ACC产品-哌拉西林他唑巴坦和实验之间的相互作用

BRIEF REPORTThe interaction between piperacillin/tazobactam and assays for Aspergillus galactomannan and 1,3-beta-D -glucan in patients without risk factors for invasive fungal infectionsG.Metan •C ¸.Ag ˘kus ¸•H.Buldu •A.N.Koc ¸Received:27August 2009/Accepted:12January 2010/Published online:17March 2010ÓUrban &Vogel 2010AbstractBackground The aim of this study was to investigate the interaction between intravenous piperacillin/tazobactam treatment and Aspergillus galactomannan antigen (GM)and 1,3-beta-D -glucan (BDG)test results in patients with-out known risk factors for invasive fungal infections (IFI).Patients and methods Patients without known risk factors for IFI and who were to receive piperacillin/tazobactam monotherapy were considered eligible for the study.Serum samples were obtained both before and after antibiotic infusion on the first,third,seventh and tenth days of a piperacillin/tazobactam treatment course and 4days after the last dose.GM was determined by Platelia Aspergillus ELISA (Bio-Rad Laboratories)and BDG was assayed using the Fungitell kit (Associates of Cape Cod,East Fal-mouth,MA)according to manufacturers’specifications.Results A total of 135serum samples were collected from 15patients.When a cut-off level of C 0.7was used for GM positivity,there were no false positive results.When a cut-off level of C 0.5was used,six serum samples were positive.There were no statistically significant differences between the median GM indices or median BDG levels of the vari-ous sampling times.However,24of 135serum samples were positive for BDG for a threshold of 80pg/mL.After ruling out fungal infections and all known potential causes of false BDG positivity,environmental contamination remained a possible cause of BDG reactivity.Conclusion No significant interaction was observed bet-ween piperacillin/tazobactam administration and Asper-gillus GM and BDG assays.Positive results for these tests should be evaluated cautiously in patients at high risk for IFI receiving piperacillin/tazobactam.Keywords Aspergillus galactomannan antigen Á1,3-Beta-D -glucan ÁFalse positivity ÁPiperacillin/tazobactamIntroductionInvasive fungal infections (IFI)remain a significant cause of morbidity and mortality in patients with haematological malignancies.Serial monitoring of 1,3-beta-D -glucan (BDG)and galactomannan (GM)is important for the early diagnosis of IFI;however,there are some clinical cir-cumstances that cause false positivity and decrease the specificity of these tests [1].Contamination of the blood specimen with cotton,contamination of microcentrifuge tubes with cardboard,enteral feeding with soybean pro-tein,gastrointestinal colonisation with Bifidobacterium sp.,and infections with fungi other than Aspergillus sp.are thought to be the major items causing GM false positivity [2].Antibiotics derived from fungi might be associated with false positive test results,including ampicillin/sulbactam,piperacillin/tazobactam (TZP)and amoxicillin/A part of this study was presented at the 11th InternationalSymposium on Febrile Neutropenia,20–21February 2009,Valencia,Spain (Oral presentation 003),under the title of ‘The interaction between piperacillin/tazobactam treatment and Aspergillus galactomannan test in patients without risk factors for invasive aspergillosis’.G.Metan (&)ÁC ¸.Ag ˘kus ¸Department of Infectious Diseases and Clinical Microbiology,Faculty of Medicine,Erciyes University,Kat 10,Melikgazi,38039Kayseri,Turkeye-mail:gokhanmetan@;gmetan@.tr H.Buldu ÁA.N.Koc ¸Department of Microbiology and Clinical Microbiology,Faculty of Medicine,Erciyes University,Kayseri,TurkeyInfection (2010)38:217–221DOI 10.1007/s15010-010-0003-6clavulanic acid.Among these,the greatest problem for GM testing has been in patients receiving TZP.Some authors have reported false GM positivity in patients treated with TZP[3–7],while other investigators could not reproduce the rate of false positivity[8,9].However,most of these studies were performed in the early2000s in patients at high risk for IFI.After2005,a decrease in the GM content of TZP batches was reported[10],and in a recent study from Turkey,the GM index was0.23in TZP vials[11].BDG false positivity has not been widely studied;however,it may be falsely elevated in the serum of patients undergoing haemodialysis with cellulose membranes;patients treated with immunoglobulin,albu-min,or other blood productsfiltered through cellulose filters containing BDG;and in patients with serosal exposure to glucan-containing gauze[12].The number of studies evaluating the interaction between BDG tests and beta-lactam antibiotics is limited.A case report has described false positive BDG assay results in six patients receiving treatment with amoxicillin/clavulanic acid[13]. However,in a study that tested44antimicrobials for the presence of BDG,none were positive when diluted to the usual maximum plasma concentrations[14].As therapeutic decisions may be made based on the results of GM and/or BDG tests,it is important to under-stand their potential limitations.The aim of this study was to investigate the interaction between intravenous TZP treatment and Aspergillus GM and BDG test results in patients without known risk factors for IFI.Patients and methodsThis study was conducted at the Infectious Diseases Clinic of Erciyes University Faculty of Medicine,Kayseri, Turkey.Patients older than18years without history of allergy to beta/lactam antibiotics and who were to receive TZP monotherapy for urinary tract or soft tissue infections were considered eligible for the study.The exclusion cri-teria were use of a beta-lactam antibiotic during the pre-vious15days,suspected or proven fungal infection during the previous15days,history of haematological malig-nancy or solid tumour,use of corticosteroids longer than 15days with a dose of20mg/day or treatment with other recognised T cell immunosuppressants such as cyclospor-ine or NF-a blockers,specific monoclonal antibodies(such as alemtuzumab)or nucleoside analogues during the past 30days,acute renal failure or history of chronic renal insufficiency,any operation during the last2months,and the presence of diarrhea or severe mucositis.The study was approved by the local Ethics Committee and patients were required to give written informed con-sent.In order to examine the interaction between TZP and GM and BDG test results,serial blood samples were col-lected.Thefirst samples were obtained before thefirst dose of TZP and30min after the end of the antibiotic infusion. This procedure was repeated on the third,seventh,and tenth days of the antibacterial treatment.Afinal serum sample was obtained4days after the last dose of TZP. Blood samples were drawn from a peripheral vein that was not used for the infusion of TZP.Serum samples were immediately separated,aliquoted and frozen at-80°C until GM and BDG testing.Four vials of TZP were also tested for GM and BDG. Vials containing4.5g TZP were resuspended in100mL of 0.9%NaCl for clinical use,and5mL of each vial was stored for analysis.The galactomannan antigen levels in sera were deter-mined with the Platelia Aspergillus ELISA kit(Bio-Rad Laboratories)according to the manufacturer’s instructions. The results were expressed in terms of the galactomannan index.Cut-off levels of0.5[15]and0.7[16]were used to define the positivity of the test.BDG levels in sera were assayed using the Fungitell kit(Associates of Cape Cod, East Falmouth,MA,USA)according to manufacturer’s specifications.The cut-off was80pg/mL[17].Statistical analyses were performed with SPSS for Windows(version15.0;SPSS,Chicago,IL,USA).Median and interquartile ranges were used as descriptive methods. Friedman analysis was used to test the differences where appropriate,and a two-sided P value less than0.05was considered significant.ResultsFifteen patients with a median age of47years(23–78) were included in the study.Eleven of the patients were female.All patients received the original TZP(Wyeth Pharmaceuticals)from different batches.Fourteen patients received a daily dose of394.5g TZP for urinary tract infections,and one received a daily dose of494.5g TZP for diabetic foot infection.Escherichia coli was recovered from urine cultures of nine patients,Klebsiella pneumonia e from urine culture of two patients and Proteus spp.from urine culture of one patient.E.coli was isolated from the diabetic foot infection.None of the patients had a blood-stream infection based on the blood culture results.Urine cultures did not yield any yeast,and all patients had normal chest X-rays.A total of135serum samples were collected from15 patients.When a cut-off level of C0.7was used for GM positivity,there were no false positive results.When we used a cut-off level of C0.5,six serum samples were positive.Two of the false positive serum samples were obtained before the administration of TZP on thefirst day218G.Metan et al.of the treatment(Table1).There was no statistically sig-nificant difference in median GM index according to the sampling time(P=0.706).Median GM indices before and after TZP infusion are shown in Fig.1.Of the135serum samples,24were positive for BDG. Two serum samples taken before infusion on thefirst day of antibacterial treatment were positive(Table1),and seven taken before infusion later in the treatment course were positive.However,the statistical analysis showed no association between TZP administration and median BDG levels(P=0.411).Three of135serum samples were false positive for both GM and BDG tests at the same sampling time(Table1).Median BDG levels before and after TZP infusion are shown in Fig.2.None of the TZP vials tested positive for GM or BDG.DiscussionTZP is a fungus-derived broad spectrum antibiotic that is effective and well-tolerated in patients with febrile neu-tropenia.The interaction between TZP and GM positivity is of great concern in patients at high risk for invasive aspergillosis(IA).In a previous study from Turkey,28of 43sera(65.1%)were positive in patients receiving con-comitant TZP in the absence of IA[6].When another institution from Turkey analysed the false positivity of GM due to TZP treatment with the same method during the same period,the false positive rate was12.5%[9].Lot-to-lot variability in the GM content of TZP batches could explain this difference.Machetti et al.[18]investigated the kinetics of GM in seven patients having undergone abdominal surgery with perioperative prophylactic TZP. None of the patients who received TZP from batches with a ‘medium’GM index had a false positive GM test result (C0.5).Orlopp et al.[16]detected a small but significant increase in GM indices immediately after TZP infusion in 30patients receiving it for febrile neutropenia.When they used a cut-off level of C0.5,this led to21%(7/30)false positive results.The authors mentioned that there were no false positive tests if samples were collected prior to infusion and a cut-off level of[0.7was used.In our study, false positivity of GM was avoided with a cut-off level of 0.7,and there was no evidence of GM accumulation even after several infusions of TZP.The lower rate of interaction between TZP and GM in recent studies including our own could be due to a change in the manufacturing process of the antibiotic;this possibility could be clarified by the manufacturer.There are several studies that attributed false positive BDG results to beta-lactam antibiotics.Pickering et al.[19] reportedfive patients with false positive BDG tests receiving beta-lactam antibiotics including TZP.In another study that evaluated the role of BDG in the diagnosis of IFI,5of the16patients who had a false positive GM assay due to cross-reaction with beta-lactams were BDG positiveTable1Galactomannan index and1,3-beta-D-glucan levels(pg/mL)at each sampling time for the patients with two consecutive results over the cut-off levelsBefore TZP infusion day 0After TZPinfusion dayBefore TZPinfusion day3After TZPinfusion day3Before TZPinfusion day7After TZPinfusion day7Before TZPinfusion day10After TZPinfusion day104days afterlast TZPinfusionPatient1GM0.55*0.53*0.320.200.200.200.220.450.27BDG108*90*203*118*41493031310*Patient3GM0.57*0.210.230.230.270.460.210.240.28BDG206*112*68261324606160Patient8GM0.210.280.330.390.260.61*0.200.150.19BDG796850716655112*93*77Patient10GM0.370.420.180.230.200.210.280.250.19BDG121299*84*2518747725Patient13GM0.150.140.220.150.210.140.140.160.18BDG94447134*156*611212118*TZP Piperacillin/tazobactamThe values above the cut-off are indicated with an asteriskPositivity of galactomannan and1,3-beta-D-glucan due to piperacillin/tazobactam219[17].However,these were retrospective analyses,and in vitro studies from TZP vials did not confirm any BDG positivity [13,14].To the best of our knowledge,our study is the first to prospectively examine BDG false positivity due to TZP administration.We did not observe any sta-tistically significant interaction between median BDG levels and TZP treatment,but 17.8%of the samples were positive at a threshold of 80pg/mL.All known causes of BDG reactivity were ruled out in these patients,including haemodialysis with cellulose membranes;receipt of immunoglobulin,albumin,or other blood products filtered through cellulose filters containing BDG;and serosal exposure to glucan-containing gauze [12].In this study,we did not check Candida colonisation as a possible factor for false BDG positivity because previous studies showed that Candida colonisation is an unlikely cause of false positive results in the BDG assay [20,21].Pickering and colleagues reported BDG reactivity in the sera of patients with gram negative bacteraemia [19].In our study,however,13patients had microbiologically documented gram negative bacillus infections,and none of them had a positive blood culture.False positive BDG results have been described after contamination by environmental BDG [22].During this study,the sera were tested in the same laboratory where all fungal cultures are performed.This could cause environ-mental contamination of the samples.The exclusion criteria allowed us to study patients without risk factors for IFI and rule out occult fungal infections that could cause GM or BDG positivity.Kinetic analysis of the BDG levels helped in the identification of false positive results since in these patients BDG levels showed abrupt rises and falls (Table 1)[21].For the diagnosis of invasive aspergillosis,a combina-tion of GM and BDG tests improved the specificity (to 100%)and positive predictive value (to 100%)of each individual test without affecting the sensitivity and nega-tive predictive values [21].In this study only 3of 24BDG positive serum samples were also GM positive.The com-bined use of two tests could be useful to identifiy thefalseFig.1Median galactomannan index at each sampling time (IQR interquartile range)Fig.2Median 1,3-beta-D -glucan level at each sampling time (IQR interquartile range).BAI-0before piperacillin/tazobactam (TZP )infusion day 0,AAI-0after TZP infusion day 0,BAI-3before TZP infusion day 3,AAI-3after TZP infusion day 3,BAI-7before TZPinfusion day 7,AAI-7after TZP infusion day 7,BAI-10before TZP infusion day 10,AAI-10after TZP infusion day 10,4-DAYS ALI 4days after last TZP infusion220G.Metan et al.positive results.However,increased cost will be a matter of concern.In conclusion,in a group of patients without risk factors for IFI,we did not observe a significant interaction between TZP and aspergillus GM and BDG test results.Positive results for these tests should be evaluated cautiously in patients at high risk for IFI receiving TZP treatment. However,further studies are needed to better understand the possible causes of false positive BDG tests. Acknowledgments We thank Ferhan Elmali(Department of Bio-statistics,Faculty of Medicine,Erciyes University,Kayseri,Turkey) for help with the statistical analysis.This study was supported with a grant from the Scientific and Technological Research Council of Turkey(project number108S076).Conflicts of interest statement Gokhan Metan has received travel grants from Merck-Sharp and Pfizer,and the other authors have no conflicts to declare.References1.Del Bono V,Mikulska M,Viscoli C.Invasive aspergillosis:diagnosis,prophylaxis and treatment.Curr Opin Hematol.2008;15:586–93.2.Wheat LJ,Walsh TJ.Diagnosis of invasive aspergillosis bygalactomannan antigenemia detection using an enzyme immuno-assay.Eur J Clin Microbiol Infect Dis.2008;27:245–51.3.Viscoli C,Machetti M,Cappellano P,et al.False-positive galac-tomannan platelia Aspergillus test results for patients receiving piperacillin-tazobactam.Clin Infect Dis.2004;38:913–6.4.Adam O,Aupe´rin A,Wilquin F,et al.Treatment with pipera-cillin-tazobactam and false-positive Aspergillus galactomannan antigen test results for patients with hematological malignancies.Clin Infect Dis.2004;38:917–20.5.Walsh TJ,Shoham S,Petraitiene R,et al.Detection of galacto-mannan antigenemia in patients receiving piperacillin/tazobactam and correlations between in vitro,in vivo,and clinical properties of the drug antigen interaction.J Clin Microbiol.2004;42:4744–8.6.Tanriover MD,Metan G,Altun B,et al.False positivity forAspergillus antigenemia related to the administration of pipera-cillin/tazobactam.Eur J Intern Med.2005;16:489–91.7.Aubry A,Porcher R,Bottero J,et al.Occurrence and kinetics offalse-positive Aspergillus galactomannan test results followingtreatment with beta-lactam antibiotics in patients with hemato-logical disorders.J Clin Microbiol.2006;44:389–94.8.Penack O,Schwartz S,Thiel E,et ck of evidence that false-positive Aspergillus galactomannan antigen test results are due to treatment with piperacillin-tazobactam.Clin Infect Dis.2004;39:1401–2.9.Ozkalemkas F,Ozcelik T,Ozkocaman V.Treatment withpiperacillin-tazobactam and Aspergillus galactomannan test results for patients with hematological malignancies.Eur J Intern Med.2007;18:79.10.Penack O,Rempf P,Graf B,et al.False-positive Aspergillusantigen testing due to application of piperacillin/tazobactam–is it still an issue?Diagn Microbiol Infect Dis.2008;60:117–20. 11.Yu¨cesoy M,Ergon MC.Investigation of Aspergillus galacto-mannan levels in antimicrobial agents.Mikrobiyol Bul.2007;41:565–70.12.Marty FM,Koo S.Role of(1?3)-beta-D-glucan in the diag-nosis of invasive aspergillosis.Med Mycol.2008;13:1–8.13.Mennink-Kersten MA,Warris A,Verweij PE.1,3-Beta-D-glucanin patients receiving intravenous amoxicillin-clavulanic acid.N Engl J Med.2006;354:2834–5.14.Marty FM,Lowry CM,Lempitski SJ,et al.Reactivity of(1?3)-beta-d-glucan assay with commonly used intravenous antimicrobials.Antimicrob Agents Chemother.2006;50:3450–3.15.Maertens JA,Klont R,Masson C,et al.Optimization of the cutoffvalue for the Aspergillus double-sandwich enzyme immunoassay.Clin Infect Dis.2007;44:1329–36.16.Orlopp K,von Lilienfeld-Toal M,Marklein G,et al.False posi-tivity of Aspergillus galactomannan Platelia ELISA because of piperacillin-tazobactam treatment:does it represent a clinical problem?J Antimicrobial Chemother.2008;62:1109–12.17.Persat F,Ranque S,Derouin F,et al.Contribution of the(1?3)-beta-D-glucan assay for diagnosis of invasive fungal infections.J Clin Microbiol.2008;46:1009–13.18.Machetti M,Majabo MJ,Furfaro E,et al.Kinetics of galactomannanin surgical patients receiving perioperative piperacillin/tazobactam prophylaxis.J Antimicrob Chemother.2006;58:806–10.19.Pickering JW,Sant HW,Bowles CA,et al.Evaluation of a(1?3)-beta-D-glucan assay for diagnosis of invasive fungal infections.J Clin Microbiol.2005;43:5957–62.20.Ponto´n J,del Palacio A.Influence of Candida colonization on the(1?3)beta-D-glucan assay.Clin Infect Dis.2006;43:263–4.21.Pazos C,Ponto´n J,Del Palacio A.Contribution of(1?3)-beta-D-glucan chromogenic assay to diagnosis and therapeutic moni-toring of invasive aspergillosis in neutropenic adult patients:a comparison with serial screening for circulating galactomannan.J Clin Microbiol.2005;43:299–305.22.Kelaher A.Two non-invasive diagnostic tools for invasiveaspergillosis:(1–3)-beta-D-glucan and the galactomannan assay.Clin Lab Sci.2006;19:222–4.Positivity of galactomannan and1,3-beta-D-glucan due to piperacillin/tazobactam221。