Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis

We studied cefotaxime (CTX) and desacetylcefotaxime (dCTX) pharmacokinetics in 19 children (ages, 7 to 16 years) with various degrees of renal function. The patients were stratified into three groups according to 24-h urinary creatinine clearance (CLCR) values: group I, CLCR > 80 ml/min/1.73 m2 (n = 7); group II, CLCR from 30 to 80 ml/min/1.73 m2 (n = 6); and group III, CLCR < 30 ml/min/1.73 m2 (n = 6). A single 50-mg/kg dose of CTX was given intravenously to each patient after which blood and urine samples were collected and analyzed for CTX and dCTX by high-performance liquid chromatography. Safety was assessed by pre-and poststudy blood chemistries and urinalysis. The mean values for total body clearance of CTX for groups I, II, and III were 158.1 ± 38.8, 118.3 ± 50.8, and 84.8 ± 11.7 ml/min/1.73 M2, respectively (P < 0.01). Renal clearance also decreased across groups, I, II, and III, with values of 77.5 ± 20.2, 41.3 ± 18.5, and 11.4 ± 7.7 ml/min/1.73 m2 respectively (P < 0.0001). Both the CTX fraction nonrenally cleared and elimination half-life increased with decreasing renal function. The CTX volume of distribution at steady state was not affected by renal disease. The renal clearance values of dCTX were 146.4 ± 71.4, 64.5 ± 32.1, and 14.4 ± 8.7 ml/min/1.73

Section: Discussionsupporting

confidence: 83%

Section: Discussioncontrasting

confidence: 57%

Pharmacokinetics of cefotaxime and its active metabolite in children with renal dysfunction

Paap¹,

Nahata²,

Mentser³

et al. 1991

“…Previous studies in human have explored only cefotaxime distribution in cerebrospinal fluid (CSF) (5)(6)(7)(8). Among them, two in adults (5, 6) and one in children (7) reported CSF-to-plasma AUC ratios lower than 20%, indicating poor penetration of cefotaxime in CSF as reported now in brain (26.1 Ϯ 12.1% in the present study).…”

Section: Discussionmentioning

confidence: 62%

“…The exact location of bacteria in meningitis is still unclear. Few studies, limited to investigations in cerebrospinal fluid (CSF), were performed (5)(6)(7)(8), and they found a low central distribution of cefotaxime (5,6). In humans, the easiest way to study antibiotic penetration into CNS is to measure the concentration in CSF from lumbar puncture or external ventricular drainage.…”

mentioning

confidence: 99%

Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

Dahyot‐Fizelier

Frasca

Grégoire

et al. 2013

Central nervous system (CNS) antibiotic distribution was described mainly from cerebrospinal fluid data, and only few data exist on brain extracellular fluid concentrations. The aim of this study was to describe brain distribution of cefotaxime (2 g/8 h) by microdialysis in patients with acute brain injury who were treated for a lung infection. Microdialysis probes were inserted into healthy brain tissue of five critical care patients. Plasma and unbound brain concentrations were determined at steady state by high-performance liquid chromatography. In vivo recoveries were determined individually using retrodialysis by drug. Noncompartmental and compartmental pharmacokinetic analyses were performed. Unbound cefotaxime brain concentrations were much lower than corresponding plasma concentrations, with a mean cefotaxime unbound brain-to-plasma area under the curve ratio equal to 26.1 ؎ 12.1%. This result was in accordance with the brain input-to-brain output clearances ratio (CL in,brain /CL out,brain ). Unbound brain concentrations were then simulated at two dosing regimens (4 g every 6 h or 8 h), and the time over the MICs (T>MIC) was estimated for breakpoints of susceptible and resistant Streptococcus pneumoniae strains. T>MIC was higher than 90% of the dosing interval for both dosing regimens for susceptible strains and only for 4 g every 6 h for resistant ones. In conclusion, brain distribution of cefotaxime was well described by microdialysis in patients and was limited.

“…In addition, cefotaxime can be metabolized to desacetylcefotaxime, an active compound most similar in activity to some older cephems, such as cefuroxime (3). Favorable synergistic and additive interactions have been reported in vitro and in vivo and attributed to the presence of the desacetyl metabolite (3,17). Ceftriaxone is not significantly metabolized, but it does have >95% protein binding compared with 10 to 40% for cefotaxime or desacetylcefotaxime (13,15).…”

mentioning

confidence: 99%

Antimicrobial activity of ceftriaxone, cefotaxime, desacetylcefotaxime, and cefotaxime-desacetylcefotaxime in the presence of human serum

Jones¹,

Barry²

1987

Eighty-seven organisms were tested against ceftriaxone, cefotaxime, desacetylcefotaxime, and the combination of cefotaxime and desacetylcefotaxime (1:1 ratio) in broth containing 0, 25, or 50% human serum. In the presence of human serum, ceftriaxone MICs were four-to eightfold higher than those obtained in broth, changing 98% of Staphylococcus aureus strains from the susceptible to the moderately susceptible category and 53% of selected gram-negative strains to a more resistant category. The MICs of cefotaxime, desacetylcefotaxime, and cefotaxime plus desacetylcefotaxime were not adversely affected by human serum; in fact, the bactericidal activity was slightly improved.Serum protein binding by antimicrobial agents can profoundly affect pharmacokinetic properties and antimicrobial activity (4,5,8,16,18,19). In an earlier report (2), we demonstrated that the antistaphylococcal activities of two cephalosporins (cefonicid and ceforanide) tested with human serum were very different, although tests by standardized broth methods generally showed similar spectra. These results favoring ceforanide were attributed to the 98% protein binding of cefonicid.Other newer cephalosporins, i.e., cefotaxime and ceftriaxone, with very similar antimicrobial spectra (7, 13) also greatly differ in their serum half-lives, tissue distribution, and protein binding. In addition, cefotaxime can be metabolized to desacetylcefotaxime, an active compound most similar in activity to some older cephems, such as cefuroxime (3). Favorable synergistic and additive interactions have been reported in vitro and in vivo and attributed to the presence of the desacetyl metabolite (3, 17). Ceftriaxone is not significantly metabolized, but it does have >95% protein binding compared with 10 to 40% for cefotaxime or desacetylcefotaxime (13,15).The purpose of this investigation was to determine the influence of human serum proteins on the in vitro antimicrobial activity of ceftriaxone, cefotaxime, desacetylcefotaxime, and cefotaxime plus desacetylcefotaxime. Broth microdilution susceptibility tests were performed with 51 oxacillin-susceptible Staphylococcus aureus (26 penicillinase producers) strains, 2 enterococci, and 6 Acinetobacter spp., 3 Pseudomonas aeruginosa, 1 Pseudomonas cepacia, 1 Pseudomonas fluorescens, 1 Pseudomonas maltophilia, 4Enterobacter aerogenes, 4 Enterobacter cloacae, 2 Klebsiella oxytoca, 2 Morganella morganii, 1 Providencia stuartii, and 9 Serratia marcescens strains. Serial twofold dilutions of each drug and the combination of cefotaximedesacetylcefotaxime (1:1 ratio) were tested in cationsupplemented Mueller-Hinton broth in concentrations ranging from 0.5 to 32 ,ug/ml. The broth was also diluted with 25 and 50% (vol/vol) of a heat-inactivated human serum pool taken from two normal healthy volunteers. Growth control experiments using Mueller-Hinton broth with and without 50% serum were conducted with each isolate. Strains that * Corresponding author.were inhibited by the serum are not included in this report: nine isolates showed re...