects (25 to 45 years of age). No dosage adjustment is necessary in patients with CLCR > 31 mL/min/1.73 m2. The unbound AUC increased 4.4-fold and 7.6-fold in subjects with advanced renal impairment (CLCR 5-30 mL/min/1.73 m2) and end-stage renal disease (CLCR < 10 mL/min/1.73 m2), respectively, compared with healthy young subjects. The effects of renal impairment on AUC of total drug were of smaller magnitude. The recommended dose of ertapenem in adult patients with CLCR < 30 mL/min/1.73 m2 is 0.5 grams every 24 hours. Following a single 1 g IV dose given immediately prior to a 4 hour hemodialysis session in 5 adult patients with end-stage renal disease, approximately 30% of the dose was recovered in the dialysate. Dose adjustments are recommended for patients with severe renal impairment and end-stage renal disease [see DOSAGE AND ADMINISTRATION]. There are no data in pediatric patients with renal impairment.
The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. However, ertapenem does not appear to undergo hepatic metabolism based on in vitro studies and approximately 10% of an administered dose is recovered in the feces [see DOSAGE AND ADMINISTRATION].
The effect of gender on the pharmacokinetics of ertapenem was evaluated in healthy male (n=8) and healthy female (n=8) subjects. The differences observed could be attributed to body size when body weight was taken into consideration. No dose adjustment is recommended based on gender.
The impact of age on the pharmacokinetics of ertapenem was evaluated in healthy male (n=7) and healthy female (n=7) subjects > 65 years of age. The total and unbound AUC increased 37% and 67%, respectively, in elderly adults relative to young adults. These changes were attributed to age-related changes in creatinine clearance. No dosage adjustment is necessary for elderly patients with normal (for their age) renal function.
Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and adults following a 1 g once daily IV dose.
Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients 13 to 17 years of age (N=6) were generally comparable to those in healthy young adults.
Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg IV dose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at the midpoint of the dosing interval following a 1 g once daily IV dose in adults. The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years of age is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value (doubled to model a twice daily dosing regimen, i.e., 30 mg/kg/day exposure) in patients 3 months to 12 years of age was comparable to the AUC value in young healthy adults receiving a 1 g IV dose of ertapenem.
When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem. Based on total ertapenem concentrations, probenecid increased the AUC of ertapenem by 25%, and reduced the plasma and renal clearance of ertapenem by 20% and 35%, respectively. The half-life of ertapenem was increased from 4.0 to 4.8 hours.
In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
Ertapenem has in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins (PBPs). In Escherichia coli, it has strong affinity toward PBPs 1a, 1 b, 2, 3, 4 and 5 with preference for PBPs 2 and 3.
Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases. Ertapenem is hydrolyzed by metallo-beta-lactamases.
Ertapenem has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS section:
Gram-positive bacteria:
Staphylococcus aureus (methicillin susceptible isolates only)
Streptococcus agalactiae
Streptococcus pneumoniae (penicillin susceptible isolates only)
Streptococcus pyogenes
Gram-negative bacteria:
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Anaerobic bacteria:
Bacteroides fragilis
Bacteroides distasonis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Clostridium clostridioforme
Eubacterium lentum
Peptostreptococcus species
Porphyromonas asaccharolytica
Prevotella bivia
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ertapenem. However, the efficacy of ertapenem in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials:
Gram-positive bacteria:
Staphylococcus epidermidis (methicillin susceptible isolates only)
Streptococcus pneumoniae (penicillin-intermediate isolates)
Note: Methicillin-resistant Staphylococcus epidermidis are resistant to ertapenem.
Gram-negative bacteria:
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella oxytoca (excluding ESBL producing isolates)
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia marcescens
Anaerobic bacteria:
Bacteroides vulgatus
Clostridium perfringens
Fusobacterium spp.
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a broth dilution method {1,2} or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to criteria provided in Table 11.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure {2,3} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg ertapenem to test the susceptibility of microorganisms to ertapenem. The disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 11.
For anaerobic bacteria, the susceptibility to ertapenem as MICs can be determined by standardized test methods {2,4}. The MIC values obtained should be interpreted according to criteria provided in Table 11.
Table 11: Susceptibility Interpretive Criteria for Ertapenem
| Pathogen | Minimum Inhibitory Concentrations* MIC (µg/mL) |
Disk Diffusion* Zone Diameter (mm) |
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| S | I | R | S | I | R | |
| Enterobacteriaceae and Staphylococcus aureus | ≤ 2.0 | 4.0 | ≥ 8.0 | ≥ 19 | 16-18 | ≤ 15 |
| Haemophilus spp. | ≤ 0.5 | - | - | ≥ 19 | - | - |
| Streptococcus pneumoniae†‡ | ≤ 1.0 | 2 | ≥ 4 | - | - | - |
| Streptococcus spp. other than Streptococcus pneumoniae §¶ | ≤ 1.0 | - | - | - | - | - |
| Anaerobes | ≤ 4.0 | 8.0 | ≥ 16.0 | - | - | - |
| * The current absence of data in resistant isolates precludes
defining any results other than "Susceptible". Isolates yielding
MIC results suggestive of a "Nonsusceptible" category should be
submitted to a reference laboratory for further testing. † Streptococcus pneumoniae that are susceptible to penicillin (penicillin MIC ≤ 0.06 µg/mL) can be considered susceptible to ertapenem. Testing of ertapenem against penicillin-intermediate or penicillin-resistant isolates is not recommended since reliable interpretive criteria for ertapenem are not available. ‡ Streptococcus pneumoniae that are susceptible to penicillin (1-µg oxacillin disk zone diameter ≥ 20 mm), can be considered susceptible to ertapenem. Isolates with 1-µg oxacillin zone diameter ≤ 19 mm should be tested against ertapenem using an MIC method. § Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (MIC ≤ 0.12 µg/mL) can be considered susceptible to ertapenem. Testing of ertapenem against penicillin-intermediate or penicillin-resistant isolates is not recommended since reliable interpretive criteria for ertapenem are not available. ¶ Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (10-units penicillin disk zone diameter ≥ 24 mm), can be considered susceptible to ertapenem. Isolates with 10-units penicillin disk zone diameter < 24 mm should be tested against ertapenem using an MIC method. Penicillin disk diffusion interpretive criteria are not available for viridans group streptococci and they should not be tested against ertapenem. |
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Note: Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin MIC is ≤ 0.12 µg/mL If the penicillin MIC is > 0.12 µg/mL, then test oxacillin. Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin MIC is ≤ 2.0 µg/mL and resistant to ertapenem if the oxacillin MIC is ≥ 4.0 µg/mL. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin MIC is < 0.25 µg/mL and resistant to ertapenem if the oxacillin MIC is ≥ 0.5 µg/mL.
Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin (10 U disk) zone is ≥ 29 mm. If the penicillin zone is ≤ 28 mm, then test oxacillin by disk diffusion (1 µg disk). Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin (1 µg disk) zone is ≥ 13mm and resistant to ertapenem if the oxacillin zone is ≤ 10mm. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin zone is ≥ 18 mm and resistant to ertapenem if the oxacillin (1 µg disk) zone is ≤ 17 mm.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory control microorganisms to ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test {1,2,3,4}. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. Standard ertapenem powder should provide the following range of values noted in Table 12.
Table 12: Acceptable Quality Control Ranges for Ertapenem
| Microorganism | Minimum Inhibitory Concentrations MIC Range (µg/mL) |
Disk Diffusion Zone Diameter (mm) |
| Escherichia coli ATCC 25922 | 0.004-0.016 | 29-36 |
| Haemophilus influenzae ATCC 49766 | 0.016-0.06 | 27-33 |
| Staphylococcus aureus ATCC 29213 | 0.06-0.25 | - |
| Staphylococcus aureus ATCC 25923 | - | 24-31 |
| Streptococcus pneumoniae ATCC 49619 | 0.03-0.25 | 28-35 |
| Bacteroides fragilis ATCC 25285 | 0.06-0.5* 0.06-0.25† |
- |
| Bacteroides thetaiotaomicron ATCC 29741 | 0.5-2.0* 0.25-1 .0† |
- |
| Eubacterium lentum ATCC 43055 | 0.5-4.0* 0.5-2.0† |
- |
| * Quality control ranges for broth mlcrodllutlon testing † Quality control ranges for agar microdilution testing. |
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Ertapenem was evaluated in adults for the treatment of complicated intra-abdominal infections in a randomized, double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 5 to 14 days and enrolled 665 patients with localized complicated appendicitis, and any other complicated intra-abdominal infection including colonic, small intestinal, and biliary infections and generalized peritonitis. The combined clinical and microbiologic success rates in the microbiologically evaluable population at 4 to 6 weeks posttherapy (test-of-cure) were 83.6% (163/195) for ertapenem and 80.4% (152/189) for piperacillin/tazobactam.
Ertapenem was evaluated in adults for the treatment of complicated skin and skin structure infections in a randomized, double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 7 to 14 days and enrolled 540 patients including patients with deep soft tissue abscess, posttraumatic wound infection and cellulitis with purulent drainage. The clinical success rates at 10 to 21 days posttherapy (test-of-cure) were 83.9% (141/168) for ertapenem and 85.3% (145/170) for piperacillin/tazobactam.
Ertapenem was evaluated in adults for the treatment of diabetic foot infections without concomitant osteomyelitis in a multicenter, randomized, double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours). Test-of-cure was defined as clinical response between treatment groups in the clinically evaluable population at the 10-day posttherapy follow-up visit. The trial included 295 patients randomized to ertapenem and 291 patients to piperacillin/tazobactam. Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of 5 to 28 days of treatment (parenteral and oral). All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement, as is typically required in the treatment of diabetic foot infections, and most patients received these treatments. Patients with suspected osteomyelitis could be enrolled if all the infected bone was removed within 2 days of initiation of study therapy, and preferably within the prestudy period. Investigators had the option to add open-label vancomycin if enterococci or methicillin-resistant Staphylococcus aureus (MRSA) were among the pathogens isolated or if patients had a history of MRSA infection and additional therapy was indicated in the opinion of the investigator. Two hundred and four (204) patients randomized to ertapenem and 202 patients randomized to piperacillin/tazobactam were clinically evaluable. The clinical success rates at 10 days posttherapy were 75.0% (153/204) for ertapenem and 70.8% (143/202) for piperacillin/tazobactam.
Ertapenem was evaluated in adults for the treatment of community acquired pneumonia in two randomized, double-blind, non-inferiority clinical trials. Both trials compared ertapenem (1 g parenterally once a day) with ceftriaxone (1 g parenterally once a day) and enrolled a total of 866 patients. Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of 10 to 14 days of treatment (parenteral and oral). In the first trial the primary efficacy parameter was the clinical success rate in the clinically evaluable population and success rates were 92.3% (168/182) for ertapenem and 91.0% (183/201) for ceftriaxone at 7 to 14 days posttherapy (test-of-cure). In the second trial the primary efficacy parameter was the clinical success rate in the microbiologically evaluable population and success rates were 91% (91/100) for ertapenem and 91.8% (45/49) for ceftriaxone at 7 to 14 days posttherapy (test-of-cure).
Ertapenem was evaluated in adults for the treatment of complicated urinary tract infections including pyelonephritis in two randomized, double-blind, non-inferiority clinical trials. Both trials compared ertapenem (1 g parenterally once a day) with ceftriaxone (1 g parenterally once a day) and enrolled a total of 850 patients. Both regimens allowed the option to switch to oral ciprofloxacin (500 mg twice daily) for a total of 10 to 14 days of treatment (parenteral and oral). The microbiological success rates (combined trials) at 5 to 9 days posttherapy (test-of-cure) were 89.5% (229/256) for ertapenem and 91.1% (204/224) for ceftriaxone.
Ertapenem was evaluated in adults for the treatment of acute pelvic infections in a randomized, double-blind, non-inferiority clinical trial. This trial compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 3 to 10 days and enrolled 412 patients including 350 patients with obstetric/postpartum infections and 45 patients with septic abortion. The clinical success rates in the clinically evaluable population at 2 to 4 weeks posttherapy (test-of-cure) were 93.9% (153/163) for ertapenem and 91.5% (140/153) for piperacillin/tazobactam.
Ertapenem was evaluated in adults for prophylaxis of surgical site infection following elective colorectal surgery in a multicenter, randomized, double-blind, non-inferiority clinical trial. This trial compared a single intravenous dose of ertapenem (1 g) versus cefotetan (2 g) administered over 30 minutes, 1 hour before elective colorectal surgery. Test-of-prophylaxis was defined as no evidence of surgical site infection, post-operative anastomotic leak, or unexplained antibiotic use in the clinically evaluable population up to and including at the 4-week posttreatment follow-up visit. The trial included 500 patients randomized to ertapenem and 502 patients randomized to cefotetan. The modified intent-to-treat (MITT) population consisted of 451 ertapenem patients and 450 cefotetan patients and included all patients who were randomized, treated, and underwent elective colorectal surgery with adequate bowel preparation. The clinically evaluable population was a subset of the MITT population and consisted of patients who received a complete dose of study therapy no more than two hours prior to surgical incision and no more than six hours before surgical closure. Clinically evaluable patients had sufficient information to determine outcome at the 4-week follow-up assessment and had no confounding factors that interfered with the assessment of that outcome. Examples of confounding factors included prior or concomitant antibiotic violations, the need for a second surgical procedure during the study period, and identification of a distant site infection with concomitant antibiotic administration and no evidence of subsequent wound infection. Three-hundred forty-six (346) patients randomized to ertapenem and 339 patients randomized to cefotetan were clinically evaluable. The prophylactic success rates at 4 weeks posttreatment in the clinically evaluable population were 70.5% (244/346) for ertapenem and 57.2% (194/339) for cefotetan (difference 13.3%, [95% C.I.: 6.1, 20.4], p < 0.001). Prophylaxis failure due to surgical site infections occurred in 18.2% (63/346) ertapenem patients and 31.0% (105/339) cefotetan patients. Post-operative anastomotic leak occurred in 2.9% (10/346) ertapenem patients and 4.1% (14/339) cefotetan patients. Unexplained antibiotic use occurred in 8.4% (29/346) ertapenem patients and 7.7% (26/339) cefotetan patients. Though patient numbers were small in some subgroups, in general, clinical response rates by age, gender, and race were consistent with the results found in the clinically evaluable population. In the MITT analysis, the prophylactic success rates at 4 weeks posttreatment were 58.3% (263/451) for ertapenem and 48.9% (220/450) for cefotetan (difference 9.4%, [95% C.I.: 2.9, 15.9], p=0.002). A statistically significant difference favoring ertapenem over cefotetan with respect to the primary endpoint has been observed at a significance level of 5% in this trial. A second adequate and well-controlled trial to confirm these findings has not been conducted; therefore, the clinical superiority of ertapenem over cefotetan has not been demonstrated.
Ertapenem was evaluated in pediatric patients 3 months to 17 years of age in two randomized, multicenter clinical trials.
The first trial enrolled 404 patients and compared ertapenem (15mg/kg intravenous (IV) every 12 hours in patients 3 months to 12 years of age, and 1 g IV once a day in patients 13 to 17 years of age) to ceftriaxone (50mg/kg/day IV in two divided doses in patients 3 months to 12 years of age and 50 mg/kg/day IV as a single daily dose in patients 13 to 17 years of age) for the treatment of complicated urinary tract infection (UTI), skin and soft tissue infection (SSTI), or community-acquired pneumonia (CAP). Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of up to 14 days of treatment (parenteral and oral). The microbiological success rates in the evaluable per protocol (EPP) analysis in patients treated for UTI were 87.0% (40/46) for ertapenem and 90.0% (18/20) for ceftriaxone. The clinical success rates in the EPP analysis in patients treated for SSTI were 95.5% (64/67) for ertapenem and 100% (26/26) for ceftriaxone, and in patients treated for CAP were 96.1% (74/77) for ertapenem and 96.4% (27/28) for ceftriaxone.
The second trial enrolled 112 patients and compared ertapenem (15mg/kg IV every 12 hours in patients 3 months to 12 years of age, and 1 g IV once a day in patients 13 to 17 years of age) to ticarcillin/clavulanate (50 mg/kg for patients < 60 kg or 3.0 g for patients > 60 kg, 4 or 6 times a day) up to 14 days for the treatment of complicated intra-abdominal infections (IAI) and acute pelvic infections (API). In patients treated for IAI (primarily patients with perforated or complicated appendicitis), the clinical success rates were 83.7% (36/43) for ertapenem and 63.6% (7/11) for ticarcillin/clavulanate in the EPP analysis. In patients treated for API (post-operative or spontaneous obstetrical endomyometritis, or septic abortion), the clinical success rates were 100% (23/23) for ertapenem and 100% (4/4) for ticarcillin/clavulanate in the EPP analysis.
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 8th Edition; CLSI Document M7-A8. Clinical and Laboratory Standards Institute, Wayne, PA, 2009.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing - 21st Informational Supplement. CLSI Document M100-S21. Clinical and Laboratory Standards Institute, Wayne, PA, 2011.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests. 10 Edition; CLSI Document M2-A10. Clinical and Laboratory Standards Institute, Wayne, PA, 2009.
4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria - 7th Edition; CLSI Document M11-A7. Clinical and Laboratory Standards Institute, Wayne, PA, 2007.
Last reviewed on RxList: 8/26/2011
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