Drug–laboratory interaction between beta-lactam antibiotics and the galactomannan antigen test used to detect mould infections

braz j infect dis.2014;18(5):544–547

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Brief

communication

Drug–laboratory

interaction

between

beta-lactam

antibiotics

and

the

galactomannan

antigen

test

used

to

detect

mould

infections

Kristin

A.

Otting

_,

_Kayla

_R.

_Stover

_,

_John

_D.

_Cleary

a_{DepartmentofPharmacy,UniversityofMississippiMedicalCenter,Jackson,UnitedStates}

b_{DepartmentofPharmacyPractice,SchoolofPharmacy,UniversityofMississippi,Jackson,UnitedStates}

c_{SchoolofMedicine,UniversityofMississippiMedicalCenter,Jackson,UnitedStates}

d_{DepartmentofPharmacy,St.Dominic-JacksonMemorialHospital,Jackson,UnitedStates}

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Articlehistory:

Received24December2013 Accepted28March2014 Availableonline13May2014

Keywords: Piperacillin–tazobactam Galactomannan Beta-lactams Druginteraction

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Severalstudieshavedemonstratedthatpiperacillin/tazobactamproducesafalse-positive resultforthegalactomannanantigentest.However,themostrecentliteraturehas demon-stratedthatthisinteractionisnolongeraconcern.Thereislittleinformationregarding the drug–laboratory interaction with the generics of piperacillin/tazobactam or other broad-spectrumbeta-lactams,suchasceftaroline,doripenem,imipenem/cilastatin,and meropenem.Thepurposeofthisstudywastodetermineifadrug–laboratoryinteraction existswiththeseantibiotics.Testsshowedthatonelotofimipenem/cilastatinbyHospira HealthcareIndiaPrivateLimitedproducedafalse-positiveresultforthegalactomannan antigentest.Allothermedicationstested,includingpiperacillin/tazobactamfromseven manufacturersandimipenem/cilastatinbyHospiraInc.,didnotproducepositiveresults. Sincethereasonforthisdrug–laboratoryinteractionwithimipenem/cilastatinisunknown, morestudiesareneededtofurtherinvestigatethisinteraction.Providersalsoshouldbe educatedofthesefindings:nodrug–laboratoryinteractionwithpiperacillin/tazobactamand apossibledrug–laboratoryinteractionwithimipenem/cilastatin(HospiraHealthcareIndia PrivateLimited).

©2014ElsevierEditoraLtda.Allrightsreserved.

Patients with invasive Aspergillus infections have a high mortalityrate; therefore, early diagnosis isimportant. The galactomannan antigen test, marketed as the PlateliaTM

∗ _{Correspondingauthorat:UniversityofMississippiMedicalCenter,2500NorthStateStreet,Jackson,MS39216,UnitedStates.}

E-mailaddresses:kstover@umc.edu,stoverkr@hotmail.com(K.R.Stover).

e_{TheauthoriscurrentlyaffiliatedwiththeG.V.(Sonny)MontgomeryVAMedicalCenter;however,shewasaffiliatedwiththeUniversity}

ofMississippiMedicalCenter,Jackson,MS,atthetimetheresearchwasconducted.

Aspergillus Ag (Bio-Rad), is a noninvasive tool used with

other diagnostic tests for the early identification of

inva-sive Aspergillus infections.Thisantigentest works through

http://dx.doi.org/10.1016/j.bjid.2014.03.009

brazj infect dis.2014;18(5):544–547

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detection of galactomannan, an antigen found in the cell

wallofAspergillus species.1 _{Limitationsofthis test include}

lowsensitivity(50–80%)andcross-reactionwithotherfungi (e.g.,Penicilliumspecies,Histoplasmaspecies,andBlastomyces

species).1,2

Certainpenicillinantibioticshavebeenreportedtoproduce afalse-positivegalactomannantest,likelybecausetheyare derivedfromPenicilliumspecies.Althoughafewreportshave shownthattheintravenousformulationsofamoxicillinand amoxicillin/clavulanate (not available inthe United States) produceafalse-positiveresultforthegalactomannanantigen test,1,3,4_{mostofthedatademonstratingthisdrug–laboratory} interaction is with brand name piperacillin/tazobactam (Zosyn®_{, Wyeth).}1,3,5–12 _{Inaddition, researchershave found} that the degree of positivity varies among batches of piperacillin/tazobactamand isdependentuponthe timeof thephlebotomy.5,7–9,11–13_{Mostoftheseinvitroandinvivo} stud-ieswere conductedpriortoSeptember 2009,whengeneric piperacillin/tazobactambecameavailable.14_{Asaresult,little} informationisavailableregardingthedrug–laboratory inter-actionwiththe genericversions ofpiperacillin/tazobactam andotherbroad-spectrumantibiotics.Thesebroad-spectrum antibioticsareoftenusedtoempiricallytreat immunocompro-misedpatients,thepopulationinwhichthisgalactomannan antigentestismostcommonlyperformed.Becausepositive galactomannanantigentestsmayresultintheovertreatment ofthesepatients,broad-spectrumantibioticsshouldbetested forthisinteraction.

Theaimofthisstudywastoscreenwhetherthesixgeneric brands of piperacillin/tazobactam that are availablein the UnitedStates,aswellasotherbroad-spectrumbeta-lactam antibiotics,produceafalse-positiveresultforthe galactoman-nanantigentest.

AvialofeachantibioticofinterestavailableintheUnited Stateswasobtainedfromthemanufacturers,andpure chem-icalpowderswereorderedforcomparison.Purepiperacillin and tazobactam powders were included in this study to investigate whether this interaction is due to the chemi-calitselforrelatedtomanufacturingprocesses. Antibiotics testedincludedpiperacillin[purechemical,TokyoChemical Industry(LotIK2QM-BM,ExpNA)],tazobactam[pure chem-ical, Chem-Impex Int’l (Lot TB00N110629, Exp 6/28/2014)], piperacillin/tazobactam [Zosyn®_{, Wyeth (Lot AH1C/11, Exp}

4/2015);sixgenerics: Apotex(Lot500C003,Exp 1/2014),APP (Lot 2C08TN, Exp 2/2015), Auromedics (Lot PT0212001-A, Exp 2/2014), Hospira (Lot 110278M, Exp 11/1/2013), Sagent (Lot PT0211008-A, Exp 8/2013), and Sandoz (Lot BY0110, Exp 9/2013)], imipenem/cilastatin [Primaxin®_{, Merck (Lot}

H007317,Exp 3/2014); two generics, APP (Lot 0013D21, Exp 4/2014) and Hospira (Batch 1, Lot 613C015, Exp 12/2013; Batch 2, Lot 613C025, Exp 8/2013)], meropenem [Merrem®_,

AstraZeneca(Lot JX109, Exp 2/2015)], doripenem[Doribax®_,

Ortho-McNeil (Lot ALZT600, Exp 11/2013)], and ceftaroline [TeflaroTM_{,Forest(Lot0012D16,Exp11/2013)].Antibiotic}

pow-dersweremeasuredanddividedintoaliquotsrepresentingthe reconstitutedconcentrationperthemanufacturers’package inserts when 1mL of diluent was added (i.e., 225mg/mL ofpiperacillin/tazobactam,50mg/mLofimipenem/cilastatin, 50mg/mL of meropenem, 50mg/mL of doripenem, and 30mg/mLofceftaroline).

Presence of the interaction was tested utilizing the PlateliaTM _{AspergillusAg(Bio-Rad)kit(Kit1,Prod#62793,Lot}

9J0030, Exp 11/30/2010; Kit2, Prod# 62794,Lot 2F0017, Exp 6/5/2013)accordingtostandardmethods.Twokitswere uti-lizedforthisstudy;oneexpiredkitwasusedforapracticerun whiletheresultsofthis studywereproduced andreported using the in-date kit. All tests were run in quadruplicate betweenDecember2012andApril2013.Foranymedication withapositiveinitialresult,fourdilutionsweresubsequently tested tomimicdrugconcentrations inthebody.Dilutions includedtheaveragepeakserumconcentrationinthebody according to the manufacturers’ package inserts plus one dilution aboveand twodilutions belowthat concentration. Dilutionswerefirsttestedinnormalsalineandtheninhuman serum (drawn from the principle investigator). Antibiotics weredilutedinserumtoevaluatethedrug–laboratory inter-actioninaclinicalsample.

Imipenem/cilastatin by Hospira was the only medi-cation that produced a positive galactomannan antigen test. All other reconstituted medications tested (including imipenem/cilastatinfromtwoothermanufacturers)didnot produceapositiveresult.Forimipenem/cilastatinbyHospira, the reconstitutedmedication(i.e.,50mg/mL),four dilutions in normalsaline (i.e.,10,20, 40,and 80mcg/mL), and four dilutionsinhumanserum(i.e.,10,20,40,and80mcg/mL) pro-ducedpositiveantigentests.Theopticaldensity(OD)indices ofthereconstituted medicationwere2.96 and2.97.Similar results were foundwith the four dilutions in bothnormal salineandhumanserum(Table1),andwhenutilizingboth galactomannan antigenkits. When testing a second batch ofimipenem/cilastatinbyHospira(i.e.,thesamemedication with a differentlot number), the reconstituted medication andfourdilutionsinnormalsalinetestednegative(i.e.,OD indices<0.5).Thefourdilutionsofthesecondbatchwerenot tested inhumanserum sincethe four dilutions innormal salinewerenegative.

Tothebestofourknowledge,thisisthefirststudy evalu-atingthedrug–laboratoryinteractionamongthesixgenerics ofpiperacillin/tazobactamavailableintheUnitedStatesand otherbroad-spectrumantibiotics.Allpiperacillin/tazobactam brands produced negativeresults with the galactomannan antigentestinthisstudy,whichisconsistentwiththemost recentdataregardingthisdrug–laboratoryinteraction.Xavier etal.15_{conductedaninvitrostudyinBrazilthatinvestigated} thedrug–laboratoryinteractionwiththebrandandfour gener-icsofpiperacillin/tazobactamavailableinBrazilatthattime. Whentestingtheconcentratedmedications(i.e.,45mg/mL), onlyone ofthefive brandsof piperacillin/tazobactam pro-ducedapositivegalactomannanantigentest, showingthis drug–laboratoryinteractiontobemanufacturerdependent.15 However,whentestingthedilutedmedications(i.e.,average peakserumconcentrationinthebody,300mcg/mL;one dilu-tionabove,600mcg/mL;andtwodilutionsbelow,150mcg/mL and75mcg/mL),allconcentrationsproducedanegative anti-gentest.15_{Theseauthorsconcludedthatthisdrug–laboratory} interaction between piperacillin/tazobactam and the galac-tomannan antigentestwas nolonger clinicallyrelevantin Brazil.15_{Similarly,Mikulskaetal.}16_{conductedastudyinItaly} thatinvestigatedthedrug–laboratoryinteractionwithbrand piperacillin/tazobactam(TazocinTM_{,Pfizer).Whentesting90}

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Table1–Positiveresults:opticaldensityindicesofdilutions.

Concentrationofimipenem/cilastatin(mcg/mL) Innormalsaline Inhumanserum ODforWell1 ODforWell2 ODforWell1 ODforWell2

80 6.11 5.88 4.96 5.10

40 1.58 1.74 3.23 3.34

20 0.64 0.80 1.78 1.78

10 0.61 0.61 1.13 1.03

OD,opticaldensity.

randomlyselectedvialsofpiperacillin/tazobactam,none pro-ducedapositiveantigentest.16_{Whentestingpatients’serum,} theantigentestwaspositiveinslightlymoreserumsamples from patients receiving piperacillin/tazobactam than those patientswhodidnot,whichwasnotfoundtobestatistically significant (2.5% vs. 1.6%; p=0.18).16 _{These authors} con-cludedthatbrandpiperacillin/tazobactamnolongerproduces a false-positiveresult for the galactomannan antigentest; however,thereisaconcernwiththemultiplegenericsthatare available.16_{Basedonourstudy,thedrug–laboratory} interac-tionwiththesixgenericsofpiperacillin/tazobactamavailable intheUnitedStatesrevealednopositiveresults.Researchers have speculated that the reason for this drug–laboratory interaction no longer existing is secondary to changing manufacturing processes.8,17 _{Based on the package insert} information,the brand name productwas reformulated in 2005fromcontainingnoexcipientsorpreservativesto con-tainingedetatedisodiumdehydrateandsodiumcitrate.18

Thisstudy didfind thatimipenem/cilastatin byHospira Healthcare India Private Limited, a subsidiary of Hospira Inc.,produced apositive antigen test. Thisfinding is puz-zling especially since imipenem/cilastatin is derived from a bacterium Streptomyces cattleya and, therefore, does not containgalactomannanand should not produceapositive galactomannanantigentest. Morespecifically, twobatches ofimipenem/cilastatinmanufacturedbyHospiraweretested that produced conflicting results. In comparison of these twovials of imipenem/cilastatin, bothbatches had similar National Drug Code (NDC) numbers (i.e., same manufac-turer,samemedication,anddifferentpackagesize),different lot numbers, and different expiration dates. Batch 1 that producedapositiveantigentestwasmanufacturedby Hos-piraHealthcareIndiaPrivateLimited(Chennai,India)while Batch2thattestednegativewasmanufacturedbyHospira, Inc. (Lake Forest, Illinois). The reasonfor theseconflicting resultsremainsunknownbutmaypossiblybeduetodiffering manufacturingprocessesbetweenthetwolocations.Because positiveresultswereseenwithonlyonemanufacturer,this observationmaynotbegeneralizabletoimipenem/cilastatin asawhole.

Although this study reports in vitro data of limited scope, there are important clinical implications. Results suggest there is no longer a drug–laboratory interaction between piperacillin/tazobactam and the galactomannan antigentest,butthereisapossibledrug–laboratoryinteraction withimipenem/cilastatin (Hospira Healthcare India Private Limited).Knowingwhichmedicationsproduceafalse-positive result for the galactomannan test is important since the

resultsofthistestmayaffectthetreatmentofpatients result-inginunnecessarytreatment,increasedhealthcarecosts,risk ofadverseeffects,anddrug–druginteractions.

Ourstudyhasseverallimitations.Thisstudywasaninvitro

study, and not all in vitrodata correlate with in vivo data. However,clinicalsamplesweretested(i.e.,fourdilutionsin serum)oncethemedicationproducedapositiveresultin nor-malsaline.Asinglevialofeachmedication(i.e.,onebatch) wasusedinthisstudy,whichmaynotbegeneralizabletoevery manufacturerorlot.Lastly,onlyonein-datePlateliaAspergillus

Agkitwasusedforthisstudy;thus,thenumberofteststhat wererunwaslimited.

In conclusion, this in vitro study suggests that imipenem/cilastatin by Hospira Healthcare India Private Limitedproducesafalse-positiveresultforthe galactoman-nanantigentestinatleastsomelots.Sincethemechanism of this drug–laboratory interaction is unknown, this inter-action should be further investigated with more in vitro

studiestestingadditionalbatchesofimipenem/cilastatinby HospiraHealthcareIndiaPrivateLimitedandinvivostudies testing patients’ serum who are receiving this medication. Inaddition,providereducationwillbenecessaryinorderto ensureeffectivediagnosesandpatientcareinpatientswith suspectedAspergillusinfections.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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