Reduced Acquisition and Overgrowth of Vancomycin-Resistant Enterococci and Candida Species in Patients Treated With Fidaxomicin Versus Vancomycin for Clostridium difficile Infection.

2012·0.16 MB·English

by  Nerandzic, Michelle M.

SUPPLEMENT ARTICLE
Reduced Acquisition and Overgrowth
of Vancomycin-Resistant Enterococci and
Candida Species in Patients Treated With
Fidaxomicin Versus Vancomycin for
fi
Clostridium dif cile Infection
MichelleM.Nerandzic,1KathleenMullane,2MarkA.Miller,3FarahBabakhani,4andCurtisJ.Donskey1,5
1ResearchService,ClevelandVeteransAffairsMedicalCenter,Ohio,2SectionofInfectiousDiseases,UniversityofChicago,Illinois;3Divisionof
InfectiousDiseases,JewishGeneralHospital,McGillUniversity,Montreal,Quebec,Canada;4OptimerPharmaceuticals,Inc.,SanDiego,California,
and5GeriatricResearchEducationandClinicalCenter,Cleveland,Ohio
FidaxomicincauseslessdisruptionofanaerobicmicrobiotaduringtreatmentofClostridiumdifficileinfection
(CDI) than vancomycin and has activity against many vancomycin-resistant enterococci (VRE). In conjunc-
tion with a multicenter randomizedtrialoffidaxomicin versus vancomycin for CDI treatment, we tested the
hypothesis that fidaxomicin promotes VRE and Candida species colonization less than vancomycin. Stool
was cultured for VRE and Candida species before and after therapy. For patients with negative pretreatment
cultures, the incidence of VRE and Candida species acquisition was compared. For those with preexisting
VRE, the change in concentration during treatment was compared. The susceptibility of VRE isolates to
fidaxomicin was assessed. Of 301patients, 247 (82%) had negativeVRE culturesand 252 (84%) had negative
Candida species cultures before treatment. In comparison with vancomycin-treated patients, fidaxomicin-
treatedpatientshadreducedacquisitionofVRE(7%vs31%,respectively;P<.001)andCandidaspecies(19%
vs 29%, respectively; P=.03). For patients with preexisting VRE, the mean concentration decreased signifi-
cantly in the fidaxomicin group (5.9 vs 3.8log VRE/g stool; P=.01) but not the vancomycin group (5.3 vs
10
4.2log VRE/g stool; P=.20). Most VRE isolates recovered after fidaxomicin treatment had elevated fidaxo-
10
micin minimum inhibitory concentrations (MICs; MIC , 256µg/mL), and subpopulations of VRE with ele-
90
vated fidaxomicin MICs were common before therapy. Fidaxomicin was less likely than vancomycin to
promote acquisition of VRE and Candida species during CDI treatment. However, selection of preexisting
subpopulationsofVREwithelevatedfidaxomicinMICswascommonduringfidaxomicintherapy.
ClinicalTrialsRegistration.NCT00314951.
Oral metronidazole and oral vancomycin are the Clostridium difficile infection (CDI) [1].Current prac-
agents most often prescribed for treatment of tice guidelines recommend metronidazole for treat-
ment of mild to moderate CDI and vancomycin for
severe cases and in the setting of multiple recurrences
Correspondence: Curtis J. Donskey, MD, Geriatric Research Education and
[1,2].Although these antibiotics are effective in sup-
Clinical Center, Cleveland Veterans Affairs Medical Center, 10701 East Blvd,
Cleveland,OH44106([email protected]). pressing C. difficile, they are nonselective agents that
ClinicalInfectiousDiseases 2012;55(S2):S121–6 alsocausesignificantdisruptionoftheindigenousmi-
©TheAuthor2012.PublishedbyOxfordUniversityPressonbehalfoftheInfectious
crobiota of the colon [3–5].For example, oral vanco-
DiseasesSocietyofAmerica.Allrightsreserved.ForPermissions,pleaseemail:
[e-mail]edistributedunder mycin achieves high concentrations in the intestinal
thetermsoftheCreativeCommonsAttributionNon-CommercialLicense(http://
tract,resultinginmarkedsuppressionofanaerobicor-
creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-
commercialuse,distribution,andreproductioninanymedium,providedtheoriginal ganisms,including Bacteroides species [5,6].Suchdis-
workisproperlycited.
ruption of the indigenous microbiota may predispose
DOI:10.1093/cid/cis440
(cid:129) (cid:129)
VREandCandidainCDIPatients CID 2012:55 (Suppl2) S121
patients to recurrent CDI and intestinal colonization by
healthcare-associated pathogens such as vancomycin-resistant
enterococci (VRE) and Candida species [7, 8]. In a previous
study, we demonstrated that both oral metronidazole and oral
vancomycinpromotedpersistentovergrowthofVREinstoolof
patients with CDI with preexisting VRE colonization, resulting
in frequent contamination of skin and environmental surfaces
[3,4].Antibiotic-induced overgrowth ofCandida speciesinthe
gastrointestinal tract is an important factor that predisposes to
Candida infection and dissemination [8, 9]. These findings
highlight the need for new CDI treatments that cause less dis-
ruptionoftheindigenousmicrobiota.
Fidaxomicin (formerly OPT-80) is a naturally occurring
Figure1. Flowdiagramofsubjects enrolledintherandomizedtrialof
18-member macrocycle being developed as a therapy for CDI fidaxomicinversusvancomycinfortreatmentofClostridiumdifficileinfec-
[6, 10, 11]. Fidaxomicin is minimally absorbed after oral ad- tionandofthesubsetevaluatedforacquisitionandovergrowthofvanco-
ministrationandachieveshighconcentrationsintheintestinal mycin-resistant enterococci and Candida species. Abbreviations: CDI,
Clostridiumdifficileinfection;VRE,vancomycin-resistantenterococci.
tract [10, 11]. The compound has excellent in vitro activity
against C. difficile (minimum inhibitory concentration re-
quired to inhibit the growth of 90% of organisms [MIC90], of symptoms of diarrhea and a positive result of a stool toxin
0.125µg/mL), moderate activityagainst VRE(MIC90, 4µg/mL), assay, using commercial enzyme immunoassays. Patients with
but minimal activity against Bacteroides species (MIC90, fulminantCDIortoxicmegacolonwereexcluded.Arandomly
>1024µg/mL) and other gram-negative organisms [6,10,11]. selectedsubsetofpatientshadstool samples collectedpriorto
In a phase II clinical trial, fidaxomicin was effective in sup- andattheendoftherapyformeasurementofdruglevels.The
pressing C. difficile but did not reduce Bacteroides fragilis stool samples were frozen at −80°C. At the completion of the
group concentrations; in a separate group of patients with trial, the samples were transferred to a central laboratory for
CDI, oral vancomycin treatment caused marked suppression assessment of VRE and yeast colonization. Information re-
of Bacteroides organisms [6].In a phase III clinical trial, oral garding demographic characteristics, coexisting illnesses, and
fidaxomicin was as effective as oral vancomycin for the treat- antibiotic therapy was collected prospectively through the
ment of CDI but was associated with a significantly reduced standardized clinical study report. The Cleveland Veterans
recurrence rate (13% vs 24%), presumably because it caused Affairs Medical Center’s Institutional Review Board approved
less disruption of the anaerobic microbiota [12]. Here, we thislaboratorystudyprotocol.
tested the hypothesis that oral fidaxomicin promotes acquisi-
tion and overgrowth of VRE less than oral vancomycin Microbiology
because it has activityagainst many VRE species but lacks ac- StoolsampleswereseriallydilutedandplatedonEnterococco-
tivity against many intestinal anaerobes, including Bacteroides sel agar (Becton Dickinson, Sparks, MD) containing 6µg/mL
species.Tofurtherinvestigatetheimportanceoflimitingalter- ofvancomycinandonSabourauddextroseagar (Becton Dick-
ation of the anaerobic microbiota during CDI therapy, we ex- inson) to determine the presence and concentration of VRE
amined the effects of the treatment regimens on colonization and Candida species, respectively [7]. The limit of detection
by Candida species, because neither agent has activity against was approximately 1log colony-forming unit (CFU) per
10
fungi and because the gastrointestinal tract is an important gram of stool. Identification and susceptibility testing of VRE
reservoirforCandidaspecies. isolates was performed in accordance with Clinical Laboratory
Standards Institute guidelines [13].Yeast species that were ac-
METHODS quired during CDI treatment were identified using VITEK 2
YST cards (bioMerieux, Marcy l’Etoile, France). Enterococcus
SettingandStudyDesign gallinarum and Enterococcus casseliflavus, species that are in-
The double-blind, randomized, phase III clinical trial of 10 trinsically resistant to low concentrations of vancomycin,
days of fidaxomicin versus 10 days of vancomycin for treat- wereexcluded.ForVREisolatesrecoveredatthehighestlevelof
ment of CDI enrolled 548 subjects (265 were treated with dilution,broth-dilutionMICsforvancomycinandfidaxomicin
fidaxomicin, and 283 were treated with vancomycin) in weredeterminedusingstandardmethods[12].Becausefidaxo-
multiple hospitals in the United States and Canada [11] micinresistancebreakpointshavenotbeenestablished,weex-
(Figure1).PatientsweregivenadiagnosisofCDIonthebasis amined the change in fidaxomicin MICs for isolates recovered
(cid:129) (cid:129)
S122 CID 2012:55 (Suppl2) Nerandzicetal
before versus after fidaxomicin therapy. Broth-dilution MICs data, respectively. The Pearson χ2 and Fisher exact tests were
forrifampinwereperformedforallstrainsthatwereresistantto used for categorical data. We compared proportions of pa-
fidaxomicin 32µg/mL. In addition, we tested the fidaxomicin tients who acquired VRE and Candida species colonization in
susceptibilityofarifampin-resistantVREstrainthatwasselect- each group. For patients with preexisting VRE colonization
ed throughserialgrowth inthepresence ofsubinhibitorycon- before treatment, we compared the proportions of patients
centrations of rifampin. For a subset of patients, levels of who developed undetectable VRE levels at the end of therapy
Bacteroides species were measured by plating dilutions onto and the VRE concentrations before and after therapy. The
BacteroidesBileEsculinagar(BectonDickinson). concentrations of Bacteroides organisms in stool before and
after therapy were compared for each treatment group. Pro-
EvaluationforSubpopulationsofVREWithElevated portions were compared using Pearson χ2 and Fisher exact
FidaxomicinMICsPriortoTherapy tests, and concentrations of organisms were compared using
New detection of VRE with elevated fidaxomicin MICs after theStudentpairedttest.
fidaxomicintherapycouldrepresentdenovoemergenceofre-
sistance (eg, mutations in RNA polymerase genes) or expan- RESULTS
sion of subpopulations of VRE with elevated MICs due to
selective pressure during therapy. Therefore, we examined all
Of548totalpatientsenrolledinthetrial,301(55%)hadstool
stool samples obtained before therapy by using a replica
samples available both prior to and at completion of CDI
plating method to determine whether subpopulations of VRE
therapy.Table1providesacomparisonofthecharacteristicsof
with elevated fidaxomicin MICs were present. Dilutions of the 160 vancomycin-treated patients and the 141 fidaxomicin-
stool samples were incubated for 48 hours on Enterococcosel treated patients. There were no significant differences in age,
agar containing vancomycin 20µg/mL and then were trans-
clinical characteristics, and proportions of cases with severe
ferred using sterile velvet onto Enterococcosel agarcontaining disease or infected with epidemic BI C. difficile strains. With
vancomycin 20µg/mL plus fidaxomicin 32µg/mL. The pro-
theexceptionof1Enterococcusfaecalisisolate,allVREisolates
portion of total VRE colonies that were resistant to fidaxomi-
were Enterococcus faecium. The MICs of vancomycin for all
cin32µg/mLwascalculated.
VREisolatestestedwere>256µg/mL.
StatisticalAnalysis AcquisitionofVREandCandidaSpeciesColonizationDuring
Data were analyzed with the use of SPSS statistical software, Treatment
version 10.0 (SPSS, Chicago, IL) and STATA 9.1 (StataCorp, Of 301 patients with CDI, 247 (82%) had negative cultures for
College Station, TX). Distributions of clinical and demographic VRE and 252 (84%) had negative cultures for Candida species
characteristics of patients treated with oral vancomycin versus priortoCDItreatment(Figure1).Incomparisonwithvancomy-
oralfidaxomicinwerecompared.UnpairedtandKruskal-Wallis cin-treated patients, fidaxomicin-treated patients had less fre-
tests were used for normally and nonnormally distributed quent acquisition ofVRE(8of114patients[7%] vs41of133
Table1. Characteristicsof301PatientsWithClostridiumdifficileInfectionRandomizedtoReceiveOralFidaxomicinorOralVancomy-
cinTherapy
Characteristic Overall(n=301) Fidaxomicin(n=141) Vancomycin(n=160) P
Age,years,mean±SD 60.9±17.3 59.3±17.0 62.4±17.4 .11
Women 169(56.2) 80(56.7) 89(55.6) .85
Country:US(vsCanada) 188(62.5) 84(59.6) 104(65.0) .33
InitialinfectingC.difficilestrainrestrictionendonucleasetypeBI 78(32.9) 35(31.5) 43(34.1) .67
SevereCDIa 74(24.6) 31(22.0) 43(26.9) .33
Metronidazoletreatmentfailurepriortoenrollment 19(6.3) 11(7.8) 8(5.0) .32
Inpatient(vsoutpatient) 160(53.2) 73(51.8) 87(54.4) .65
Receivedpriororalmetronidazoleorvancomycintherapy(<24hours) 103(34.2) 48(34.0) 55(34.4) .95
SinglepriorepisodeofCDI(vsnopriorepisode) 52(17.3) 23(16.3) 29(18.1) .68
Unformedbowelmovementsperdayatenrollment,no.mean(±SD) 8.4±5.2 8.0±4.1 8.7±5.9 .24
DataareNo.(%)ofpatients,unlessotherwiseindicated.
Abbreviations:CDI,Clostridiumdifficileinfection;SD,standarddeviation.
aSevereCDIwasdefinedasacasewith≥1ofthefollowingcriteria:fever(temperature>38.5°C),leukocytecount>15000leukocytes/μL,andincreaseinserum
creatininelevel(>50%abovethebaselinelevel).
(cid:129) (cid:129)
VREandCandidainCDIPatients CID 2012:55 (Suppl2) S123
Figure 2. Percentages of patients with negative pretreatment cultures
for vancomycin-resistant enterococci and Candida species who acquired
Figure3. Changeinconcentrationofvancomycin-resistantenterococci
VRE or Candida species in stool during treatment of Clostridium difficile
instoolofcolonizedpatientsduringtreatmentofClostridiumdifficilein-
infection with vancomycin or fidaxomicin. The lower limit of detection
fection with vancomycin (n=27) and fidaxomicin (n=27). The thin lines
was approximately 1log colony-forming units per gram of stool. P
10 connect pre- and posttreatment values for the subset of 12 fidaxomicin-
values and 95% confidence intervals are included for the differences
and 10 vancomycin-treated patients with posttreatment concentrations
between treatment groups in the primary end point. Abbreviation: CI,
less than the limit of detection (approximately 1log colony-forming
confidenceinterval. 10
unit [CFU] per gram of stool). The thick horizontal lines show the mean
concentrationofVRE(log CFU/gofstool)foreachgroup.Abbreviations:
10
CFU,colony-formingunit;VRE,vancomycin-resistantenterococci.
patients [31%]; P<.001) and Candida species (22 of 116 pa-
tients[19%]vs40of136patients[29%];P=.03)(Figure2).For
patientswho acquiredVRE,mean concentrations at the end of
treatmentweresimilarinthevancomycinandfidaxomicintreat- group, from 5.9 to 3.8log CFU/g stool (95% confidence in-
10
ment groups (mean [±standard deviation {SD}], 5.8±0.5 and terval [CI] for the difference in concentrations, 0.8–3.8log
10
5.8±0.8 log CFU/g stool, respectively; P=1). Four of the 8 CFU/gstool;P=.01).ThemeanVREconcentrationdecreased
10
fidaxomicin-treated patients (50%) were colonized with VRE from 5.3 to 4.2log CFU/g stool in the vancomycin group,
10
isolates with fidaxomicin MICs ≥256µg/mL, compared with but the difference was not statistically significant (95% CI for
only 4 of 41 vancomycin-treated patients (10%) (P=.02). Iso- thedifferenceinconcentrations,−0.5to2.6log CFU/gstool;
10
lates with fidaxomicin MICs ≥32µg/mL had variable suscept- P=.20). However, there was no difference in the proportion
ibility patterns to rifampin (MIC range, 0.06–64µg/mL), of patients for whom cultures performed by the end of treat-
suggesting that mutations leading to rifampin resistance were mentwerenegativeforVRE(12of27fidaxomicin-treatedpa-
notresponsiblefortheelevatedfidaxomicinMICs.Moreover,a tients [44%] vs 10 of 27 vancomycin-treated patients [37%];
rifampin-resistant VRE strain (MIC, >256µg/mL) selected P=.78). For the fidaxomicin group, there was an increase in
through serial growth in the presence of subinhibitory concen- thefidaxomicinMICsofVREisolatesrecoveredbefore(MIC ,
90
trations of rifampin remained fully susceptible to fidaxomicin 4µg/mL; range, 2–256µg/mL) versus after (MIC , 256µg/mL;
90
(MIC,0.05µg/mL). range, 1–>256µg/mL) treatment. Replica plating experiments
For patientswhoacquiredCandidaspecies,meanconcentra- demonstratedthat9ofthe11fidaxomicin-treatedpatientswith
tionsattheendoftreatmentforthevancomycinandfidaxomi- new detection of isolates with fidaxomicin MICs >32µg/mL
cin groups were 4.5 and 4.4log CFU/g stool, respectively had subpopulations (1%–10%) of VRE with similarly elevated
10
(P=.87).Of37Candidaspeciesisolatessubjectedtospeciation, MICs in samples prior to treatment. For vancomycin-treated
12(32%)wereCandidaalbicans,20(54%)wereCandidaglabra- patients for whom cultures performed by the end of treatment
ta,and5(14%)wereothernon-albicansCandidaspecies. were negative for VRE, the vancomycin MICs of the initial
VREisolatesrangedfrom256to1024µg/mL.
EffectofCDITreatmentonPreexistingVREColonization
Fifty-four study patients (18%) had VRE stool colonization in EffectofCDITreatmentonPreexistingCandidaSpecies
the samples collected prior to the start of the study medica- Colonization
tions, of whom 27 were treated with vancomycin and 27 were Forty-nine study patients (16%) had Candida species stool
treated with fidaxomicin. As shown in Figure 3, VRE concen- colonization prior to the start of the study medications, of
trations were similar in both groups at baseline. The mean whom 25 were treated with vancomycin and 24 were treated
VRE concentration decreased significantly in the fidaxomicin withfidaxomicin.ThemeanconcentrationofCandidaspecies
(cid:129) (cid:129)
S124 CID 2012:55 (Suppl2) Nerandzicetal
decreased significantly in the fidaxomicin (4.1 vs 2.1log susceptible to low levels of fidaxomicin. The inhibitory
10
CFU/g stool; P=.001) and vancomycin (4.3 vs 3.2log CFU/g activity against VRE may prevent the establishment of colo-
10
stool;P=.04)groups.Therewasanonsignificanttrendtoward nizationbysusceptiblestrains.Notably,ofthe7fidaxomicin-
more fidaxomicin-treated patients having negative culture treatedpatientswhoacquiredVRE,4(57%)acquired isolates
results by the end of treatment (12 of 24 fidaxomicin-treated withelevatedfidaxomicinMICs.Becauseneitherfidaxomicin
patients [50%] vs 6 of 25 vancomycin-treated patients [24%]; nor vancomycin has inhibitory activity against fungi, the
P=0.07). differences in inhibition of anaerobic intestinal bacteria by
these agents are likely to explain the lower frequency of
EffectofTreatmentonLevelsofBacteroidesSpeciesinStool acquisitionofCandidaspeciesinthefidaxomicingroup.The
For 30 patients (15 per group), the effect of treatment on reductioninconcentrationsofpreexistingCandidaspeciesin
levels of Bacteroides species in stool was assessed. Prior to patients treated with fidaxomicin may be due to recovery of
treatment, levels of Bacteroides organisms (mean [±SD], Bacteroides species and other anaerobes; however, it should
4.8±3.3 log10CFU/g for the vancomycin group and 4.1±1.2 be noted that a statistically significant but more modest re-
log10CFU/g for the fidaxomicin group) were low in compari- duction in Candida species was also seen in the vancomycin
son with typical levels for healthy humans [4]. Vancomycin group.
treatment was associated with a further significant reduction Nearly20%ofpatientswithCDIwerecolonizedwithVRE
in Bacteroides species levels (4.1–2.6log10CFU/g stool; prior to initiation of CDI therapy. It is likely that this per-
P<.001), whereas levels increased during fidaxomicin treat- centage would have been even higher if only US hospitals
ment (4.8–6.1log10CFU/gstool;P<.01). had been included in the study.In 2 previous studies in hos-
pitalsinCaliforniaandCleveland,Ohio,prevalencesofcoex-
DISCUSSION isting VRE colonization at the time of CDI diagnosis were
41% and 62%, respectively [2, 16]. In 44% of patients with
In a substudy conducted in conjunction with a randomized, preexisting VRE colonization, fidaxomicin therapy was asso-
double-blind clinical trial, we found that fidaxomicin was sig- ciatedwithareductioninVREconcentrationtoundetectable
nificantly less likely than vancomycin to promote acquisition levels. For fidaxomicin-treated patients with persistent VRE
ofVRE(7%vs31%)andCandidaspecies (19%vs29%) colo- colonization at the end of treatment, the fidaxomicin MICs
nization during CDI treatment. This finding has important of VRE isolates were higher at the end of treatment (MIC ,
90
clinical and infection control implications. VRE is an impor- 256µg/mL; range, 1–>256µg/mL) than prior to treatment
tant healthcare-associated pathogen in North America and (MIC ,4µg/mL; range,2–256µg/mL),suggestingthatresis-
90
Europe [6], and the intestinal tract is an important reservoir tance to fidaxomicin had emerged during therapy. The pres-
forCandidaspeciesinfection,particularlyinimmunocompro- ence of fidaxomicin resistance did not correlate with
mised patients [8, 14]. Many patients with CDI who acquire rifampin resistance, suggesting that mutations leading to
VRE and Candida species colonization have multiple risk rifampinresistancearenotresponsiblefortheelevatedfidax-
factors for thedevelopment of infection (eg, olderage,immu- omicinMICs.
nocompromise,andpresenceofdevices)[15].Inaddition,pa- OurdatasuggestthatthenewdetectionofVREwithelevat-
tients with CDI pose a high risk for transmission of VRE edfidaxomicinMICs afterfidaxomicintherapymaybedueto
becausediarrheaisassociatedwithincreasedsheddingofVRE expansion of subpopulations of VRE with elevated fidaxomi-
intotheenvironment [4].Oralvancomycinandmetronidazole cin MICs due to selective pressure during therapy rather than
promote persistent high concentrations of VRE in stool, todenovoemergenceofresistance(eg,mutationsinRNApo-
further increasing the risk for shedding of VRE into the envi- lymerase genes). We found that a majority of patients colo-
ronment and onto skin [4]. Our findings suggest that fidaxo- nized with VRE with elevated fidaxomicin MICs after therapy
micin may provide an effective alternative therapy for CDI had detectable minor subpopulations of these organisms
that is less likely to promote colonization with VRE and presentinstoolsamplespriortotherapy.
Candidaspecies. Surprisingly,wefoundthatvancomycintreatmentwasasso-
It is microbiologically plausible that fidaxomicin may be ciated with reduction of VRE to undetectable levels in 37% of
less likely than vancomycin to promote colonization with patients. Because oral vancomycin treatment results in high
VREandotherpathogens.Wedemonstratedthatoralvanco- concentrations in the intestinal tract that are higher than the
mycin treatment significantly reduced Bacteroides levels in MICs of many VRE strains, it is possible that vancomycin
stool, whereas fidaxomicin treatment did not. These data are might have eliminated colonization or suppressed VRE levels
consistentwiththefindingsofLouieetal[6].We alsofound below the limit of detection (approximately 1log CFU/g of
10
that many VRE strains in North American hospitals are stool) in some patients. The reduction in VRE was not
(cid:129) (cid:129)
VREandCandidainCDIPatients CID 2012:55 (Suppl2) S125
attributable to relatively low MICs in the preexisting VRE References
strains (vancomycin MIC range, 25–1024µg/mL). In contrast
1. CohenSH,GerdingDN,JohnsonS,etal.;SocietyforHealthcareEpi-
to the present study, we found that vancomycin therapy was demiologyofAmerica;InfectiousDiseasesSocietyofAmerica.Clini-
associated with reductions in preexisting VRE to undetectable calpracticeguidelinesforClostridiumdifficileinfectioninadults:2010
update by the Society for Healthcare Epidemiology of America
levelsinonly1of19colonized patientsinaprevious studyin
(SHEA)andtheInfectiousDiseasesSocietyofAmerica(IDSA).Infect
aVeteransAffairshospital[3]. ControlHospEpidemiol2010;31:431–55.
Our study has some limitations. Assessment of acquisition 2. Bauer MP, Kuijper EJ, van Dissel JT; European Society of Clinical
of VRE and Candida species was based on stool samples ob- Microbiology and Infectious Diseases. European Society of Clinical
MicrobiologyandInfectiousDiseases(ESCMID):treatmentguidance
tained at the end of treatment, so subsequent acquisition oc- for Clostridium difficile infection (CDI). Clin Microbiol Infect 2009;
curring after CDI treatment could have occurred in some 15:1067–79.
patients. However, for many of the study patients, additional 3. Al-Nassir WN, Sethi AK, Li Y, Pultz MJ, Riggs MM, Donskey CJ.
Both oral metronidazole and oral vancomycin promote persistent
stool samples were analyzed after completion of therapy, and
overgrowth of vancomycin-resistant enterococci during treatment of
results were similar to those for samples obtained at the end Clostridiumdifficile-associateddisease.AntimicrobAgentsChemother
of therapy (data not shown). Because all patients were treated 2008;52:2403–6.
4. SethiAK,Al-NassirWN,NerandzicMM,DonskeyCJ.Skinandenvi-
for CDI, there was no untreated control group. Therefore, we
ronmental contamination with vancomycin-resistant enterococci in
cannot definitively state that the vancomycin or fidaxomicin
patients receiving oral metronidazole or oral vancomycin treatment
therapy was the cause of VRE or Candida species acquisition forClostridiumdifficile-associateddisease.InfectControlHospEpide-
or persistence (ie, other antibiotics received prior to the diag- miol2009;30:13–7.
5. EdlundC,BarkholtL,Olsson-LiljequistB,NordCE.Effectofvanco-
nosis may have contributed). However, we have previously mycinonintestinalfloraofpatientswhopreviouslyreceivedantimi-
demonstrated that the concentration of VRE in stool of colo- crobialtherapy.ClinInfectDis1997;25:729–32.
nized patients decreases significantly by 1–2 weeks after dis- 6. LouieTJ,EmeryJ,KrulickiW,ByrneB,MahM.OPT-80eliminates
ClostridiumdifficileandissparingofBacteroidesspeciesduringtreat-
continuationofantibiotictreatment [7].
ment of C. difficile infection. Antimicrob Agents Chemother 2009;
In summary, we found that fidaxomicin did not suppress 53:261–3.
Bacteroides organisms and was less likely than vancomycin to 7. Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of antibiotic
therapy on the density of vancomycin-resistant enterococci in the
promote acquisition of VRE or Candida species during CDI
stoolofcolonizedpatients.NEnglJMed2000;343:1925–32.
treatment. However, the ability of fidaxomicin to suppress es-
8. PultzNJ,StiefelU,GhannoumM,HelfandMS,DonskeyCJ.Effectof
tablished VRE colonization appeared to be limited because of parenteralantibioticadministrationonestablishmentofintestinalcol-
the selection of subpopulations of VRE with elevated MICs to onizationbyCandidaglabratainadultmice.AntimicrobAgentsChe-
fidaxomicin. Additional studies are needed to determine mother2005;49:438–40.
9. Cole GT, Halawa AA, Anaissie EJ. The role of the gastrointestinal
whether fidaxomicin isless likely than vancomycintopromote tractinhematogenouscandidiasis:fromthelaboratorytothebedside.
colonizationwithotherhealthcare-associatedpathogens(eg,an- ClinInfectDis1996;22(Suppl2):S73–88.
10. Louie T, Miller M, Donskey C, Mullane K, Goldstein EJ. Clinical
timicrobial-resistant gram-negative bacilli) and to assess
outcomes,safety,andpharmacokineticsofOPT-80inaphase2trial
whether use of fidaxomicin for CDI therapy will be associated with patients with Clostridium difficile infection. Antimicrob Agents
with reduced risk for VRE and Candida species infection and Chemother2009;53:223–8.
11. ShueYK,SearsPS,ShangleS,etal.Safety,tolerance,andpharmacoki-
transmission. There is also a need for studies to determine the
netic studies of OPT-80 in healthy volunteers following single and
mechanismoffidaxomicinresistanceinVREstrains. multipleoraldoses.AntimicrobAgentsChemother2008;52:1391–5.
12. LouieTJ,MillerMA,MullaneKM,etal.;OPT-80-003ClinicalStudy
Notes Group.FidaxomicinversusvancomycinforClostridiumdifficileinfec-
tion.NEnglJMed2011;364:422–31.
Financial support. This work was supported by the Department of 13. National Committee for Clinical Laboratory Standards. Methods for
Veterans Affairs, Optimer Pharmaceuticals, Inc., and the National Insti- dilutionantimicrobialsusceptibilitytestsforbacteriathatgrowaerobi-
tuteofAllergyandInfectiousDiseases(grant5R44AI63692-4). cally. Approved standard M7. Wayne, PA: National Committee for
Supplementsponsorship. Thisarticlewaspublishedaspartofasup- ClinicalLaboratoryStandards,2005.
plement entitled “Fidaxomicin and the Evolving Approach to the Treat- 14. PappasPG,KauffmanCA,AndesD,etal.;InfectiousDiseasesSociety
ment of Clostridium difficile Infection,” sponsored by Optimer ofAmerica.Clinicalpracticeguidelinesforthemanagementofcandi-
Pharmaceuticals,Inc. diasis:2009updatebytheInfectiousDiseasesSocietyofAmerica.Clin
Potentialconflictsofinterest. C.J.D.isaconsultantforViroPharma, InfectDis2009;48:503–35.
Optimer,Merck,andGOJOandhasreceivedresearchgrantsfromViro- 15. EdmondMB,OberJF,WeinbaumDL,etal.Vancomycin-resistantEn-
Pharma,Ortho-McNeil,andPfizer.M.A.M.isaconsultantforOptimer terococcus faecium bacteremia: risk factors for infection. Clin Infect
Pharmaceuticals. F. B. is an employee of Optimer Pharmaceuticals. All Dis1995;20:1126–33.
otherauthorsreportnopotentialconflicts. 16. LeberAL,HindlerJF,KatoEO,BrucknerDA,PeguesDA.Laborato-
AllauthorshavesubmittedtheICMJEFormforDisclosureofPotential ry-based surveillance for vancomycin-resistant enterococci: utility of
Conflicts of Interest. Conflicts that the editors consider relevant to the screening stool specimens submitted for Clostridium difficile toxin
contentofthemanuscripthavebeendisclosed. assay.InfectControlHospEpidemiol2001;22:160–4.
(cid:129) (cid:129)
S126 CID 2012:55 (Suppl2) Nerandzicetal