Journal of Infection and Public Health 11 (2018) 85–88

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Journal of Infection and Public Health

journal homepage: http://www.elsevier.com/locate/jiph

Probiotic containing Lactobacillus casei, Lactobacillus bulgaricus, and

Streptococcus thermophiles (ACTIMEL) for the prevention of
Clostridium difficile associated diarrhoea in the elderly with proximal
femur fractures
Ravi Mallina (MD) a,∗ , J. Craik (FRCS) a , N. Briffa (FRCS) a , Viren Ahluwalia (BSc, MBChB) b ,
J. Clarke (FRCP) c , A.G. Cobb (FRCS) a
a
Department of Trauma & Orthopaedic Surgery, Epsom & St. Helier’s Hospital, Carshalton, SM5 1AA, UK
b
Academic Foundation Trainee, St George’s Hospital, Tooting, London SW17 0QT, UK
c
Department of Microbiology, Epsom & St. Helier’s Hospital, Carshalton, SM5 1AA, UK

a r t i c l e i n f o a b s t r a c t

Article history: The incidence of Clostridium difficile associated diarrhoea (CDAD) is greater in elderly patients. Probiotics
Received 28 May 2016 may have a beneficial effect in the prevention of CDAD. However, their effect in elderly orthopaedic
Received in revised form 12 March 2017 patients has not been previously reported. Between April 2013 and April 2014, 105 patients admitted
Accepted 28 April 2017
with femoral neck fractures, and who required 3 days of antibiotics for infection of any cause, were
prescribed the probiotic ACTIMEL until 3 days after the last antibiotic dose. The incidence of CDAD was
Keywords:
compared with historical controls (April 2011–April 2012). There was no significant reduction in the
Clostridium difficile—associated diarrhoea
incidence of CDAD in patients receiving probiotics (OR: 0.9; 95% CI 0.27–2.91; p = 0.8) and therefore
Probiotics
Antibiotics
we cannot recommend the use of ACTIMEL containing Lactobacillus casei, Lactobacillus bulgaricus, and
Streptococcus thermophiles for this purpose in this patient group.
Crown Copyright © 2017 Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz
University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction megacolon [26–28]. Elderly patients are both more likely to require
long term antibiotics and more susceptible to the disease due to a
Prolonged use of broad spectrum antibiotics and advanced age reduced immune response and lower physiological reserve [40].
are the two most common pre-disposing factors for the develop- In addition, the incidence of CDAD is greater in elderly patients
ment of Clostridium difficile associated diarrhoea (CDAD) [9–12]. admitted from long-term care facilities [10,29,30]. As a result, 90%
Antibiotics result in alterations in the normal gut microbiota which of all CDAD attributed deaths occur in persons over the age of 65
can lead to a proliferation of C. difficile and the production of exotox- [16–18]. Incidence of CDAD in elderly orthopaedic patients with
ins [15]. Antibiotics have been shown to increase the risk of CDAD femoral fractures treated surgically around 7% with case fatality
by eight to ten-fold during, and for one month after administration rate as high as 35% in this group of patients [45,46].
[14,15], resulting in an incidence of CDAD in patients on long term In addition to the morbidity and mortality associated with
antibiotics of approximately 4% [11,13]. CDAD, there is also a significant financial cost. Recent evidence
There have been widespread infection prevention efforts to emerging from the US suggests that the associated cost of treat-
reduce the incidence of CDAD over the past few years [19–21]. ing CDAD has increased to over $6 billion over the last decade
Several studies have demonstrated benefits in the use of probi- [2–4]. Similar data from France on treatment costs for CDAD in
otics for the prevention of antibiotic associated diarrhoea (AAD) public acute-care hospitals, indicates an annual cost of D 163 mil-
[9,22–25]. Unlike AAD however, CDAD is associated with serious lion per annum [5]. In the UK, for the financial year April 2011 to
gastrointestinal complications ranging from acute colitis to toxic March 2012, 17.3 cases per 100,000 bed-days and 1646 deaths were
attributed to C. difficile infection [6,7]. The estimated cost to treat
one case of un-complicated CDAD in the UK is £4107 [8].
Patients with femoral neck fractures often require peri-opertive
∗ Corresponding author.
courses of antibiotics due to the high incidence of serious co-
E-mail address: ravi.mallina@nhs.net (R. Mallina).

https://doi.org/10.1016/j.jiph.2017.04.001
1876-0341/Crown Copyright © 2017 Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
86 R. Mallina et al. / Journal of Infection and Public Health 11 (2018) 85–88

morbidities and the complications of immobility. In April 2013 a Table 1

Patients excluded from the analysis (n = 49/154).
departmental protocol was introduced, in accordance with our clin-
ical governance policy and available evidence, to offer ACTIMEL Poor patient compliance 22
(Danone, UK: Lactobacillus casei; 1.0 × 108 colony forming units/ml, Lack of stock of probiotic 12
Late prescribing of probiotic beyond 48 h of the start of antibiotic 7
Lactobacillus bulgaricus; 1.0 × 107 cfu/ml, and Streptococcus ther-
History of active malignancy 3
mophiles; 1.0 × 108 cfu/ml) to this patient group if they were over Prosthetic valve in-situ 2
the age of 70 and receiving more than 3 days of antibiotics for infec- Long term prophylaxis for urinary tract infection (UTI) 3
tion of any cause [31]. The aim of this study was to determine
if ACTIMEL is effective in reducing the incidence of CDAD in this
Table 2
patient group.
Indications for antibiotic therapy.

Hospital Acquired Pneumonia (HAP) 32

Methods UTI/Urosepsis 20
Urosepsis + HAP 14
From April 2013, all patients over the age of 70 years of age Superficial Wound Infection (SWI) 12
treated surgically for femoral neck fractures and who recieved more Community Acquired Pneumonia 8
Sepsis? Source 8
than 3 days of antibiotics for infection of any cause were offered
Deep wound Infection (DWI) 4
twice daily 100 gm (97 ml) ACTIMEL according to our departmental Infective Leg Ulcers 4
protocol. ACTIMEL was provided within 48 h of starting antibiotics Arm Cellulitis 3
and continued for up to 3 days after the last dose. Six random sam-
ples of ACTIMEL were tested for the viability of L. casei, L. bulgaricus,
Table 3
and S. thermophiles to confirm the stains recieved.
Antibiotic usage in patients receiving probiotics.
The incidence of CDAD was calculated retrospectively over a
one year period, both before (April 2011–April 2012) and after the Piperacillin + Tazobactam (TAZOCIN) 27
Tazocin + Clarithromycin 20
introduction of the protocol (April 2013–April 2014). Patients were
Co-Amoxiclav (AUGMENTIN) 18
included in the analysis if they had received at least 70% of the Co-amoxiclav + Clarithromycin 13
probiotic course, and were excluded if they had a history of: Cefuroxime 8
Caphalexin + Co-amoxiclav 7
Clindamycin 6
(i) Immunosuppression secondary to conditions such as HIV and
Benzylpenicillin + Flucloxacillin 6
active malignancy, or medications such as disease-modifying
anti-rheumatic drugs and chemotherapy
(ii) Prosthetic valve replacement penicillin allergic). Additional antibiotic therapy for more than
(iii) Lactose intolerance 3 days to treat various per-operative infections was necessary in
(iv) Long term prophylaxis for recurrent urinary tract infections 133 (28.6%) patients. Of these, 9 developed CDAD. 2 were excluded
(v) Usage of any antibiotics within 30 days of the index admission as they were on antibiotics prior to hospital admission, such that
(vi) Inflammatory bowel disease, proven on upper/lower gastroin- the incidence of CDAD in this group was 5.26%. There were no cases
testinal endoscopy. of CDAD in the patients who did not require additional antibiotic
therapy.
All patients were monitored for the development of CDAD for 6 Between April 2013 and April 2014, 493 patients with frac-
weeks after completing their antibiotic course at which point the tured neck of femur were treated surgically in our unit. All patients
risk of developing CDAD is known to sharply decrease [13]. A posi- received a peri-operative prophylactic course of antibiotics. A total
tive diagnosis of C. difficile was made by the hospital microbiology of 154 (31.2%) patients received additional antibiotics for more
laboratory according to UK Department of Health (DoH) guidelines than 3 days. 49 patients were excluded from the analysis due to
[7]. All patients who suffered diarrhoea (Bristol Stool Chart types confounding medical issues and failures of probiotic compliance
6–7, or stool that takes the shape of its container) were tested for and administration (Table 1). For the remaining 105 patients, the
C. difficile using a two test screening protocol comprising a gluta- clinical indications for additional antibiotics and the antibiotics
mate dehydrogenase (GDH) enzyme immunoassay followed by a prescribed are shown in Tables 2 and 3 respectively. 6 of these
sensitive toxin enzyme immunoassay (EIA). In a typical UK District patients developed CDAD. However, one patient was excluded due
General Hospital microbiology lab it is not a routine practice to to the development of CDAD within 48 h of admission (community
measure the C. difficile counts. Patients testing positive for C. dif- acquired CDAD) such that the incidence of CDAD is this group was
ficile toxin and with clinical signs of CDAD were treated with oral 4.76%(5/105). The total cost of probiotic treatment in this group of
metronidazole and/or oral vancomycin as per the UK DoH guide- patients was £1617.
lines [6,7]. There was no statistical difference between the groups in terms
Statistical analysis was performed using Graphpad Prism Ver- of patient age, co-morbidities, admission from long term health
sion 6. D’Agostino Normality Test was conducted to determine the care facilities and antibiotic duration (Table 4). Piperacillin plus
distribution of data. Non-parametric data was assessed using the Tazobactam (Tazocin) and Amoxicillin plus Clavulanic acid (Co-
Mann Whitney U test and Chi Squared Analysis to compare the amoxiclav) regimen were associated with 8 of the 12 cases of CDAD
incidence of CDAD between the groups. A p value of <0.05 was identified from both groups. All 5 cases of CDAD in the probiotic
considered significant. group were due to either tazocin or Co-amoxiclav. There was no
difference in the incidence of CDAD between the patient groups
Results (OR: 0.9; 95% CI 0.27–2.91; p = 0.8).

Between April 2011 and April 2012, 464 patients with frac- Discussion
tured neck of femur were treated surgically in our unit. All patients
received a peri-operative prophylactic course of antibiotics (3 doses This is the first study to evaluate the use of probiotics for the
of IV co-amoxiclav 8 hourly, or teicoplanin once only if they were prevention of CDAD in a high risk orthogeriatric group of patients.
 R. Mallina et al. / Journal of Infection and Public Health 11 (2018) 85–88 87

Table 4
Results of statistical analysis of the control and probiotic group who had positive diagnosis of CDAD.

Group A Group B Statistical significance

Mean age (years) 86(SD = 3.43) 84(SD = 4.37) P = 0.2857a

Number of patients admitted from long term health care facilities 76 71 P = 0.385b
>/ = 2 significant medical co-morbiditiesc 70 78 P = 0.46
Antibiotic duration (days) 14.9(SD = 4.69) 15.7(SD = 5.93) P = 0.1952a
Number of cases of CDAD 7/133 5/105 OR: 0.9
P = 0.8608

Group A: Historical controls.

Group B: Patients on Probiotic treatment.
a
Mann Whitney U test.
b
Fishers Exact test.
c
Siginificant medical co-morbidities: Chronic Obstructive Airway Disease, Ischaemic Heart Disease, Diabetes, Hypothyroidism, Cerebro-Vascular Accident including
Transient Ischaemic Attack, Active malignancy, Hypertension requiring atleast two anti-hypertensives. Arrhythmias needing oral anticoagulation and Dementia.

Table 5
Summary of clinical studies on efficacy of Probiotics in prevention of CDAD in patients age >65 years.

Author Mean age (y) Probiotics CDAD (C/P* )

Hickson et al. [31] 73.7(SD = 11.1) Lactobacillus casei, L. bulgaricus, and Streptococcus thermophiles 9/0
Pozzoni et al. [34] 78 ± 10 Saccharomyces boulardii 2/5
Allen et al. [33] 77 ± 7 L. acidophilus and Bifidobactrium bifidum 17/12

C/P* = Number of CDAD cases in Control group/Probioitc.

**
= Non-randomized study.

The results suggest that the probiotic yoghurt drink ACTIMEL, Hickson et al., in a randomized, double-blinded study, evalu-
containing L. casei, L. bulgaricus, and S. thermophiles is not effec- ated the use of ACTIMEL for the prevention of CDAD in patients
tive in reducing the incidence of CDAD in elderly inpatients with over 70 years of age. They identified a reduction in CDAD rates with
femoral neck fractures receiving antibiotics for infection of any probiotic use of 70%. However, due to stringent exclusion criteria
cause. These results are in keeping with the PLACIDE trial, a multi- and a high drop-out rate, only 6.4% of the study population was
center randomized double-blinded placebo trail evaluating the included in the final analysis which puts into question the valid-
role of multistrain probiotic in the prevention of CDAD or AAD ity of their findings [31]. A large 10-year observational study from
in patients over the age of 65. The PLACIDE trial failed to iden- Canada on primary prevention of CDAD using a probiotic combina-
tify a benefit in the use of a probiotics in the prevention of AAD tion of Lactobacillus acidophilus, L. casei, and L. rhamnosus (Bio-K+)
and CDAD [33]. However, it is important to note that CDAD was an revealed encouraging results [22]. In addition to the routine stan-
uncommon cause of AAD in the PLACIDE trial with only 12 cases dard protective measures(SPMs), all patients (age >18y) received
(0.8%) in the probiotic group and 17 cases (1.2%) in the placebo the probiotic between April 2004 to March 2014; between March
group. As a result, the study may have been underpowered to detect 1998–March 2004 SPMs alone were used to prevent the spread
a beneficial effect. Pozzoni et al., in their single-centre random- of C. difficile infection. A significant reduction of CDAD rate from
ized double-blind placebo-controlled trial, similarly reported that 18.0 cases/10,000 patient-days to 2.3 cases/10,000 patient-days
a probiotic containing Saccharomyces boulardii was not effective in was noted with the introduction the probiotic, Bio-K+ to the SPMs.
preventing both AAD and CDAD [34]. However, the actual observed Although, the beneficial effects of Bio-K+ could have contributed
rates of AAD and CDAD in their study was lower than expected, to the improvements of CDAD rates during the study period, other
thereby reducing power from 80% to 63.9%, and increasing the risk factors such as antibiotic stewardship may have contributed to the
of a type 2 error. It is noteworthy to mention that that several other decline in CDAD rates.
studies on probiotics published prior to 2012 have reported AAD, Over the last decade several level 1 studies have been pub-
rather than CDAD, as the primary endpoint and therefore it is dif- lished on the efficacy of probiotics, however, the results of these
ficult to draw any meaningful conclusions on the specific role of trials have not been consistent. Subgroup analysis of publicly and
probiotics for the prevention of CDAD. industry funded probiotic trials have demonstrated that industry-
Hempel et al. conducted a meta-analysis of 63 RCTs incorporat- supported trials are twice as likely to report a decrease of CDAD
ing 11,811 patients, evaluating the effect of probiotic provision for rates with probiotic use as compared with publicly funded studies
the prevention of AAD [37]. They identified a significant reduction [35]. A major problem in conducting robust clinical trials on pro-
in AAD rates (RR: 0.58, CI: 0.50–0.68) with the use of probiotics. biotics is determining the true incidence of CDAD and the number
However, they were unable to distinguish CDAD from other forms needed to treat(NNT) to prevent a single episode of CDAD. The NNT
of AAD. In addition, due to significant heterogeneity in the pooled figure is usually based on the historical incidence of CDAD and the
results, the authors could not determine the relative influence of power of the study is designed accordingly. However, as seen in
patient demographics, antibiotic type, or probiotic preparation on many well executed clinical trails, by the end of completion of the
the development of AAD. clinical trial a decrease in the observed rates of CDAD results in the
Johnston et al., in a systematic review and meta-analysis involv- study being under-powered [33,34,38].
ing pooled data from 20 studies and 3818 patients. Their analysis Antibiotic resistance patterns of Lactobacillus are complex as
revealed that the use of probiotics could prevent 33 cases of CDAD antimicrobial susceptibilities of individual species of Lactobacil-
per 1000 patients, with a reduction in incidence of CDAD of 66% lus is largely dependent on the strain of the Lactobacillus spp. The
[36]. However, the heterogeneity of the final population in the majority of strains of Lactobacillus are generally resistant to metron-
pooled analysis and the type of probiotic used, together with the idazole, aminoglycosides and ciprofloxacin [42,43]. In one study
lack of clarity on the duration probiotic use, are important limita- assessing antibiotic resistance in Lactobacillus spp. it was concluded
tions of their study. Table 5 summarizes the current literature on that L. casei and bulgaricus are resistant to penicillins and van-
probiotics in patients over the age of 70. comycin [44]. Overall, antiomicrobial susceptibility studies report
88 R. Mallina et al. / Journal of Infection and Public Health 11 (2018) 85–88

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