Characteristics ofCeftriaxone Binding toImmunoglobulin G andPotential Clinical Significance

Theinteraction between immunoglobulin G (IgG)andceftriaxone was studied. Usingan ultrafiltration method, we performed doseranging studies ata ceftriaxone concentration rangeof1to720,ug/ml inthe presenceofvarious concentrations ofhumanIgG,humanserum albumin (HSA), andcombinations ofIgGand HSAatpH7.4and37°C. Theresults showedthatceftriaxone binding toIgGwas nonlinear andwasconsistent withthepresenceoftwobinding sites thatpossessdifferent binding capacities andaffinities. Exceptfor increased peakpercent binding astheIgGconcentration increased, thebinding characteristics didnotchange withIgGconcentration. Binding toHSAwas consistent, withthepresenceofonly onehigh-affinity binding site. A mathematical modelbased on theobserved datawas constructed; thismodelwas usedtopredict protein binding atvarious concentrations ofdrug, IgG,HSA,orcombinations ofIgGandHSA inbuffer andinplasma medium.Correlations betweentheobserved versusthepredicted values were excellent inbothmedia. Simulations withthemodelindicated thatpatients withhypergammaglobulinemia havean increased potential ofbeing exposed toprolonged subinhibitory concentrations ofceftriaxone ifthedrugisgiven onceevery24h. Increasing use oflarge dosesofintravenous (i.v.) immunoglobulin G (IgG) necessitates acloser examination ofdrug binding toimmunoglobulins toascertain whether drugdosingregimens needtobealtered tomaintain drugeffectiveness.Suspicion that certain drugs may bindtoimmunoglobulins hasbeenheightened bya recentreportshowing that large dosesofhumanIgGgiven inconjunction withceftriaxonetoneonatal ratsinfected with agroupB streptococcus raised themortality ratefrom56.5%whenceftriaxone was usedalone to95.7%whenthey were usedtogether (10). One potential explanation forthis phenomenon isthatIgGbinds ceftriaxone. Morerecently, Cantuetal.(7)reported unusual vancomycin pharmacokinetics ina patient withIgAmyeloma. Totalconcentrations ofvancomycin inserum were extremely elevated, butthefreefraction inserum was only 3%,whilecontrol samples fromotherpatients receiving vancomycin were 62to90%.Theelimination half-life was prolonged despite normalrenal function, andvancomycin therapy was clinically ineffective. Extensive binding ofvancomycin, presumably tohighconcentrations oftheIgA protein, was suspected toaccountforthese observations. TheIgAsubtype involved was notcharacterized. To prove thehypothesis that some drugs may bindto immunoglobulins, a detailed invitro kinetic evaluation was undertaken withIgG.Sinceceftriaxone was theantibiotic usedintheratstudy notedabove(10), thatdrugwas chosen forthis study. Moreover, cephalosporins arethemostcommonlyusedantibiotic drugsinhospitalized, infected patients, andtherefore, theyare themostlikely antibiotic grouptobeusedconcomitantly withlarge i.v. dosesofIgG. Theessential kinetic features ofceftriaxone areits extensiveandsaturable protein binding inthetherapeutic range andelimination about equally bybiliary secretion andbythe