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

Abstract

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...

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

“…Kill rates of amoxicillin were much higher in active serum, too, despite its low protein binding. This disconnect between MICs and kill rates is very well in agreement with previously published data [8,20,[40][41][42][43][44][45][46][47]. Wouldn't it be more conclusive to derive PD measures not from static but from dynamic endpoints like kill-rates [65]?…”

“…It has been presented that MICs of cefotaxime, its metabolite desacetylcefotaxime, or the combination of both remained unchanged in the presence of human serum while their bactericidal activities were improved [20]. The bacteriostatic activities of tetracyclines were converted into a rapid and pronounced bactericidal effect by fresh human serum [8].…”

“…On the other hand, serum proteins protect the host from serious sequelae of an infection and/or may increase antibacterial activities. It was demonstrated that human immunoglobulin G [6,7] or unknown components present in human [8][9][10][11][12][13][14][15][16][17][18][19][20] and rat-or rabbit-serum [21,22] respectively, may increase antibacterial activities of a variety of drug classes.…”

Effect of Ertapenem Protein Binding on Killing of Bacteria

“…Reductions in antibacterial effects are evident in serum-containing media compared to standard microbiological media for drugs that are extensively bound to serum proteins (7,8,14). Most studies examining changes in bioactivity in relation to protein binding have utilized changes in the MIC and have limited the human serum concentration to 50% (4).…”

Effect of serum on the in vitro activities of 11 broad-spectrum antibiotics

“…A reversible, noncovalent binding of antimicrobial agents to human proteins has been described for penicillins (4) and cephalosporins (4)(5)(6). For the former, increases in MICs were noted in the presence of serum or albumin when tested against both Staphylococcus and Streptococcus species (4).…”