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• W1498715052 abstract "β-lactam antibiotics inhibit bacterial growth by inactivating penicillin-binding proteins (PBPs), which are located on the outermost face of the cytoplasmic membrane [1Spratt BG Distinct penicillin binding proteins involved in the division, elongation and shape of Eschetidua coli K12.Proc Nat Acad Sci USA. 1975; 72: 2999-3003Crossref PubMed Scopus (664) Google Scholar]. Affinity for PBPs is an important factor that determines the bactericidal or bacteriostatic properties of these drugs and their ultimate effectiveness on the bacterial cells [2Satta G Cornaglia G Mazzariol A Golini G Valisena S Fontana R Targets for bacteriostatic and bactericidal activities of beta-lactam antibiotics against Escherichia coli reside in different penicillin-binding proteins.Antimicrob Agents Chemother. 1995; 39: 812-818Crossref PubMed Scopus (43) Google Scholar]. The serum protein binding of a number of cephalosporins has raised a number of questions about the antimicrobial effectiveness of these agents. One of these questions is whether antibiotic molecules bound to plasma protein are likely to cross the outer membrane of Grain-negative bacteria. The addition of serum albumin in vitro does indeed diminish the effectiveness of antimicrobials that bind extensively to this protein. Ceftriaxone is a parenteral cephalosporin that displays a broad spectrum of activity against both Gram-negative and Gram-positive organisms and, like other β-lactams, inhibits bacterial growth by inactivating PBPs. It differs from the other members of this class in having a long serum half-life, which allows once-daily dosing. While helping to lengthen dosing intervals, the extensive serum protein binding of ceftriaxone obviously raises the question of its real antimicrobial effectiveness in vivo. However, high protein binding cannot impair the in vivo activity of ceftriaxone if the free drug fraction in plasma or extravascular fluids is higher than that required to inhibit essential PBPs [3McNamara PJ Trueb V Stoeckel K Protein binding of ceftriaxone in extravascular fluids.J Pharm Sci. 1988; 77: 401-404Crossref PubMed Scopus (11) Google Scholar]. We compared the PBP binding of ceftriaxone and cefotaxime (a cephalosporin with low human albumin binding) in the presence of human serum albumin (HSA) at concentrations comparable with plasma levels. Escherichia coli K12 was grown in shaken cultures of 1 L Mueller–Hinton broth in 3 L conical flasks at 37°C. When cultures reached the exponential growth phase (0.8 turbidity at OD 600), they were divided into aliquots of 200 mL and HSA was added (40 mg/mL, final concentration). After 5 min, antibiotics at different concentrations were added and incubation was continued for 15 min at 37°C with moderate shaking. Samples were then chilled rapidly in ice, centrifuged at 25 000 g for 5 min at 2°C, and washed twice with 10 mL of ice-cold 50 μm sodium phosphate buffer (pH 7). After suspension in 5 mL of ice-cold buffer, the bacteria were broken by sonication for five 15-s periods with cooling on ice. Cell envelopes were washed twice in ice-cooled buffer by centrifugation at 100000 g for 30 min at 2°C and the pellet was resuspended in 200 μL of ice-cold buffer. Radioactive penicillin (10 μg/ml.) was added to the isolated envelopes to saturate PBPs that had not previously bound unlabelled β-lactams penetrating into the living bacteria. The labelled PBPs were solubilized by Sarkosyl; PBPs were separated by SDSPAGE and detected on gels by fluorography [1Spratt BG Distinct penicillin binding proteins involved in the division, elongation and shape of Eschetidua coli K12.Proc Nat Acad Sci USA. 1975; 72: 2999-3003Crossref PubMed Scopus (664) Google Scholar]. The MICs of both ceftriaxone and cefotaxime for E. coli K12 were 0.125 μg/mL. In the presence of 4% HSA, the MIC of ceftriaxone rose to 1 μg/mL while that of cefotaxime was unchanged. When growing E. coli cells were incubated with 0.1, 1 and 10 μg/mL of ceftriaxone in the presence or absence of HSA; HSA did not impair the ability of the antibiotic to saturate PBPs 2 and 3 and to bind PBP 1 extensively at 10 μg/mL, but reduced the binding of 1 μg/mL ceftriaxone to all essential PBPs by 72%–80% and completely inhibited the binding of 0.1 μg/mL ceftriaxone. It should be borne in mind that ceftriaxone concentrations 24 h after administration are 13.2 ± 3.2 mg/L after 1 g i.v. and 12.6 μg/mL after 1 g i.m. The PBP binding of both drugs in cells growing in the presence of HSA was then compared at drug concentrations that are found in plasma after a 1-g intravenous infusion. According to published data, the plasma concentration of ceftriaxone decreases from mean levels of 119.9 ± 18.1 μg/mL to mean values of 46 ± 8.1 μg/mL in 8 h, and the plasma concentrations of cefotaxime drop from 20 ± 1.9 μg/mL to ≤0.1 μg/mL in the same interval. The lowest concentration of ceftriaxone used (i.e. that found 8 h after administration) saturated both PBP 2 and 3 and bound 90% of PBP 1; this concentration caused filament formation and rapid lysis after 2 h incubation. In contrast, concentrations of cefotaxime found 4 h after administration saturated only PBP 3 and caused filament formation and slow lysis. At concentrations maintained in the plasma for 8 h, sufficient ceftriaxone remained unbound to HSA to inhibit bacterial growth, inactivate two of three essential PBPs in E. coli, and induce morphological alterations and cell lysis. Though many cephalosporins show primary affinity for PBP 3 and bind only PBP 3 at their lowest effective concentrations [4Curtis NAC Orr D Ross GW Boulton MG Competition of beta-lactam antibiotics for the penciling-binding proteins of Pseudomonas actugiuosa, Enterobacter doacae, Klebsiella aerogenes, Proteus rettgeri, and Escherichia coli. Comparison with antibacterial activity and effects upon bacterial morphology.Antimicrob Agents Chemother. 1979; 16: 325-328Crossref PubMed Scopus (65) Google Scholar], the saturation of both PBP 2 and 3 results in more rapid lysis and an enhanced bactericidal effect [2Satta G Cornaglia G Mazzariol A Golini G Valisena S Fontana R Targets for bacteriostatic and bactericidal activities of beta-lactam antibiotics against Escherichia coli reside in different penicillin-binding proteins.Antimicrob Agents Chemother. 1995; 39: 812-818Crossref PubMed Scopus (43) Google Scholar, 5Gutmann L Vincent S Billot-Klein D Acar JF Mrèna E Williamson R Involvement of penicillin-binding protein 2 with other penicillin-binding proteins in lysis of Eschericlua coli by some beta-lactam antibrotics alone and in synergistic lytic effect of amdinocillin (mecillinam).Antimicrob Agents Chemother. 1986; 30: 906-912Crossref PubMed Scopus (43) Google Scholar]. Thus, the high serum protein binding does not impair the ability of ceftriaxone to inhibit essential PBPs and consequently the high in vivo efficacy of the drug. PBPs of all Enterobacteriaceae have similar physiological properties and β-lactam affinity; thus, the comparable efficacies shown by ceftriaxone and cefotaxime in infections caused by these organisms probably arise, as in the case of E. coli, from the fact that free ceftriaxone concentrations are maintained for several hours above the MIC and the minimum concentrations required to saturate essential PBPs. Pharmacokinetic studies have indeed shown that the serum concentrations of ceftriaxone 24 h after administration far exceed both the MICs and the MBCs of many Enterobacteriaceae, including β-lactamase-producing strains." @default.
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• W1498715052 title "Affinities of cephalosporins for penicillin-binding proteins and their antibacterial activities in the presence of human serum albumin" @default.
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• W1498715052 doi "https://doi.org/10.1111/j.1469-0691.2000.tb02052.x" @default.
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