Pharmacokinetics of cefotaxime in normal human volunteers

Section: Discussionsupporting

confidence: 89%

Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis

Trang¹,

Jacobs²,

Kearns³

et al. 1985

“…The major route of elimination for moxalactam is via the kidneys. We found a mean of 61% in the urine, which is similar to the 55 to 76% reported by others (24,29,32,35 (7,9,10,12,22) and 76.1 min calculated from our own data, is much more rapid than that of cefoperazone (1,6,33,34) and moxalactam (19,29,35,36 Elimination of cefotaxime is rapid, with about 90% of the dose recovered in urine by HPLC, of which two-thirds is detected as unchanged cefotaxime and one-third as the major metabolite desacetyl cefotaxime. Bax et al (2) reported a total urine recovery of 87% with 35% as desacetylated metabolite, compared with a total recovery rate of 89.6% with 29.1% as metabolite in our study.…”

Section: Methodssupporting

confidence: 91%

Comparative pharmacokinetics of cefoperazone, cefotaxime, and moxalactam

Kemmerich¹,

Lode²,

Belmega³

et al. 1983

The pharmacokinetics of cefoperazone, cefotaxime, and moxalactam were compared in a cross-over randomized study in 10 healthy volunteers. Each subject received 1.0 g of the three drugs by bolus intravenous injection over 3 min. Serum and urine concentrations were assayed by a microbiological method and in addition by high-pressure liquid chromatography (HPLC) for cefotaxime in five subjects. Maximal concentrations in serum 5 min after the injection were 163 ± 40.3 mg/liter for cefoperazone, 86.1 ± 19.0 mg/liter for cefotaxime, and 95.5 ± 21.1 mg/liter for moxalactam. After 12 h, 1.2 ± 1.4 mg of cefoperazone per liter and 1.8 ± 0.9 mg of moxalactam per liter could still be measured. Eight hours after the administration of cefotaxime, serum concentrations were below the detection limit of 0.3 mg/liter in most subjects. By HPLC analysis, the mean maximal concentration of desacetyl cefotaxime was 16.6 ± 10.5 mg/liter 5 min after application; the metabolite exceeded the serum concentration of the parent compound after 1 to 2 h. Relevant pharmacokinetic parameters were calculated, using two-and three-compartment models. The terminal half-life was 144.1 ± 37.3 min for cefoperazone, 76.1 ± 32.0 min for cefotaxime, and 272.4 ± 114.1 min for moxalactam. The apparent volume of distribution corresponded to the extracellular volume. Only 25.1 ± 8% of cefoperazone could be detected in urine compared with 53.3 ± 8.1% of cefotaxime and 61.0 ± 9.2% of moxalactam in 24 h. A total of 89.6 ± 11.4% of the cefotaxime dose could be recovered by HPLC in urine, 60.6 ± 7.7% as cefotaxime and 29.1 ± 7.0% as desacetyl cefotaxime.Cefoperazone, cefotaxime, and moxalactam are three newly developed cephalosporins with a high level of resistance to P-lactamase hydrolysis and a broad range of antibacterial action (13,18,28). The purpose of the present study was to compare the pharmacokinetics of these cephalosporins after a single intravenous (i.v.) bolus injection. MATERIALS AND METHODSSubjects. Ten healthy volunteers, five males and five females, 21 to 51 years of age (mean, 32 years of age), 44 to 82 kg (mean, 66.7 kg), participated as test subjects. Informed written consent was obtained from each subject.Administration of antibiotics. Cefoperazone sodium (Ch.-BI 130) was supplied by Pfizer GmbH, Karlsruhe, Federal Republic of Germany; moxalactam disodium (Ch.-BI-4473-9C) by E. Lilly Giessen, and cefotaxime (batch no. 100 N31) by Hoechst AG, Frankfurt, Federal Republic of Germany. The compounds were reconstituted in sterile water just before administration. Each subject received 1.0 g of cefoperazone, cefotaxime, and moxalactam by an i.v. injection over 3 min. The antibiotics were given by random allotment with a 1-to 2-week interval between the injections.Sampling. Blood samples were taken over 12 h: before injection; after 5, 10, 20, 30, and 45 min; and after 1, 1.5, 2, 3, 4, 6, 8, and 12 h. Blood specimens were centrifuged at 4°C after clotting at room temperature. Urine was collected 0 to 3, 3 to 6, 6 to 12, and 12 to 24 h after dosage.An...

“…The single nucleotide polymorphisms (SNPs) are displayed in Table 1. The DAP susceptibility of each isolate was determined by broth microdilution (11) in the presence or absence of static concentrations of nine different ␤-lactam antibiotics corresponding to the maximum, average, and minimum free concentrations (fC max , fC avg , and fC min , respectively) of that agent in serum (12)(13)(14)(15)(16)(17)(18). All antibacterials were purchased as commercial agents, except cefuroxime and cefotaxime (CTX), which were purchased from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

β-Lactam Antibiotics Targeting PBP1 Selectively Enhance Daptomycin Activity against Methicillin-Resistant Staphylococcus aureus

Berti

Sakoulas

Nizet

et al. 2013

The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of subinhibitory concentrations of antistaphylococcal ␤-lactam antibiotics by an undefined mechanism. Given the variability in the penicillin-binding protein (PBP)-binding profiles of different ␤-lactam antibiotics, the purpose of this study was to examine the relative enhancement of DAP activity against MRSA by different ␤-lactam antibiotics to determine if a specific PBP-binding profile is associated with the ability to enhance the anti-MRSA activity of DAP. We determined that both broad-and narrowspectrum ␤-lactam antibiotics known to exhibit PBP1 binding demonstrated potent enhancement of DAP anti-MRSA activity, whereas ␤-lactam antibiotics with minimal PBP1 binding (cefoxitin, ceftriaxone, cefaclor, and cefotaxime) were less effective. We suspect that PBP1 disruption by ␤-lactam antibiotics affects pathways of cell division in S. aureus that may be a compensatory response to DAP membrane insertion, resulting in DAP hypersusceptibility. The presence of subinhibitory concentrations of ␤-lactam antibiotics has been shown to increase daptomycin (DAP) activity against both DAP-susceptible and DAP-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) strains (1, 2). The mechanisms of this are not fully understood, but it has been attributed to a ␤-lactam-induced increase in the binding of DAP to bacterial cell membranes (3, 4). These observations fall in line with the observed DAP-␤-lactam "seesaw effect" whereby S. aureus frequently gains susceptibility to ␤-lactams upon the acquisition of the DNS phenotype (5). Collectively, these in vitro observations have been translated to antimicrobial therapy combinations to successfully manage difficult-to-treat MRSA infections (2, 3, 5, 6).Most in vivo studies have focused on three antistaphylococcal ␤-lactams, oxacillin, nafcillin (NAF), and ceftaroline, the latter because of its unique anti-MRSA properties among the ␤-lactam classes. However, no studies have compared the relative differences among the various ␤-lactam classes in their DAP-potentiating properties at therapeutically relevant concentrations.The potentiation of DAP activity obtained by the addition of a ␤-lactam antibiotic may provide a straightforward way to enhance anti-MRSA therapy against both DAP-susceptible and DNS MRSA. Achieving a bacteriostatic DAP area under the concentration-time curve (AUC)/MIC ratio against S. aureus (438 Ϯ 67) is challenging at a normal dose of 6 mg/kg (AUC ϭ 705 Ϯ 67) when the organism's DAP MIC is 2 g/ml or greater (7). Dose escalation to 8 or 10 mg/kg improves the likelihood of attaining this target parameter against strains with elevated MICs but results in a higher minimum drug concentration in serum (C min ), which has been associated with an increased risk of creatine phosphokinase elevation (8). High-dose DAP therapy is of particular concern in obese patients, where DAP AUCs are reported to be 30% greater than in nonobese matched co...