Role of serum protein binding and multiple antibiotic doses in the extravascular distribution of ceftizoxime and cefotaxime

The effect of protein binding on drug penetration into blister fluid was evaluated by using cefonicid, ceftizoxime, and cefotaxime. Drug concentrations in a chamber with a high surface area/volume ratio (i.e., paper disk) follow changes in serum more closely than do those in a chamber with a low surface area/volume ratio. Both the area under the concentration-time cu'rve ratio and the concentration ratio (by the disk method) for cefonicid were statistically lower than the ratios for ceftizoxime and cefotaxime. The high degree of protein binding of cefonicid results in the availability of less drug for diffusion to blister fluid than with the low-protein-binding ceftizoxime and cefotaxime.Drug concentrations in blister fluid are critical, since most bacterial infections occur in the interstitial space and not the intravascular space. Many investigators have tried to correlate the penetration of P-lactam antibiotics into interstitial fluid with the degree to which the drugs bind protein.However, such studies have yielded disparate results, as shown by reports of poor cefazolin extravascular penetration in one study (11,12) and of good penetration in other studies (1,4,5,7,8).Cefonicid is 98% bound to serum protein and is used for the treatment of skin and soft tissue infections (3). In view of the high degree of protein binding of this compound, the penetration of the drug into blister fluid was compared with the penetrations of ceftizoxime and cefotaxime (<40% bound) by using a modified suction blister technique (10).Six healthy volunteers (four male and two female) between the ages of 25 and 29 years and weighing 51 to 80 kg were enrolled in this study. Female volunteers were not pregnant or receiving oral contraceptives.Each subject received a single 30-mg/kg (body weight) dose of cefonicid, ceftizoxime, or cefotaxime on three occasions. A treatment schedule was assigned randomly to each subject. There was at least 1 week between doses. Drugs were given by constant intravenous infusion over 5 min into an antecubital vein via an indwelling intravenous catheter. Nornmal saline (3 ml) was injected immediately after the infusion to flush the catheter. Blood samples were obtained from the cannulus, after discarding the first 2 ml, at 0,5,10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 480, 600, 720, and 1,440 min after dosing. Each volunteer had eight skiii blisters produced on his or her forearm by the modified suction blister technique previously described by Shyu et al. (10).In the protein-binding study, cefonicid standards were prepared in freshly pooled human serum at 37°C at 450, 400, 350, 300, 250, 175, 150; 125, 100, 75, 50, 25, and 12.5 immediately after preparation. Ultrafiltration was performed at 37°C and 1,000 x g for 15 min.Cefonicid concentrations were determined by a microbiological assay with Bacillus subtilis ATCC 6633 as the test organism. Serum standards were prepared in pooled serum, and blister fluid standards were prepared in 50% pooled serum and 50% phosphate buffer (0.1 M, p...

supporting

confidence: 81%

Effect of protein binding on drug penetration into blister fluid

Shyu

Quintiliani

Nightingale

et al. 1988

“…A delay in the onset of antibacterial effects might be most important in the setting of surgical prophylaxis, in which the protective effect is greatest when therapeutic drug concentrations are present in extravascular tissues at the time of bacterial inoculation (1,5). However, the large amount of drug ultimately accumulating in peripheral protein-containing extravascular spaces results in a relatively more protracted antibacterial effect following the suspension of treatment, since drug concentrations tend to decline more slowly under these conditions (6,11,13).…”

Section: Discussionmentioning

confidence: 99%

Significance of "extravascular" protein binding for antimicrobial pharmacodynamics in an in vitro capillary model of infection

Dudley

Blaser

Gilbert

et al. 1990

The effect of protein binding in an "extravascular" space on antimicrobial pharmacodynamics was studied in an in vitro capillary model of infection. Simulated 500-mg oral doses of dicloxacillin (-96% bound) or cephalexin (<5% bound) were administered every 6 h for four doses. A 10-fold-higher dose of dicloxacillin was also studied to determine the effect of drug concentration on Studies in animals (6,19,20), in vitro models (21), and humans (16,22,25) have shown that high serum protein binding significantly affects the kinetics of extravascular drug distribution. High binding to serum proteins (e.g., albumin) in the intravascular space tends to reduce the amount of drug available for diffusion into extravascular spaces (22,25). However, a considerable amount of serum protein also is distributed to the extravascular space; for example, approximately 60% of the total exchangeable albumin in the body is found in the extravascular space, but at lower concentrations than in the intravascular space (17). These proteins can bind a drug and result in higher concentrations of total (i.e., bound plus unbound) drug than those observed in protein-free spaces (2,9,11,19,21).There are few data on the effect of protein binding in an infected extravascular space on antibacterial pharmacodynamics following multiple simulated human doses. Therefore, the pharmacodynamics of simulated doses of a highly protein-bound drug (dicloxacillin) was compared with that of a drug with negligible protein binding (cephalexin) in an in vitro model of infection. The results show that during the early stages of treatment, high protein binding significantly retards the antimicrobial effects of dicloxacillin. MATERIALS AND METHODSDrugs. Cephalexin and dicloxacillin analytical-grade powders were supplied by Eli Lilly & Co., Indianapolis, Ind. Stock solutions were prepared in appropriate amounts of sterile, distilled, deionized water, which was further diluted in Mueller-Hinton broth (MHB) for dose administration. * Corresponding author.Bacteria. Staphylococcus aureus ATCC 25923 was used as the test strain. Susceptibility testing was done by the method of Stratton and Reller (24), with the exception that serumsupplemented medium (MHB-SER) was 75% MHB and 25% human serum. The MIC and MBC for dicloxacillin against this strain in MHB were 0.25 ,g/ml; in MHB-SER, they were 2 and 8 ,ug/ml, respectively. The MIC and MBC for cephalexin against this strain were 4 and 8 ,ug/ml, respectively, in both MHB and MHB-SER.Protein binding. The binding of dicloxacillin in MHB-SER was measured with an Amicon MPS-1 unit with YMT membranes (Amicon Corp., Danvers, Mass.). Dicloxacillin was prepared in MHB-SER, and approximately 1 ml was added to ultrafiltration units. Samples were centrifuged for 20 min at 1,000 x g (swinging bucket) at 37°C. The ultrafiltrate was collected and assayed for dicloxacillin content by agar well diffusion assay using Bacillus subtilis.In vitro capillary model of infection. A two-compartment in vitro model was modified to simulate first-order ...

“…The choice of a broad-spectrum cephalosporin (representing firstline therapy today) was based on the current increase in penicillinase-secreting E. coli strains (29). Ceftriaxone was preferred to cefotaxime for practical reasons, as its binding to rabbit serum proteins is similar to that in humans (11,18).…”

Section: Discussionmentioning

confidence: 99%

Persistent Bacteremia in Rabbit Fetuses despite Maternal Antibiotic Therapy in a Novel Intrauterine-Infection Model

Guen

Debillon

Toquet

et al. 2003

The effect of optimized maternal therapy by bactericidal agents was evaluated in a reproducible rabbit model of Escherichia coli maternofetal infection simulating human pharmacokinetics. Intravenous antibiotic therapy was begun in the pregnant rabbit 12 h after bacterial intrauterine inoculation, using a computer-controlled pump to simulate human pharmacokinetics of ceftriaxone (1 g/day) associated or not with gentamicin (3 mg/kg of body weight/day). Data were compared for fetal survival, quantitative blood cultures, fetal histology in treated versus untreated groups, and maternal and fetal antibiotic concentrations in plasma in treated animals. Antibiotic therapy led to dramatic improvement in maternal outcome (100% survival versus 100% death in the untreated group in association with maternal septicemia). Fetal survival also improved, with the two-drug combination providing a more potent effect. After 3 days of treatment, 32% of fetuses survived with one-drug therapy and 62% with two-drug therapy (Yates corrected 2 , P < 0.05). In untreated animals, bacterial counts in blood cultures increased rapidly during the first 24 h up to 8.1 ؎ 0.5 log CFU/ml, but remained relatively constant at all times with antibiotic treatment: 4.5 ؎ 0.7 log CFU/ml at the start of treatment and 6.2 ؎ 0.4 and 5.2 ؎ 0.9 log CFU/ml after 72 h for one-and two-drug therapy, respectively (data are means ؎ standard deviations). The failure of animals to be cured after 3 days of treatment was not due to an inadequate concentration of ceftriaxone, as the residual level in fetal serum at sacrifice was more than 1,000 times the MIC of the microbe. Unexpectedly, inflammation in fetal lung decreased in the treated group after as little as 24 h of antibiotic therapy, despite persistent bacteremia. Although maternal outcome improved and drug concentrations were above the MIC, the treatment did not achieve sterilization of fetuses in utero for this rabbit E. coli maternofetal infection. However, fetal survival showed some improvement, and the histologic features of lung inflammation were reduced.