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Age and Ageing 2021; 50: 2123–2132https://doi.org/10.1093/ageing/afab169Published electronically 28 August 2021
© The Author(s) 2021. Published by Oxford University Press on behalf of the British GeriatricsSociety. All rights reserved. For permissions, please email: journals.permissions@oup.com
RESEARCH PAPER
Reduced Clostridioides difficile infections inhospitalised older people through multiplequality improvement strategiesCarla Maria Dohrendorf1,2,†, Steffen Unkel3,†, Simone Scheithauer4, Martin Kaase4,Volker Meier5, Diana Fenz4, Jürgen Sasse6, Manfred Wappler7, Jutta Schweer-Herzig7,Tim Friede3, Utz Reichard8, Helmut Eiffert8, Roland Nau1,2, Jana Seele1,2
1Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, Göttingen, Germany2Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany3Department of Medical Statistics, University Medical Center Göttingen; Göttingen, Germany4Institute for Infection Control and Infectious Diseases, University Medical Center Göttingen; Göttingen, Germany5Hospital hygiene, Evangelisches Krankenhaus Göttingen-Weende; Göttingen, Germany6Clinic for Geriatric Medicine, DRK Kliniken-Nordhessen; Kaufungen, Germany7Clinic for Geriatric Medicine, Evangelisches Krankenhaus Gesundbrunnen Hofgeismar; Hofgeismar, Germany8MVZ Wagnerstibbe for Medical Microbiology, Göttingen, Germany
Address correspondence to: Dr. Jana Seele, Department of Neuropathology, University Medical Center Göttingen, Göttingen,Germany & Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, Göttingen, Germany, Robert-Koch-Str. 40,37075 Göttingen, Germany; Tel: +49-551-39-20489; Fax: +49-551-39-10800. Email: jana.seele@med.uni-goettingen.de†Contributed equally
AbstractObjectives: To reduce infections with Clostridioides difficile (CDI) in geriatric patients by interventions easily implementablein standard clinical care.Methods: Prevalence and incidence of CDI between January 2015 and February 2020 were analysed (n = 25,311 patients).Pre-intervention status was assessed from April 2016 to March 2017 (n = 4,922). Between May 2017 and August 2019, amonocentric interventional crossover study (n = 4,655) was conducted including standard care and three interventions: (A)sporicidal cleaning of hospital wards, (B) probiotics and (C) improvement in personal hygiene for CDI patients. This wasfollowed by a multicentric comparison of the interventional bundle (A + B + C) between September 2019 and February2020 (n = 2,593) with the pre-intervention phase. In 98 CDI cases and matched controls individual risk factors for thedevelopment of CDI were compared.Results: Time series analyses of CDI cases revealed a reduction in the prevalence of CDI in all three participating centres priorto the multicentric intervention phase. In the monocentric phase, no effect of individual interventions on CDI prevalence wasidentified. However, an aggregated analysis of CDI cases comparing the pre-intervention and the multicentric phase revealed asignificant reduction in CDI prevalence. Risk factors for the development of CDI included use of antibiotics, anticoagulants,previous stay in long-term care facilities, prior hospital admissions, cardiac and renal failure, malnutrition and anaemia.Conclusions: The observed reduction in CDI may be attributed to heightened awareness of the study objectives and specificstaff training. Individual interventions did not appear to reduce CDI prevalence. A further randomised trial would be necessaryto confirm whether the bundle of interventions is truly effective.
Keywords: Clostridioides difficile infections,reduction of spores,probiotics, interventional study,geriatric patients,older people
Key Points• Reduction of infections with toxigenic Clostridioides difficile in geriatric patients.• Conduction of a monocentric interventional cross-over study followed by a multicentric evaluation of the interventional
bundle.• Combination of the reduction of spores in the environment and strengthening of the patients’ gut flora.
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Introduction
Infections with Clostridioides (C.) difficile (CDI) are amongthe leading causes of nosocomial infections [1]. Transmissionoccurs primarily by ingestion of C. difficile spores shed invast quantities with the stools by infected and colonised indi-viduals. Spores can be found in the environment of affectedpatients and are easily distributed via the hands of healthcareproviders because of their resistance to conventional alcohol-based disinfectants [2].
Depending on immunocompromising factors, perturba-tions in the gut microbiome, the C. difficile strain involvedand the ingested dose, an exposure to C. difficile can resultin asymptomatic colonisation or lead to an infection, whoseclinical presentation ranges from mild diarrhoea to toxicmega-colon, sepsis and death [3].
Geriatric inpatients are particularly vulnerable as manyknown risk factors for the development of CDI pertain tothem: old age, exposure to antibiotics, long hospitalisationduration, stay in long-term care facilities and severecomorbidities such as chronic renal failure or malnutrition[4]. The risk of infection among persons ≥65 yearswas 8.65 times higher than the risk among patients<65 years (95% confidence interval [CI] 8.16 to 9.31).Over 80% of CDI deaths occur in patients ≥65 years[1, 5].
There are several different approaches to prevent CDI.One is to limit exposure to C. difficile spores, e.g. by routineuse of sporicidal agents for surface cleaning or by a dailychange of hospital bed linen [6, 7]. Despite current standardinfection control measures that focus on the isolation ofinfected patients, C. difficile spores can still be found in wardenvironments [6–8]. They are at least in part presumed tostem from asymptomatic carriers. In a study based on a smallnumber of patients, 84% of nosocomial CDI appeared tobe caused by strains introduced by asymptomatic carriers[9]. Other preventive approaches concentrate on the role ofthe microbiome: probiotics have shown promising results inthe prevention of CDI, especially in geriatric wards, withreductions in CDI incidence of 61–66% as reported in threemeta-analyses [10–12].
In the present study, we aimed to develop and evaluate theeffect of interventions to reduce infections with C. difficilethat are easily implemented in geriatric standard hospitalcare. These included the reduction of spores in the wardenvironment, the use of probiotics and improvement in thepersonal hygiene of CDI patients.
Methods
Study design and setting
The incidence [(CDI cases/occupancy days)∗1,000] andprevalence [(CDI cases/total cases)∗100] of all CDI and ofnosocomial CDI were monitored in the three participatingcentres [Geriatrische Klinik, Evangelisches KrankenhausGöttingen-Weende (EKW), Klinik für Geriatrie, DRK
Kliniken-Nordhessen Kassel (DRKK), Klinik für Geriatrie,Evangelisches Krankenhaus Gesundbrunnen Hofgeismar(EKH)] from January 2015 to February 2020 (last monthincluded). The development of symptoms of a CDI within48 h of admission to a geriatric ward was defined as a caseacquired outside the geriatric departments and >48 h afteradmission as a nosocomial case. From May 2017 to August2019 a monocentric four-armed interventional effectivenessstudy with crossover design was conducted at the EKW. Thefollowing interventions were implemented in four differenthospital wards of the EKW: (group A) cleaning of all surfacesin all patients‘ rooms (Cleanisept� Wipes Forte containingbenzalkonium chloride and didecyldimethylammoniumchloride, Dr. Schumacher, Malsfeld, Germany), all handcontact surfaces (Cleanisept� Wipes Forte) and floors(Ultrasol� active containing peracetic acid, Dr. Schumacher,Malsfeld, Germany) with a sporicidal disinfectant; (groupB) daily provision of probiotics (Actimel� containingStreptococcus thermophilus, Lactobacillus bulgaricus andLactobacillus casei, Danone Germany, München-Haar,Germany) for all patients; and (group C) improvementin personal hygiene of patients with symptomatic CDIincluding a sporicidal laundry service for the personalclothes and daily change of the bedding. These interventionswere carried out in addition to the standard hospital carewhich included isolation of patients with a symptomaticinfection and sporicidal cleaning of the infected patient’sroom once per day. The fourth ward (group D, standardhospital care) served as a control. Every ward comprised19–25 beds and went through every intervention for6 months and 3 weeks with 1 week wash-out in between.The interventions were randomly allocated to the wards(Figure 1). In the multicentric phase, a bundle comprising allthree interventions in addition to the standard hospital carewas implemented in the geriatric wards of EKW (4), EKH(3) and DRKK (3) in a total of 294 beds from September2019 to February 2020 (Figure 1).
Twice per week the study nurse and/or study coordinatorspoke with the hospital staff (including nurses, physiciansand cleaning staff) about the study concept and implementa-tion of interventions as well as to listen closely to their needsand concerns.
Endpoints of the monocentric phase were the influenceof the interventions A, B and C compared to standardhospital care on the infection rate and the dependence of theCDI rate on (1) the immune status of the patient, (2) theduration of the hospital stay, (3) the medication, especiallythe use of antibiotics and (4) comorbidities and underlyingdiseases.
The endpoint of the multicentric phase was the CDIprevalence during the multicentric phase (September 2019–February 2020) compared to a 1-year interval prior to thestart of the monocentric phase (April 2016–March 2017).All endpoints of both the monocentric and the multicentricphase were evaluated on total CDI and nosocomial CDI asdefined previously.
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Reduced Clostridioides difficile infections in hospitalised older people
Figure 1. Study design and implemented interventions. (A) The incidence and prevalence of CDI was calculated from January 2015to February 2020. The monocentric phase of the study was implemented from May 2017 to August 2019 in the geriatric centre ofEKW. The interventions were carried out for 6 months and 3 weeks with 1 week wash-out following. Afterwards the interventionsrotated on the wards. The standard hospital care served as control. During the multicentric phase from September 2019 to February2020 the bundle of the interventions A, B and C in addition to the standard hospital care was implemented in the geriatric centresof EKW, EKH and DRKK. (B) The interventions served to (A) reduce C. difficile and its spores in the hospital environment, (B)strengthen the gut microbiome of all patients and (C) improve the personal hygiene of patients with a symptomatic CDI in additionto (D), the standard hospital care.
Participants
Pre-intervention status was assessed from April 2016 toMarch 2017 (4,922 patients). The monocentric phaseincluded 4,655 inpatients admitted to the geriatric depart-ment of the EKW between May 2017 and September 2019;in the multicentric phase 2,593 inpatients in the geriatricdepartments of EKW, EKH and DRKK between September2019 and February 2020 were analysed.
For change point analyses, CDI cases from January 2015to February 2020 were analysed (25,311 patients).
Microbiology
Stool samples of symptomatic patients were analysed by anenzyme immunoassay (EIA) detecting Clostridoides-specificglutamate dehydrogenase (GDH) to prove the presence ofC. difficile. Then, the bacterial DNA encoding Toxin B wasamplified by polymerase chain reaction (PCR) to identifytoxigenic strains.
Case definition and data collection
A CDI case was defined by (i) unformed stools and (ii)positive results for GDH EIA and Toxin B PCR. CDI caseswere identified by the routine hospital infection surveillancesystems. Only the patient’s first episode during the studyperiod was recorded as a new case. CDI was consideredsevere, if the patient died, was transferred to an ICU orreceived colonic surgery with CDI as a plausible cause basedon the medical records.
Data of CDI patients were compared with data of controlpatients by matched-pairs analysis. For the control group,patients without CDI or known C. difficile colonisation who
had stayed at the EKW during the monocentric phase forat least 2 days were selected in a 1:1 matching with respectto age and sex. Laboratory data, medication during hospitalstay, demographics and comorbidities were collected usingthe medical records. Laboratory results were collected atadmission to the geriatric ward (or from the sample closest tothis time point; t0). As a second blood analysis in CDI casesthe measurements obtained closest to the C. difficile-positivestool sampling were used (t1). For control patients, t1 wasset at 12 days after admission (or the latest results available,if the stay was shorter than 12 days). This was based on a pre-evaluation of CDI patients from 2016 in which the medianof the interval admission – CDI was 12 days.
Ethics
This study was approved by the Ethics Committee ofthe University Medical Centre Göttingen, Georg-August-University Göttingen (application number 22/1/17).Individual informed consent was waived since all measuresimplemented in this study aimed to maintain and improvethe quality of patient care. Upon admission, all patients gaveconsent that their data can be used for research purposes bystaff subjected to medical confidentiality. A data protectiondeclaration was signed by all project members.
Statistical power calculation and data analysis
A full survey was carried out on all wards of the EKW(phase 1) and in all participating centres (phase 2). Statisticalpower calculation based on the pre-defined endpoints wasperformed prior to the beginning of the study under thefollowing assumptions. Monocentric phase (phase 1): onaverage, 225 patients will be treated on each ward of the
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EKW during one intervention period of 6 months plus3 weeks (1 week wash-out period), i.e. after four rotations,900 patients are treated with intervention A, B, C and stan-dard care (D). Compared with the pre-intervention status,the number of CDI cases will be reduced by each interven-tion (A, B, C) by 25%. These assumptions led to an estimatedpower of >80%. Multicentric phase (phase 2): a total of2,700 patients will be treated in the centres participating inthe 6-months period of the bundle intervention. Withoutinterventions, a total number of 90 CDI cases were assumedto occur. The number of CDI cases will be reduced by 50%during the multicentric phase. These assumptions led to anestimated power of >95%.
Univariate analysis of individual risk factors was con-ducted that compared CDI patients with their matchedcontrols, and a subgroup analysis was performed, includingonly nosocomial cases and their respective control patients.Dichotomous variables were compared by using Fisher’sexact test. Categorical variables (with more than two cat-egories on one variable) were compared using Wilcoxon’ssigned rank test after being ranked according to the severityof the impairment of the function studied. Continuousvariables were compared using Wilcoxon’s signed rank testfor matched pairs, and if matching was not feasible byMann–Whitney U test. Change point analyses were carriedout to detect the point at which a structural break (changein the normally distributed mean) of the times series ofmonthly CDI prevalences and incidences occurred [13].The results of the change point analyses were visualised ina similar fashion as in statistical process control, in whichcontrol charts are used to distinguish between common andspecial causes of variation. Control charts typically includea plot of the data over time, and one or more additionallines, which e.g. represent the means of the time series, orindicate when a signal of special cause variation has occurred[14].
A two-tailed P value ≤ 0.05 was considered statisti-cally significant. Statistical analyses were conducted usingR version 4.0.1. [15] and GraphPad Prism, Version 6.01(2012).
Results
Change point analyses of CDI prevalence andincidence
In the present study the effect of interventions to reduceinfections with C. difficile that are easily implementableinto geriatric standard hospital care were evaluated. Theseincluded (A) the reduction of spores in the ward, (B) theuse of probiotics and (C) improvement in personal hygieneof CDI patients. The prevalence and incidence of CDI caseswere analysed from January 2015 to February 2020, i.e. from16 months prior to the start of the monocentric phase upto the end of the multicentric phase of the study. Changepoint analyses revealed that the prevalence of nosocomial andtotal (nosocomial, i.e. acquired in the geriatric department,
plus externally acquired) CDI cases significantly droppedat the Departments of Geriatrics of the EKW betweenMarch and April 2015, at the EKH between March andApril 2017 and at the DRKK between April and May 2016(Figure 2). A change point in regard to the incidence of CDIcases was only detectable for total CDI cases at the EKW(Supplementary Figure 1).
Influence of the individual interventions on CDIinfection rate (monocentric phase)
During the monocentric phase of the study, the interven-tions A–D were carried out as individual interventions onfour different geriatric wards of the EKW from May 2017to August 2019 with a rotation of the interventions after6 months and 3 weeks, each separated by 1 week of wash-out.An analysis of CDI cases at the end of the monocentric phaseshowed that none of the experimental interventions A, B orC (total CDI incidence A: 1.37, B: 1.99, C: 1.33; nosocomialCDI incidence A: 1.20, B: 1.29, C: 1.04) reduced theCDI infection rate compared to standard hospital care D(total CDI incidence 0.86, nosocomial CDI incidence 0.59).Because of differences in the composition of the patientstreated on the individual wards, their CDI incidence wasnot equal. Total CDI incidence on the individual wardsranged from 1.02 to 1.97, and nosocomial CDI incidencefrom 0.91 to 1.42 illustrating the necessity of the chosenstudy design (allocation of the sequence of interventionsto the wards randomly, every ward went through everyintervention).
Individual risk factors for the development of CDI
During the monocentric phase of the study, data of 98matched pairs (CDI vs. control) were analysed for individualrisk factors for the development of CDI (Tables 1 and 2,Supplementary Table 1). The median age in both groups was82 years. Of the 98 CDI cases, 88.8% were nosocomialinfections, 11.2% were recurrent episodes and 4.3% metcriteria of severe CDI. Median length of stay at the geriatricward was 6.5 days longer for CDI patients, and they weredischarged with a worse outcome. CDI was significantlyassociated with prior hospital stays, previous residency in along-term care facility, invasive feeding and worse scores ingeriatric assessments including the Charlson ComorbidityIndex (CCI). CDI patients suffered more often from cardiacfailure, malnutrition, anaemia, hypothyroidism, renal failureand dialysis, while Parkinson’s disease and conservativelytreated fractures were more frequent in the control group.
CDI patients showed higher levels of serum immunoglob-ulin A (IgA), infection parameters (both at time of admissionand sampling) and plasma alanine transaminase, whereastotal plasma calcium was lower as a consequence of lowertotal protein and albumin concentrations. When plasmacalcium was corrected for albumin using Payne’s formula[16], calcium was not lower in CDI than in the respectivecontrol patients. Plasma potassium levels fell in CDI patients
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Reduced Clostridioides difficile infections in hospitalised older people
Tabl
e1.
Cha
ract
erist
icso
fCD
Icas
esan
dco
ntro
lsVa
riabl
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DI,
med
ian
(IQ
R)
(N=
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cont
rols,
med
ian
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OR
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lue
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ocom
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med
ian
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rols,
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OR
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Leng
thof
stay
inge
riatr
icw
ard
[day
s]22
.5(1
6;35
.25)
16(1
4;20
)<
0.00
01†
27(1
7;36
)16
(14;
20)
<0.
0001
†
Prio
rhos
pita
ladm
issio
nin
the
last
4w
eeks
,No.
(%)
72(7
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(57.
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2.08
0.02
4∗63
(72.
4%)
50(5
7.5%
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940.
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CC
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(2;5
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(1;4
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0002
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003†
Car
diac
insu
ffici
ency
,No.
(%)
54(5
5%)
31(3
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2.65
0.00
15∗
46(5
3%)
29(3
3%)
2.24
0.01
4∗D
ialy
sis,N
o.(%
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0003
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0007
∗Pa
rkin
son’
sdise
ase,
No.
(%)
11(1
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34(3
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0.24
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9(1
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32(3
7%)
0.2
<0.
0001
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actu
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6†
naso
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26(2
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23(2
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(31.
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long
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lity
26(2
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20(2
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(11.
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Thyr
oid
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mea
n(I
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2.99
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025†
3.25
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0.03
8†
IgG
[mg/
dl]
906
(685
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881
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0.75
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4(6
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7(6
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IgM
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73(5
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0)61
(38.
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0.08
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(50.
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0)59
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92)
0.06
7†
IgA
[mg/
dl]
281
(194
;372
)21
2(1
56;3
17)
0.02
6†27
6(1
97;3
71.5
)20
9(1
55;3
21)
0.01
6†
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.6;6
.75)
6.6
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)0.
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6.35
(5.6
;6.7
3)6.
55(6
.2;7
.1)
0.01
6†
Albu
min
[g/l]
26.0
5(2
3.13
;29.
73)
31.8
(27.
15;3
5.5)
<0.
0001
†26
.2(2
3.4;
29.8
)31
.5(2
6.93
;35.
03)
<0.
0001
†
Cre
atin
ine
t 0[m
g/dl
]1.
14(0
.83;
1.65
)0.
97(0
.77;
1.19
)0.
0008
†1.
14(0
.83;
1.63
)0.
96(0
.78;
1.2)
0.00
2†
Hae
mog
lobi
nt 0
[g/d
l]10
.3(8
.9;1
1.55
)11
.5(9
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3.1)
0.00
05†
10.2
(8.7
;11.
5)11
.4(9
.5;1
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0.00
1†
Leuk
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est 0
[103 /μ
l]9.
5(7
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26(7
.13;
12.2
6)8.
29(6
.95;
9.6)
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4†
Leuk
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est 1
[103 /μ
l]9.
305
(6.9
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.52)
6.56
(5.4
0;8.
16)
<0.
0001
†8.
96(6
.8;1
1.95
)6.
895
(5.4
5;8.
17)
<0.
0001
†
OR
=O
dds
ratio
,IQ
R=
Inte
rqua
rtile
rang
e,C
CI=
Cha
rlson
com
orbi
dity
inde
x,PE
G=
Perc
utan
eous
endo
scop
icga
stros
tom
yt 0
=tim
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adm
issio
nto
geria
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war
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TC
D-p
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mpl
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llect
ion
(con
trols:
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disc
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efro
mge
riatr
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n12
days
),�
=t 1
–t 0
∗ Pva
lues
calc
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edw
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sher
exac
ttes
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valu
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lcul
ated
with
Wilc
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signe
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nkte
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CC
Ical
cula
ted
with
outc
onsid
erat
ion
ofth
eage
∗∗C
lass
ifica
tion
ofth
yroi
dsta
tus:
1=
over
thyp
erth
yroi
dism
,2=
subc
linic
alhy
pert
hyro
idism
,3=
euth
yreo
sis,4
=su
bclin
ical
hypo
thyr
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notr
equi
ring
treat
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t,5=
subc
linic
alhy
poth
yroi
dism
,req
uirin
gtre
atm
ent,
6=
over
thyp
othy
roid
ism
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Figure 2. Change point analysis of nosocomial (A, B, C) and total (D, E, F) CDI prevalence from January 2015 (month 0) toFebruary 2020 (month 60) in the geriatric centres of EKW (A, D), EKH (B, E) and DRKK (C, F). The prevalence per month wascalculated as CDI cases/total cases∗100.
from admission to time of stool sampling, unsurprisinglyduring a diarrhoeal illness.
Medication associated with CDI were anticoagulants,loop diuretics, antiepileptics, antimotility agents, and signif-icant only for nosocomial CDI, benzodiazepines. Calciumchannel blockers were prescribed more often in the controlgroup. The use of proton pump inhibitors and immuno-suppressants was not significantly different. The number oftotal prescriptions during the geriatric stay was higher in thenosocomial CDI group.
Further risk factors for development of CDI included theuse of antibiotics, higher numbers of different antibiotics and
more days of antibiotic use. Odds ratios (OR) were similarfor the different routes of administration.
Influence of the intervention bundle on CDIprevalence (multicentric phase)
As individual interventions during the monocentric phasedid not reduce the incidence of CDI, we decided to com-bine all interventions in addition to the standard hospitalcare during the multicentric phase in the three participat-ing geriatric centres for 6 months. An aggregated analysisof the nosocomial and total (nosocomial plus ambulant)
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Table 2. Use of antibiotics and other medication in CDI cases and controlsCDI vs. controls Nosocomial CDI vs. controls
Variable CDI, No. (%)(N = 98)
controls, No. (%)(N = 98)
OR P value Nosocomial CDI,No. (%)(N = 87)
controls, No. (%)(N = 87)
OR P value
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Antibiotics 74 (76%) 50 (51%) 2.96 0.0006∗ 68 (78%) 46 (53%) 3.19 0.0007∗Aminopenicillins 48 (49%) 23 (23%) 3.13 0.0003∗ 43 (49%) 21 (24%) 3.07 0.0009∗Piperacillin/tazobactam 32 (33%) 12 (12%) 3.47 0.001∗ 31 (36%) 11 (13%) 3.82 0.0006∗Linezolid 6 (6%) 0 (0%) n.a. 0.029∗ 6 (7%) 0 (0%) n.a. 0.029∗Days with antibiotic use,median (IQR)
6 (0.75; 12) 1 (0; 6) <0.0001† 8 (1; 12) 1 (0; 6) <0.0001†
Number of antibiotics used,median (IQR)
1 (0.75; 3) 1 (0; 1.25) <0.0001† 2 (1; 3) 1 (0; 2) <0.0001†
Anticoagulants 57 (58%) 35 (36%) 2.50 0.003∗ 55 (63%) 35 (40%) 2.55 0.004∗low molecular weightheparin
19 (19%) 7 (7%) 3.13 0.019∗ 19 (22%) 7 (8%) 3.19 0.018∗
unfractionated heparin 8 (8%) 1 (1%) 8.62 0.035∗ 8 (9%) 1 (1%) 8.71 0.034∗Loop diuretics 61 (62%) 48 (49%) 1.72 0.084∗ 58 (67%) 44 (51%) 1.95 0.045∗Calcium channel blockers 25 (26%) 41 (42%) 0.48 0.023∗ 24 (28%) 38 (44%) 0.49 0.039∗Benzodiazepines 14 (14%) 7 (7%) 2.17 0.165∗ 14 (16%) 4 (5%) 3.98 0.023∗Antiepileptics 23 (23%) 11 (11%) 2.43 0.037∗ 20 (23%) 10 (11%) 2.30 0.070∗Number of totalprescriptions, median (IQR)
9 (7; 12) 9 (6; 11) 0.145 10 (7; 12) 9 (6; 11) 0.029†
OR = Odds ratio, IQR = Interquartile range ∗P values calculated with Fisher exact test †P values calculated with Wilcoxon signed-rank test
CDI cases of all three participating centres comparing the1-year interval before the start of the study (April 2016until March 2017) with the 6-month interval of the mul-ticentric phase (from September 2019 to February 2020)revealed a significant reduction in CDI cases during thestudy (nosocomial: OR 0.60, 95% CI 0.40–0.90; total: OR0.56, 95% CI 0.39–0.81; Figure 3). When analysing eachcentre separately, the reduction in the odds of infection werestatistically significant in EKH (nosocomial: OR 0.53, 95%CI 0.25–1.11; total: OR 0.40, 95% CI 0.20–0.79) andDRKK (nosocomial: OR 0.39, 95% CI 0.16–0.95; total:OR 0.41, 95% CI 0.18–0.94), whereas in EKW it failed toreach statistical significance (nosocomial: OR 0.83, 95% CI0.46–1.50; total: OR 0.84, 95% CI 0.49–1.42; Figure 3).
Discussion
In this study, change point analyses and pre-to-post inter-vention comparison revealed that the total number as wellas number of nosocomial CDI cases declined in the partic-ipating centres. No single intervention in the monocentricphase was found to be effective, meaning that in respect tothe a priori defined endpoint of the monocentric phase ofthis study, each intervention by itself was not found to reduceCDI prevalence. However, the bundle of interventions incombination with the associated staff awareness and educa-tion appeared to be effective in the multicentric prior-postcomparison.
The change point analyses suggested that the heightenedawareness through the study objectives accompanied bydiscussions and staff training was key to the reduction in
Figure 3. Analysis of nosocomial and total CDI cases in thethree participating centres. The CDI prevalence prior the study(April 2016–March 2017) was compared with the CDI preva-lence during the multicentric phase of the study (09/2019–02/2020). The Odds ratio was calculated for each centre andin an aggregated analysis for all centres. Odds ratio and 95%confidence intervals are shown.
CDI incidence. This is similar to a situation in Great Britainin 2008, where as a consequence of the high incidence ofCDI, a national target was set for a 30% reduction in CDI by2010–11, which was achieved in spite of very heterogeneousapproaches towards CDI prevention [17].
Conceivable reasons for the failure of the monocentricphase of this study were (a) the lack of effectivity of the
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individual interventions, or (b) insufficient adherence to theintervention protocols by the participating staff or patients,or both.
As to (a): The evidence for the effectivity of some indi-vidual interventions was fairly low: chlorine or oxygen-baseddaily and terminal cleaning to reduce the concentration ofC. difficile spores was of all interventions most likely toreduce CDI [18]. Installing a laundry service for infectedpatients was supported by only few observations [6, 7]. Theuse of probiotic yoghurt was supported by more studies [11,19–22]. In studies with a baseline CDAD risk of 0 to 2%and 3 to 5%, probiotics were found to be ineffective, butstudies including patients with a baseline risk of >5% fordeveloping CDAD showed a risk reduction of approximately70% [11]. In all participating centres the baseline risk was<5%. In regard to the probiotics, the effect was not alwaysreproducible [23], and as a consequence of strong economicinterests a publication bias in favour of positive studies issuspected.
(b) The staff compliance varied: achieving compliancewith appropriate cleaning technique was difficult, becausedepending on the institution and also on the compositionof the flooring, staff and patients complained of bad odourand mucosal irritation. As a consequence, the areas cleanedby chlorine bleach had to be reduced in all centres duringthe multicentric study. Probiotic yoghurt was not distributeddaily on all wards as a consequence of work overload orprejudices on the part of the staff in regard to the inter-ventions. Moreover, the laundry service was not propagatedrigorously enough. The compliance of the patients dependedon this measure: The laundry service was rejected by manypatients because of the fear of losing their clothing. In total,in EKW 10% of the patients accepted the laundry service.In EKH and DRKK, it was not accepted by the patients.The daily distribution of probiotic yoghurt was the measuremost readily accepted by all patients. On an average, 81% ofthe patients received and accepted the probiotic yoghurt inall participating centres. The supply of a probiotic yoghurtwill be continued in EKW. Especially for geriatric patientswho often suffer from swallowing disorders, yoghurt is anappropriate snack.
Change point analyses of the entire study period revealedthat all centres reduced the prevalence of CDI infections.Bundled interventions of different compositions are con-sidered highly effective [18]. After we had noticed that noindividual measure appeared to be effective in the monocen-tric study, we decided to use all interventions as a bundle.The bundle of interventions was effective, when all centreswere analysed together, and in two of three centres, wheneach centre was analysed separately. This discrepancy is aconsequence of the different change points: in EKW thechange point already occurred in March 2015, i.e. prior tothe control period of the multicentric study, whereas in EKHand DRKK the change points occurred during the controlperiod of the multicentric study. No further change pointoccurred at the beginning of the multicentric phase, i.e. thebundle intervention. Due to the different times when the
change occurred, we hypothesise that the time of the changepoint depended on the awareness of the problem of frequentCDI infections by the heads of the institutions and theeducational measures taken thereafter. In EKW, the changepoint corresponded to the start of the planning of this projectincluding discussions among the staff about correct hygienemeasures. In DRKK the change point was associated withefforts of the chief physician (J.Sa.) to implement rationalantibiotic therapy. In EKH, the change point was close tojoint meetings in preparation of the multicentric phase ofthis study. In particular, the colleagues of this institutionwere impressed by a lecture of M.K. on the pathophysiol-ogy, molecular biology and epidemiology of CDI. In thisrespect, the results of the present study resemble experiencespublished concerning the prevention of overwhelming post-splenectomy infection (OPSI) where a bundle of measuresinvolving vaccination, antibiotic prophylaxis and patienteducation can prevent infections, although the effectivenessof some of the individual interventions remains unclear [24].
In general, CDI incidences and prevalences were com-parable to other clinical studies [25]. In the present study,CDI was defined by unformed stools and positive results forGDH EIA and Toxin B PCR. In older patients, infectionsmay present with mild symptoms, which may have led to aslight underestimation of the true incidence [2]. Individualrisk factors of CDI were similar in the present study as inprevious investigations: We confirmed the main risk fac-tors, previous use of antibiotics, renal failure, malnutrition,but not previous ICU stay, proton pump inhibitor andimmunosuppressant treatment. Since we matched for age,we could not reproduce this well-known fact [26]. The effectof stay in long-term care facilities, lower functional status andcomorbidities may be mediated by several factors. Frequentcontact with healthcare facilities entails increased exposureto C. difficile spores [27]. Impairment of the immune sys-tem (e.g. by malnutrition or renal failure) facilitates thedevelopment of CDI directly or may result in other infec-tions demanding antibiotic therapy thereby disbalancingthe gut microbiome. Anticoagulation was associated withan increased risk of developing CDI and nosocomial CDI.Approximately 40% of the patients at our institution receiveanticoagulants mostly due to nonvalvular atrial fibrillation orflutter (AF) [28]. AF is associated with a variety of diseasesand with an increased mortality (odds ratio approx. 2.5)[29]. Therefore, we hypothesise that in the present studyanticoagulated patients had a higher burden of diseases thanpatients receiving no anticoagulation, rendering them moresusceptible to CDI. The median CCI of anticoagulated CDI-infected patients was 4, whereas the median CCI of CDI-infected not anticoagulated patients was 3, and the CCI ofthe respective control patients in both subgroups was 2.
Our study has several limitations. It consisted of an obser-vational and a randomised intervention part. In the ran-domised intervention part (monocentric phase), no reduc-tion in CDI was achieved. For the observational part, ourstudy succeeded in reducing C. difficile infections in the par-ticipating departments. In line with the majority of the other
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studies on CDI in acute care hospitals, for the multicentricstudy we used a simple pre- and post-intervention design.The use of a step-wedge design might have improved thequality of the data [18].
Conclusion
In conclusion, the observed reduction in CDI may beattributed to a heightened awareness of the study objectives,as well as to specific staff training. The individual interven-tions did not appear to reduce CDI prevalence. The bundleof interventions and the accompanying staff training reducedthe high incidence and prevalence of CDI by approx. 40%,whereas the individual measures appeared to be ineffective.The results of the present study could be characterised by theproverb ‘A danger foreseen is half avoided’ [30]. It remainsopen whether the bundle of interventions was truly effectiveor whether the reduction in CDI incidence primarily wasachieved by an increased awareness of the problem andby training measures accompanying the implementation ofthis study. Therefore, the promising effects of the combinedintervention would need to be confirmed in a future cluster-randomised multicentre trial in which the wards representthe clusters.
Supplementary Data: Supplementary data mentioned inthe text are available to subscribers in Age and Ageing online.
Acknowledgements: We thank Cynthia Bunker for projectadministration and careful language editing.
Declaration of Sources of Funding: This study was fundedby Gemeinsamer Bundesausschuss, Innovationsausschuss,project number: 01VSF16059. The funding bodies did notinfluence the design of the study, collection, analysis, andinterpretation of data and manuscript writing.
Declaration of Conflicts of Interest: SS and TF reportother grants from Gemeinsamer Bundesausschuss (G-BA), Innovationsausschuss. TF received personal feesfrom Novartis, Bayer, Janssen, SGS, Roche, BoehringerIngelheim, Daiichi-Sankyo, Galapagos, Penumbra, Parexel,Vifor, BiosenseWebster, CSL Behring, Fresenius Kabi,Coherex Medical, LivaNova, all outside the submitted work.RN received honoraria for lectures from Bayer Vital, Pfizer,Bristol-Myers Squibb and Desitin, and research supportfrom Novartis, B. Braun Foundation, Deutsche Gesellschaftfür Geriatrie, and Strathmann GmbH, all unrelated to thesubmitted work. The other authors declare that they have noconflicts of interest.
References
1. Lessa FC, Mu Y, Bamberg WM et al. Burden of Clostridiumdifficile Infection in the United States. N Engl J Med 2015;372: 825–34.
2. Yoshikawa TT, Norman DC. Geriatric Infectious Diseases:Current Concepts on Diagnosis and Management. J AmGeriatr Soc 2017; 65: 631–41.
3. Leffler DA, Lamont JT. Clostridium difficile infection. NEngl J Med 2015; 372: 1539–48.
4. Jump RL. Clostridium difficile infection in older adults. Aginghealth 2013; 9: 403–14.
5. Balsells E, Shi T, Leese C et al. Global burden of Clostridiumdifficile infections: a systematic review and meta-analysis. JGlob Health 2019; 9: 10407.
6. Fekety R, Kim KH, Brown D et al. Epidemiology ofAntibiotic-Associated Colitis. Isolation of Clostridium Dif-ficile from the Hospital Environment. Am J Med 1981; 70:906–8.
7. Goldstein EJC, Johnson S, Maziade P-J et al. Pathway to Pre-vention of Nosocomial Clostridium difficile Infection. ClinInfect Dis 2015; 60: S148–58.
8. Dumford DM, Nerandzic MM, Eckstein BC et al. What ison that keyboard? Detecting hidden environmental reservoirsof Clostridium difficile during an outbreak associated withNorth American pulsed-field gel electrophoresis type 1 strains.Am J Infect Control 2009; 37: 15–9.
9. Clabots CR, Johnson S, Olson MM et al. Acquisition ofClostridium Difficile by Hospitalized Patients: Evidence forColonized New Admissions as a Source of Infection. J InfectDis 1992; 166: 561–7.
10. Johnston BC, Ma SSY, Goldenberg JZ et al. Probiotics forthe Prevention of Clostridium difficile-Associated Diarrhea ASystematic Review and Meta-analysis. Ann Intern Med 2012;157: 878–U225.
11. Goldenberg JZ, Ma SSY, Saxton JD et al. Probiotics forthe prevention of Clostridium difficile-associated diarrheain adults and children. Cochrane Database Syst Rev 2013;5: 1–107.
12. Johnson S, Maziade JP, McFarland LV et al. Is primary pre-vention of Clostridium difficile infection possible with specificprobiotics? Int J Infect Dis 2012; 16: e786–92.
13. Hinkley DV. Inference About the Change-Point in aSequence of Random Variables. Biometrika 1970; 57: 1–17.
14. Mohammed MA, Worthington P, Woodall WH. Plottingbasic control charts: tutorial notes for healthcare practitioners.Qual Saf Health Care 2008; 17: 137–45.
15. Core R. Team. R: A language and environment for statisticalcomputing. Vienna, Austria: R Foundation for Statistical.Computing, 2013.
16. Payne RB, Little AJ, Williams RB et al. Interpretation of serumcalcium in patients with abnormal serum proteins. Br Med J1973; 4: 643–6.
17. Duerden BI. Contribution of a government target to control-ling Clostridium difficile in the NHS in England. Anaerobe2011; 17: 175–9.
18. Louh IK, Greendyke WG, Hermann EA et al. Clostrid-ium Difficile Infection in Acute Care Hospitals: SystematicReview and Best Practices for Prevention. Infect Control HospEpidemiol 2017; 38: 476–82.
19. McFarland LV, Johnson SB, Evans CT. Perils and pitfalls ofprobiotic quasi-experimental studies for primary preventionof Clostridioides difficile infection: A review of the evidence.Am J Infect Control 2020 49: 375–84.
20. Mills JP, Rao K, Young VB. Probiotics for preventionof Clostridium difficile infection. Curr Opin Gastroenterol2018; 34: 3–10.
2131
Dow
nloaded from https://academ
ic.oup.com/ageing/article/50/6/2123/6358411 by 81695661, O
UP on 17 N
ovember 2021
C. M. Dohrendorf et al.
21. Goldenberg JZ, Yap C, Lytvyn L et al. Probiotics for the pre-vention of Clostridium difficile-associated diarrhea in adultsand children. Cochrane Database Syst Rev 2017; 12: 1–207.
22. Lau CS, Chamberlain RS. Probiotics are effective at pre-venting Clostridium difficile-associated diarrhea: a systematicreview and meta-analysis. Int J Gen Med 2016; 9: 27–37.
23. Mallina R, Craik J, Briffa N et al. Probiotic containing Lac-tobacillus casei, Lactobacillus bulgaricus, and Streptococcusthermophiles (ACTIMEL) for the prevention of Clostridiumdifficile associated diarrhoea in the elderly with proximalfemur fractures. J Infect Public Health 2018; 11: 85–8.
24. Luu S, Spelman D, Woolley IJ. Post-splenectomy sepsis:preventative strategies, challenges, and solutions. Infect DrugResist 2019; 12: 2839–51.
25. Na’amnih W, Adler A, Miller-Roll T et al. Incidence andRisk Factors for Community and Hospital Acquisition ofClostridium difficile Infection in the Tel Aviv SouraskyMedical Center. Infect Control Hosp Epidemiol 2017; 38:912–20.
26. Freedberg DE, Salmasian H, Cohen B et al. Receipt ofAntibiotics in Hospitalized Patients and Risk for Clostridiumdifficile Infection in Subsequent Patients Who Occupy theSame Bed. JAMA Intern Med 2016; 176: 1801–8.
27. McFarland LV, Mulligan ME, Kwok RYY et al. NosocomialAcquisition of Clostridium-Difficile Infection. N Engl J Med1989; 320: 204–10.
28. Djukic M, Braun LM, Unkel S et al. Introduction of Non-Vitamin K Antagonist Anticoagulants Strongly Increased theRate of Anticoagulation in Hospitalized Geriatric Patientswith Atrial Fibrillation. Drugs Aging 2018; 35: 859–69.
29. Haywood LJ, Ford CE, Crow RS et al. Atrial fibrillation atbaseline and during follow-up in ALLHAT (Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart Attack Trial).J Am Coll Cardiol 2009; 54: 2023–31.
30. Haji-Michael P. Critical care transfers – a danger foreseen ishalf avoided. Crit Care 2005; 9: 343–4.
Received 9 February 2021; editorial decision 27 June 2021
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Reduced Clostridioides difficile infections in hospitalised older people through multiple quality improvement strategies
Introduction
Methods
Results
Discussion
Conclusion
6 Supplementary Data:
7 Acknowledgements:
8 Declaration of Sources of Funding:
9 Declaration of Conflicts of Interest: