Apr. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

87（ 29 ）Is Clostridium difficile infection influenced byantimicrobial use density in wards?
NOBUMICHI OGAMI, JUNICHI YOSHIDA, TOSHIYUKI ISHIMARU,TETSUYA KIKUCHI, NOBUO MATSUBARA, TAKAKO UENO and IKUYO ASANO
Division of Infection Control, Shimonoseki City Hospital, Shimonoseki, Japan(Received for publication December 19, 2012)

This study was performed to elucidate the relationship between antimicrobial use
density (AUD) and Clostridium difficile infection (CDI) manifesting as
antimicrobial-associated diarrhea (AAD) in hospital wards during a 4-year period.
&DVHGH¿QLWLRQRI&',ZDVDQDGXOWH[KLELWLQJ$$'ZLWKDGDLO\VWRROIUHTXHQF\RIthree or more, arising at least 48 hours after ward admission, and fecal samples
WHVWLQJ SRVLWLYH IRU WR[LQ $ DQGRU %  0HWURQLGD]ROH RU YDQFRP\FLQ ZDV RUDOO\administered as treatment. AUDs were calculated for a total of 21 antimicrobials in aspan of 48 months and nine wards. We included the average value of AUDs,
representing two succeeding months of sample submission into the sample
LQIRUPDWLRQ :H DOVR HQWHUHG GDWD RQ WKH \HDU GLYLVLRQ DQG LQWHQVL¿HG FRQWDFW
precaution for statistical analysis. Of a total of 463 cases, 95 (20.5%) were CDISRVLWLYH 0XOWLYDULDWH UHJUHVVLRQ DQDO\VLV VKRZHG RGGV UDWLRV >25@ RI  FRQ¿GHQFHLQWHUYDO>&,@RI±P＝ DQG &,RI±2.539, P＝0.047) for clindamycin and piperacillin, respectively in AUD. Thus
increased ward AUDs of clindamycin and piperacillin may run the risk of CDI.

Treatment with a variety of drugs is known to cause &ORVWULGLXPGLI¿FLOH infection (CDI) as
antimicrobial-associated diarrhea (AAD)1) 6SHFL¿FDOO\ ÀXRURTXLQRORQHV ZKLFK DUH HIIHFWLYH
against anaerobes, have an association with CDI2) 5HVWULFWHG XVH RI ÀXRURTXLQRORQHV KDV DOVR
been associated with a reduction in CDI incidence3).
Few studies have described the relationship between CDI and antimicrobial use density(AUD) representing antimicrobial pressure in hospital wards. Previous studies have investigated
WKH LQÀXHQFH RI$8' RQ WKH LQFLGHQFH RI H[WHQGHGVSHFWUXP EHWDODFWDPDVHSURGXFLQJ Klebsiella pneumoniae4), Pseudomonas aeruginosa5), and methicillin-resistant Staphylococcus aureus
056$ 6). We attempted to clarify the relationship between &GLI¿FLOH and ward AUD.

88（ 30 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

Apr. 2013

Materials and Methods&DVHGH¿QLWLRQ:HGH¿QHG&',DV$$'LQDQDGPLWWHGDGXOWSDWLHQWZLWKORRVHRUZDWHU\IHFDOVDPSOHVLQ
WKHDEVHQFHRIOD[DWLYHXVHVHQWHUDOIHHGLQJRUDQWLQHRSODVWLFDJHQWVZKRDOVRPHWWKUHHDGGLWLRQDO SUHUHTXLVLWHV   DGPLVVLRQ LQ WKH ZDUG IRU DW OHDVW  KRXUV   SRVLWLYH VWRRO WHVW IRUWR[LQ$DQGRU% 72;$%48,.&+(.1LVVXL3KDUPDFHXWLFDO&R7RN\R DQG  ORRVHRUZDWHU\VWRROZLWKDIUHTXHQF\RIWKUHHRUPRUHSHUGD\Materials
From a total of nine wards in the hospital, attending physicians and infection control professionals submitted fecal samples from all inpatients presenting with AAD. All of the samples were
WHVWHGIRUWR[LQZKHUHDVDSRUWLRQRIVDPSOHVZDVFXOWXUHGIRU&GLI¿FLOH:HH[FOXGHGVDPSOHV
from patients who had already tested positive within the past month and those that did not meet
WKHFDVHGH¿QLWLRQ$QWLPLFURELDOVLQSDWLHQWVSRVLWLYHIRU&',ZHUHGLVFRQWLQXHGH[FHSWIRUSDUHQWHUDO YDQFRP\FLQ WR WUHDW FRH[LVWHQW 056$ LQIHFWLRQ DQG DJHQWV IRU OLIHWKUHDWHQLQJ FR
LQIHFWLRQ 2UDO DGPLQLVWUDWLRQ RI PHWURQLGD]ROH RU YDQFRP\FLQ ZDV FRPELQHG ZLWK SURELRWLF
agents, such as of lactobacilli for treatment.
3DWLHQWVZLWK&',ZHUHLVRODWHGDQGWKHURRPDQGHTXLSPHQWZHUHGLVLQIHFWHGZLWKVRGLXP
hydrochlorite. The use of gloves was re-enforced during the care in the patients positive for CDI
RU056$056$LVRODWHGEHIRUHWKHRQVHWRI&',ZDVUHFRUGHGLQWRDGDWDEDVHDQGQRWHGDVD
SUHYHQWLQJHYHQWE\LQWHQVL¿HGFRQWDFWSUHFDXWLRQ3RVLWLYH&',FDVHVZHUHUHSRUWHGWRKRVSLWDO
LQIHFWLRQ FRQWURO SURIHVVLRQDOV VXFK DV ERDUGFHUWL¿HG LQIHFWLRXV GLVHDVH SK\VLFLDQV EDFWHULRORgists, and nurses. They inspected compliance to the hospital guidelines by house staff.
Analysis
AUDs were calculated for a total of 21 agents, 48 months, and nine wards by the formula:
AUD＝ 7RWDODQWLPLFURELDOGRVH  '''×0RQWKO\LQSDWLHQWV ×1000'''VWDQGVIRUGH¿QHGGDLO\GRVHE\:+2 *HQHYD6ZLW]HUODQG 7). We included the averaged AUDs for two months, which included the month of sample submission and the month preceding it. In a given antimicrobial AUD, the median value was used to assign a value of 0 or 1 fordata higher or lower than the median, respectively.
Antimicrobials of parenteral use for AUD calculation are as follow: ampicillin, sulbactamDPSLFLOOLQ FHID]ROLQ FHIWD]LGLPH FHIPHWD]ROH VXOEDFWDPFHIRSHUD]RQH FHIRWD[LPH FHIRWLDPFHIR]RSUDQFHISLURPHFHIWULD[RQHFOLQGDP\FLQÀRPR[HIIRVIRP\FLQLPLSHQHPFLODVWDWLQPHURSHQHP PLQRF\FOLQH SDQLSHQHPEHWDPLSURQ SLSHUDFLOOLQ WD]REDFWDPSLSHUDFLOOLQ DQG SDUHQ-

Apr. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

89（ 31 ）WHUDOYDQFRP\FLQ4XLQRORQHVZHUHQRWLQFOXGHGEHFDXVHRIWKHLUOLPLWHGLQWUDYHQRXVXVH
7KH&KHVW0HGLFLQHZDUGZDVVHOHFWHGDVDQLQGH[ZDUGEHFDXVHRIWKHKLJKLQFLGHQFHRI&',VKRZQLQDSLORWVWXG\7KHSUHYDOHQFHUDWHRI&',LQDJLYHQ\HDUDQGZDUGZDVGH¿QHGDV
follows:
CDI prevalence rate＝ 3RVLWLYHFDVHV  6XPRILQSDWLHQWV ×1000
We included background information after the second year of data collection to see factor in
KLVWRULFDOELDVDQGLQWHQVL¿HGJORYHXVHGXHWRSUH&',LVRODWLRQRI056$'DWDXQGHUZHQWORgistic regression analysis where the outcome was determined as a positive CDI. Any variables
VLJQL¿FDQWLQXQLYDULDWHUHJUHVVLRQDQDO\VLVXQGHUZHQWPXOWLYDULDWHUHJUHVVLRQDQDO\VLV6WDWLVWLFDOVLJQL¿FDQFHZDVGH¿QHGDVP＜6366VWDWLVWLFDOVRIWZDUH ,%0,QF$UPRQN1< ZDVXVHG
for the analysis.
,Q VHOHFW VDPSOHV &&0$ 0HGLXP (; 1LVVXL 3KDUPDFHXWLFDO7RN\R  ZDV XVHG DV PHGLDIRU DQDHURELF FXOWXUH$IWHU  KRXUV FRORQ\ ZDV H[WUDFWHG DQG FXOWXUHG XVLQJ 5DEELW$%&0
%ORRG$JDU0HGLXP (LNHQ&KHPLFDO7RN\R %%/&5<67$/$15 -DSDQ%HFWRQ'LFNLQVRQ
Tokyo) was used to type &GLI¿FLOH The antibiotic susceptibility of &GLI¿FLOH isolates was de¿QHGE\WKH&OLQLFDODQG/DERUDWRU\6WDQGDUGV,QVWLWXWH :D\QH3$ 8).

Results
In a total of 463 cases, 95 (20.5%) were CDI-positive with a median duration of 27 days
DIWHUDGPLVVLRQ$PRQJWKHVHFDVHV  ZHUHSUHFHGHGE\WKHLVRODWLRQRI056$ZLWKenhanced contact precaution.
7KHXQLYDULDWHDQDO\VLVIRUEDFNJURXQGIDFWRUVRI&',UHYHDOHGVLJQL¿FDQFHLQWKH$8'VRI
clindamycin and piperacillin alone (Table 1). Using these factors, multivariate analysis showed
WKDW ERWK ZHUH VLJQL¿FDQW ZLWK WKH RGGV UDWLR IRU FOLQGDP\FLQ DQG SLSHUDFLOOLQ DW  P＝0.032) and 1.598 (P＝0.047), respectively in AUD (Table 2).
Among the wards, chest medicine ward 6A showed the highest CDI prevalence rate of
0.301, with a median of four years (Fig. 1). In 2010, neurosurgery ward 4A documented the highest prevalence rate of 0.703. In both cases, patients with recurrent CDI across several months
were included in the study and stayed in separate rooms, making an outbreak less likely.
From 2008 through 2011, median AUD levels of clindamycin peaked in 2010, whereas mean
AUD levels of piperacillin tended to decrease (Fig. 2).
The values of AUDs for 21 agents showed increased median values for clindamycin in theneurosurgery ward and sulbactam-ampicillin in both the chest medicine ward and the intensive
care unit (Fig. 3).
Out of a total of 29 specimens isolated with &GLI¿FLOH  WHVWHGSRVLWLYHIRUWR[LQ

90（ 32 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

Apr. 2013

Table 1. Univariate logistic regression analysis on risk factors for &ORVWULGLXPGLI¿FLOH infection
during a 4-year period.

Note: AUD, antimicrobial use density of the month and ward
being more than the median of all the values; *, significant at P＜
0.05.

Apr. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

91（ 33 ）Table 1. Univariate logistic regression analysis on risk factors for &ORVWULGLXPGLI¿FLOH infection
during a 4-year period. (Continued)

Note: **; intensified contact precaution as determined by preceding
isolation of methicillin-resistant Staphylococcus aureus (MRSA).

Table 2. Multivariate logistic regression analysis on risk factors for &ORVWULGLXP GLI¿FLOH
infection.

Note: AUD, antimicrobial use density of the month and ward
being more than the median of all the values; *, significant at P＜
0.05.

Fig. 1. Annual prevalence rates of &ORVWULGLXPGLI¿FLOHinfection (CDI) in wards.

Note: ICU, intensive care unit; 6A, for the chest medicine; 4A, for the neurosurgery.

92（ 34 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

Apr. 2013

Fig. 2. Antimicrobial use density (AUD) of clindamycin (CLDM) and piperacillin (PIPC) by
years.

Median values are shown in the vertical axis.
AUD of CLDM shows a peak in 2010 while AUD of PIPC is decreasing.

$ DQGRU % & GLI¿FLOH strains were susceptible to clindamycin in nine of 16 (56.3%) samples,
SLSHUDFLOOLQLQRI  VDPSOHV 7DEOH 0,&50DQG0,&90 values were not suggestive
RI PXOWLGUXJ UHVLVWDQFH 1R IXUWKHU H[DPLQDWLRQV ZHUH SHUIRUPHG LQFOXGLQJ WKRVH IRU ELQDU\WR[LQ

Discussion
Antimicrobials associated with &GLI¿FLOH diarrhea include clindamycin and cephalosporins,
especially second- and third-generation agents such as ampicillin1). Similarly, the current study
revealed that ward AUDs of piperacillin and clindamycin are risk factors for CDI. However, ureLGRSHQLFLOOLQVVXFKDVSLSHUDFLOOLQDORQHRULQFRPELQDWLRQZLWKWD]REDFWDPKDYHEHHQGHVFULEHG
as less likely to cause CDI than ampicillin9,10),QIDFWDVKRUWDJHRIWD]REDFWDPSLSHUDFLOOLQKDV
been associated with an increase in CDI11). However, one study found hospital consumption of
WD]REDFWDPSLSHUDFLOOLQWREHDVVRFLDWHGZLWKWKHRFFXUUHQFHRI&',12).
2XUVWXG\XVHG$8'WRUHÀHFWDQWLPLFURELDOSUHVVXUHDQGVKRZHGWKDWSLSHUDFLOOLQEXWQRWDPSLFLOOLQRUWD]REDFWDPSLSHUDFLOOLQZDVDVVRFLDWHGZLWK&',2XUVHULHVRI&GLI¿FLOH isolates,
however, showed only a 50% susceptibility rate with ampicillin in contrast to 100% susceptibility
UDWHZLWKSLSHUDFLOOLQVXSSRUWLQJH[LVWLQJOLWHUDWXUHRQDPSLFLOOLQDVVRFLDWHG&', 7DEOH +RZHYHU$8'V LQ RXU VWXG\ DUH SUHVXPHG WR UHÀHFW WKH ZDUGOHYHO HIIHFW RI DQWLPLFURELDOV ZKLFKPD\ H[SODLQ WKH GLVFUHSDQF\ ZLWK WKH OLWHUDWXUH RQ WKH VXVFHSWLELOLW\ RI & GLI¿FLOH strains. The

Apr. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

93（ 35 ）Fig. 3. Antimicrobial use density (AUD) of 21 agents, LH, ampicillin (ABPC), sulbactamampicillin (SBT-ABPC), cefazolin (CEZ), sulbactam-cefoperazone (SBT-CPZ),
ceftazidime (CAZ), cefmetazole (CMZ), cefotaxime (CTX), cefotiam (CTM), cefozopran&=23  FHISLURPH &35  FHIWULD[RQH &75;  FOLQGDP\FLQ &/'0  ÀRPR[HI(FMOX), fosfomycin (FOM), imipenem-cilastatin (IPM-CS), meropenem (MEPM),
minocycline (MINO), panipenem-betamipron (PAPM-BP), piperacillin (PIPC),
tazobactam-piperacillin (TAZ-PIPC), and parenteral vancomycin (VCM) by wards.

Median values are shown in the vertical axis. Note: ICU, intensive care unit; 6A, for the chest medicine; 4A, for theneurosurgery.

$8'RISDUHQWHUDOYDQFRP\FLQZDVQRWVLJQL¿FDQWSUREDEO\DVDUHVXOWRILWVPLQLPDOHIIHFWRQ
&GLI¿FLOH in the gut.
0HDQYDOXHVRIWKHWZRPRQWK$8'ZHUHHPSOR\HGEHFDXVHVSHFLPHQVVXEPLWWHGDWWKHEHJLQQLQJRIDPRQWKZRXOGEHPRUHLQÀXHQFHGE\WKH$8'RIWKHSUHYLRXVPRQWKWKDQRIWKHFXUrent month. Therefore, the averaged AUDs represented antibiotic pressure with respect to ward
volume. Despite our effort to prevent the propagation of &GLI¿FLOH, the effect of mass clindamyFLQXVHPD\KDYHLQÀXHQFHG&',LQWKHZDUGVDVLWGRHVLQDQLQGLYLGXDOSDWLHQW
7KHDVVRFLDWLRQEHWZHHQ$8'DQG056$LQFLGHQFHZDVSUHYLRXVO\GHWHUPLQHGDVEHLQJLQ-

94（ 36 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

Apr. 2013

Table 3. Susceptibility of &ORVWULGLXP GLI¿FLOH and minimum inhibitory concentration (MIC)
against &GLI¿FLOH strains (n＝16) isolated in &GLI¿FLOH infection.

Note: MIC50, 50 percentile MIC; MIC90, 90 percentile MIC; *, Withoutcilastatin as defined by Clinical and Laboratory Standards Institute (CLSI);
N/A, not available by CLSI.

ÀXHQFHGE\WKHXVHRIJORYHV6). Throughout the 10 years of our study, glove uses had been consistent once CDI was detected. However, the possibility of inconsistent glove use confounding the
DQDO\VLVUHPDLQV,QWKHDEVHQFHRIPXOWLGUXJUHVLVWDQW*UDPQHJDWLYHURGVLQRXUKRVSLWDOSUH
&',GHWHFWLRQRI056$UHSUHVHQWHGLQWHQVL¿HGXVHRIJORYHV+RZHYHUORJLVWLFUHJUHVVLRQDQDO\VLVVKRZHGQRLQÀXHQFHRIWKLVIDFWRURQ&',LQRXUVWXG\,Q D SUHYLRXV VWXG\ RQ H[WHQGHGVSHFWUXP EHWDODFWDPDVHSURGXFLQJ K. pneumoniae, an$8' IRU WKLUGJHQHUDWLRQ FHSKDORVSRULQ ZDV HPSOR\HG DV WKH LQGH[ RI FRQWURO4). In two otherstudies investigating the susceptibility of P. aeruginosa, AUDs for meropenem and doripenem
were used as indicators of antibiotic pressure13). In agreement with these studies14), our work
demonstrated that increased clindamycin AUD runs the risk of CDI in wards. The strains of C.
GLI¿FLOHKDGORZVXVFHSWLELOLW\WRFOLQGDP\FLQZKLFKPD\SDUWLDOO\H[SODLQWKH&',LQGXFWLRQE\microbial substitution. Our study supported a previous proposal to restrict hospital-wide use ofclindamycin to regain &GLI¿FLOH susceptibility to this antimicrobial15).
The limitation of the current study is its retrospective design. To validate our hypothesis that
ZDUG$8'ZRXOGLQÀXHQFH&',DUDQGRPL]HGFRQWUROVWXG\VKRXOGEHSHUIRUPHG

Apr. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―2

95（ 37 ）References
1) THIELMAN10 .+:ILSON$QWLELRWLFDVVRFLDWHGFROLWLV,Q0ANDELL*/-(%ENNETT
5'OLINHGLWRUV0DQGHOO'RXJODVDQG%HQQHWWʼs Principles and Practice of Infectious DisHDVHV3KLODGHOSKLD(OVHYLHU&KXUFKLOO/LYLQJVWRQHSS〜1263, 2005
2) STEIN * (  ( - *OLDSTEIN )OXRURTXLQRORQHV DQG DQDHUREHV &OLQ ,QIHFW 'LV  〜
1607, 2006
3) ALDEYAB0$0-'AVINE, P. FLANAGAN, et al.0XOWLKRVSLWDORXWEUHDNRI&ORVWULGLXPGLI¿FLOH
ribotype 027 infection: epidemiology and analysis of control measures. Infect. Control. Hosp. Epidemiol. 32: 210〜219, 2011  .IM-<-:6OHN, D. W. PARK, et al.&RQWURORIH[WHQGHGVSHFWUXP^EHWD`ODFWDPDVHSURGXFing Klebsiella pneumoniae using a computer-assisted management program to restrict thirdgeneration cephalosporin use. J. Antimicrob. Chemother. 62: 416〜421, 2008
5) FUKUSHIMA<))UKUSHIMA..AMIYA, et al.: Relation between the antimicrobial susceptibilityof clinical isolates of Pseudomonas aeruginosa from respiratory specimens and antimicrobial use
GHQVLW\ $8' IURPWKURXJK,QWHUQ0HG〜1340, 2010
  0ATSUMOTO.$6HIGEMI.<AJI, et al.5HGXFWLRQLQWKHLQFLGHQFHRI056$ZLWKXVHRIDOFRhol-based hand rub solutions and gloves. J. Infect. Chemother. 18: 269〜271, 2012  :+2&ROODERUDWLQJ&HQWUHIRU'UXJ6WDWLVWLFV0HWKRGRORJ\$7&''',QGH[&RQ¿UPHG
RQ6HSWHPEHU$YDLODEOHDWKWWSZZZZKRFFQRDWFBGGGBLQGH[  &OLQLFDO DQG /DERUDWRU\ 6WDQGDUGV ,QVWLWXWH 0HWKRGV IRU DQWLPLFURELDO VXVFHSWLELOLW\ WHVWLQJ RI
DQDHURELFEDFWHULDDSSURYHGVWDQGDUGVVHYHQWKHGLWLRQ&/6,GRFXPHQW0$ ,6%1
626-3). Wayne: CLSI pp. 1〜47, 2007
9) FREEMAN- 0+:ILCOX: Ureidopenicillins and risk of &ORVWULGLXPGLI¿FLOH infection. J. Antimicrob. Chemother. 47: 719, 2001
10) BAINES6'-)REEMAN 0+:ILCOX(IIHFWVRISLSHUDFLOOLQWD]REDFWDPRQClostridium dif¿FLOH JURZWK DQG WR[LQ SURGXFWLRQ LQ D KXPDQ JXW PRGHO -$QWLPLFURE &KHPRWKHU  〜982, 2005  0ENDEZ01/*IBBS, R. A. JACOBS, et al.,PSDFWRIDSLSHUDFLOOLQWD]REDFWDPVKRUWDJHRQDQtimicrobial prescribing and the rate of vancomycin-resistant enterococci and &ORVWULGLXPGLI¿FLOH
infections. Pharmacotherapy 26: 61〜67, 200612) VERNAZ1.+ILL, S. LEGGEAT, et al.: Temporal effects of antibiotic use and &ORVWULGLXPGLI¿FLOH
infections. J. Antimicrob. Chemother. 63: 1272〜1275, 200913) SHIGEMI$.0ATSUMOTO.<AJI, et al.: Correlation between meropenem and doripenem use
density and the incidence of carbapenem-resistant Pseudomonas aeruginosa. Int. J. Antimicrob.
Agents 34: 589〜591, 200914) BAXTER5*75AY %+)IREMAN&DVHFRQWUROVWXG\RIDQWLELRWLFXVHDQGVXEVHTXHQWClosWULGLXPGLI¿FLOHDVVRFLDWHGGLDUUKHDLQKRVSLWDOL]HGSDWLHQWV,QIHFW&RQWURO+RVS(SLGHPLRO
44〜50, 2008
15) CLIMO0:'6,SRAEL, E. S. WONG, et al.: Hospital-wide restriction of clindamycin: effect on
the incidence of &ORVWULGLXPGLI¿FLOHDVVRFLDWHGGLDUUKHDDQGFRVW$QQ,QWHUQ0HG〜
995, 1998