Ertapenem Pharmacokinetics and Impact on Intestinal Microflora, in Comparison to Those of Ceftriaxone, after Multiple Dosing in Male and Female Volunteers

Abstract

The pharmacokinetics of ertapenem and ceftriaxone were investigated in an open, randomized, two-period crossover study after single-and multiple-dose administration in 10 healthy volunteers (five women and five men). Both antibiotics were administered intravenously once daily for 7 days at dosages of 1 g (ertapenem) and 2 g (ceftriaxone). The concentrations of the antibiotics in serum and urine were quantified by the agar well diffusion method bioassay and, in addition, for ertapenem only, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). For ertapenem the maximum concentration of the drug in plasma (C max ) was 256 mg/liter, the half-life was 20.7 h, and the area under the plasma concentration-time curve (AUC) was 830 mg ⅐ h/ liter. The concentrations in fecal samples were (mean value) 37.2 and 32.7 mg/kg on day 4 and day 8, respectively. Ceftriaxone exhibited a mean C max of 315 mg/liter, a half-life of 7.6 h, and an AUC of 1,556 mg ⅐ h/liter. The mean concentrations in fecal samples were 153 and 258 mg/kg on day 4 and day 8, respectively. No accumulation of ertapenem or ceftriaxone was detected at steady state. A slightly but significantly decreased AUC for ertapenem was detected for the female volunteers. No serious adverse event was observed. Both antibiotics induced a marked decrease in the anaerobic microflora (4-log-unit decreases in lactobacilli, bifidobacteria, clostridia, and bacteroides) and Escherichia coli, whereas the number of enterococci increased (4 log units). A slight overgrowth of yeasts was observed with both regimens. In all cases the microflora returned to normal levels on days 21 to 35.Ertapenem, recently described as the first class 1 carbapenem (11), is a parenteral broad-spectrum beta-1-methyl-carbapenem with a long half-life in serum. It has been shown to be effective for the treatment of community-acquired pneumonia (9); intra-abdominal infections, skin and skin structure infections, and acute pelvic infections (14); and urinary tract infections (15). In contrast to imipenem and meropenem, ertapenem lacks sufficient activity against Pseudomonas aeruginosa, enterococci, and Acinetobacter spp.; but clinical trials have shown that Pseudomonas infections can be treated with ertapenem.Ertapenem can be administered once daily due to its long half-life in plasma. The long half-life in plasma reflects its high level of plasma protein binding.Ceftriaxone matches ertapenem in both its pharmacokinetics and its antibacterial spectrum for the treatment of community-acquired pneumonia and has been used as a comparator drug for ertapenem in clinical trials (9, 17). Ceftriaxone is a broad-spectrum parenteral cephalosporin with a long half-life that also requires administration only once daily.The application of antibacterial agents for the treatment of infections may have a number of potentially adverse effects on the normal oropharyngeal and intestinal microflora. The normal microflora acts as a barrier against colonization by potentially pathogenic microorganisms and agai...

Severe Sepsis Facilitates Intestinal Colonization by Extended-Spectrum-β-Lactamase-Producing Klebsiella pneumoniae and Transfer of the SHV-18 Resistance Gene to Escherichia coli during Antimicrobial Treatment

“…Second, we measured colonization by only E. coli rather than the whole intestinal microbiota, which includes anaerobic microflora. Previous studies have suggested that ceftriaxone treatment may also significantly decrease the intestinal density of anaerobes (34,45), and intestinal anaerobic microflora are more likely to be responsible for colonization resistance (5,6,31). Third, the intrinsic physiological differences between rats and humans may result in disparate microbiological and pharmacological responses, thus limiting the external validity of the conclusions of this study.…”

Relative Fecal Abundance of Extended-Spectrum-β-Lactamase-Producing Escherichia coli Strains and Their Occurrence in Urinary Tract Infections in Women

“…Stool samples for which a zone of inhibition was observed around the disc, following overnight incubation at 37°C, were determined to have antibacterial activity. Studies in which volunteers were experimentally exposed to antibiotics have shown that this test is always negative for samples taken before drug exposure began (14).…”

Acquisition of Resistant Bowel Flora during a Double-Blind Randomized Clinical Trial of Ertapenem versus Piperacillin-Tazobactam Therapy for Intraabdominal Infections

“…Treatment of patients with broad-spectrum antimicrobial agents predisposes to the emergence of resistant bowel flora during therapy (1,4,12,22,23,26,27). Resistant organisms can emerge through genetic mutation or induction, can be acquired exogenously, or, if already present in undetectably low concentrations, may overgrow under selective pressure.…”