Reviewing existing data on probiotic cleaning in hospitals
The results of published cleaning intervention trials using probiotics are summarized in Table 1.
At the Charité University Medicine hospital in Berlin, Germany, two trials were conducted with the probiotic cleaning product SYNBIO® (HeiQ Chrisal NV, Lommel, Belgium) containing five different Bacillus species, i.e. B. subtilis, B. megaterium, B. licheniformis, B. pumilus and B. amyloliquefaciens. In the first trial, one neurological ward was subsequently cleaned with the probiotic product, detergents or disinfectants (for 3 month each) [28]. The study showed significant increases in biological diversity metrics (alpha-diversity) compared with disinfection in the floor (p < 0.001) and the sink samples (p < 0.01). For the door handle samples, however, alpha-diversity was significantly more diverse (p < 0.05) for detergents (compared with disinfection). Further, the probiotic cleaning product reduced the occurrence of Pseudomonas spp. in environmental samples compared with chemical disinfection [28]. In addition, the study also demonstrated a reduction of antimicrobial resistance genes (ARG) in environmental samples after cleaning hospital rooms with probiotic cleaning products compared with chemical disinfectants [28], in particular mecA resistance genes present in methicillin resistant Staphylococcus aureus (MRSA) [28]. The second study focused on the questions whether these effects on the hospital environment may translate into clinically relevant outcomes such as HAI or MDRO incidence. The study question was addressed by a cluster randomized controlled trial (cRCT) with cross-over design conducted in 18 non-intensive care units (non-ICUs) [32]. Disinfectants, detergents and probiotics were similarly effective for environmental cleaning as well as preventing HAI or HAI with MDRO [32].
In one Belgian and five Italian hospitals, a probiotic cleaning hygiene system (PCHS®, Copma scrl, Ferrara, Italy) was introduced [22, 33,34,35,36,37,38]. This probiotic-based sanitation is a cleaning procedure involving a probiotic product provided by HeiQ Chrisal NV (Lommel, Belgium) with three Bacillus species (B. subtilis, B. pumilus and B. megaterium) as previously described [38]. In hospital environmental samples, PCHS significantly reduced the abundance of HAI-related pathogens [22, 37, 38] and the presence of ARG [22, 34, 35, 37] compared with chemical disinfection. Parallel independent studies confirmed the reduction of contamination with pathogenic microorganisms [39, 40]. Another Italian trial conducted in a children’s hospital emergency ward suggested that PCHS cleaning was as effective as chlorine-based chemical disinfection for elimination of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This enveloped virus was neither detectable after PCHS cleaning nor after chemical disinfection with chlorine [37]. However, it has been shown that SARS-CoV-2 can also be effectively removed from hard, non-porous surfaces by hard-water damped wiping only [41]. PCHS was associated with a significant reduction of cumulative HAI from 4.8 to 2.3% (OR = 0.44; CI95% 0.35–0.54), a result not observed in the German cRCT [35]. Such considerable impact of PCHS may not be reproduced in other settings as limited proportion of HAI are considered preventable [42, 43]. A systematic review and meta-analysis calculated the preventable proportion of HAI to be 35 – 55% with data from 2005 to 2016 in different economic settings [43]. Similar estimations from Germany vary between 13% and 45% of HAI [42]. Antimicrobial consumption and costs were further analysed in two studies [33, 36]. PCHS saved more than 60% of HAI-related antibiotic consumption and more than 70% of associated costs [36]. These results, however, are based on 398 patients with HAI selected from the before-after trial by Caselli et al. [35]. Tarricone and colleagues estimated that 14 million Euro might be saved if PCHS use was increased from 5 to 50% over a period of five years [33]. However, the expert group questioned that these results are transferable to other hospitals given the different hospital settings, study designs, control groups and interventions applied. The German trial used a more robust study design (cross over cRCT) but was a single-center study. In contrast, the Italian trial used a study design more prone to bias (before-after design), but was multi-centered. Cleaning protocols and disinfectants varied with 2-phenoxyethanol, 3-aminopropyldodecylamine, benzalkonium chloride (Indicin Pro®) in Germany versus chlorine-products in Italy. Most importantly, the German trial was conducted in a setting with 1.6% HAI incidence compared to the Italian trial with 4.6%. However, both products were provided by the same company. The probiotic product used in the German trial contained five different Bacillus species (B. subtilis (ATCC6051), B. megaterium (ATCC14581), B. licheniformis (ATCC12713), B. pumilus (ATCC14884) and B. amyloliquefaciens (DSL13563-0)). For the Italian trial, a patented cleaning concept (PCHS®) was implemented that included probiotic detergent with three Bacillus species (B. subtilis, B. pumilus and B. megaterium). Further, the duration of intervention was different (4 months in the German trial versus 6 months in the Italian trial), as well as timing of sampling. In the Italian trial, sampling was always performed seven hours after cleaning (thus allowing recontamination) whereas in the German study the sampling time was variable and resulting data could be affected by residual action of disinfectants in the chemical sanitation arm. Furthermore, the German study results might be limited by the fact that probiotic cleaning was interrupted by terminal and / or targeted disinfection, in particular if patient rooms were occupied with carriers of MDROs or other notifiable pathogens. Emergency chemical disinfection also occurred in the Italian studies, where only continuous usage of sporicidal disinfectants was shown to prevent probiotic sanitation effects [44, 45]. A limitation that might have occurred in both trials was cross-contamination by shoes or hands of healthcare workers between study arms or wards participating in the trials and those not.
Hospital cleaning is considered an important part of infection control [29, 46,47,48,49]. Appropriate cleaning practices require a number of careful decisions, e.g. cleaning frequencies, materials, techniques, equipment and agents used as well as identification of critical- und non-critical areas. At the same time, the amount of research on basic cleaning is limited [29]. Evidence-based decision making in this field is challenging as, to date, there is no standard methodology for measuring microbial bioburden on surfaces, nor are there international benchmark standards for surface bioburden levels indicating potential infection risks [29, 50]. Indeed, understanding the difference between the terms ‘cleaning and ‘cleanliness’ remains an issue and is crucial when sharing expertise on this topic. While ‘cleaning‘ represents the physical process of removing surface soil, ‘cleanliness‘ is defined as residual soil on surfaces after the cleaning process [29]. Assessment of cleanliness is possible by identification and quantification of indicator organisms that pose a high risk to patients (< 1 cfu/cm²) such as C. difficile or S. aureus. This can be performed alongside quantitative assessment of organisms on hand-touch sites using microbiological sampling (< 2.5–5.0 cfu/cm²) or adenosine triphosphate (ATP) counts using ATP bioluminescence systems as surrogate markers for bioburden [48, 50]. In contrast, fluorescent markers and ATP bioluminescence systems as well as direct supervision, observation and education of housekeeping staff are used to monitor the cleaning process [48]. Both surrogate markers do not necessarily correlated with the bioburden. A prospective cross-over trial conducted on two hospital wards in the United Kingdom (UK) demonstrated that enhanced cleaning was associated with a reduction of microbial contamination at hand-touch sites by 32.5% and reduced the number of new MRSA infections by 26.6% [51]. Cost savings were estimated between 30,000–70,000 pounds in this trial [51]. Enhanced cleaning was performed with detergents and included one additional cleaner per ward who focused on high-touch surfaces such as door handles, infusion pumps and computer keyboards. Disinfectants were not routinely used on these wards other than bleach (sodium hypochlorite) for bathrooms [51]. Thus, enhanced cleaning without changing any substances but increasing staff and cleaning frequencies reduced more than 25% of new MRSA infections compared with the standard cleaning protocol [51]. This supports the argument that physical removal of surface bioburden might be more important than the substances applied. It is possible that microfiber and water by themselves may be sufficient for routine cleaning in most cases. Despite the variations of the probiotic trials discussed above, there is consensus that probiotic cleaning was non-inferior compared with disinfectants in both trials [32, 35].
What is the added value of probiotic cleaning for the decontamination of the hospital environment?
Many healthcare institutions still do not prioritize environmental cleaning as essential measure for patient safety [52]. The impact of environmental control on HAI incidences is difficult to assess, as multiple factors such as failure with hand hygiene, susceptible patients, and infectious material (inoculum) are required to induce infection. Recently, awareness for this topic has grown due to an increasing number of studies that link interventions in the hospital with lower HAI rates and/ or patient colonization [52]. Further, a RCT emphasized the importance of cleaning / disinfecting the hospital room before the next patient is admitted [12].
Some evidence exists on the fact that probiotic cleaning may have additional benefits concerning sustainability, cost-effectiveness, occupational safety, sustaining a biologically diverse hospital microbiome, and odor control, compared with chemical disinfection. Chemical disinfectants have been used for decades, especially in high-risk areas such as intensive care units (ICUs). Even highly effective substances were shown to have limited impact, as re-colonization rapidly occurred after disinfection [53]. MDROs were found in dry surface biofilms from ICU surfaces despite terminal cleaning with disinfectants, e.g. with chlorine solution [54, 55]. Similarly, terminal chemical disinfection is frequently insufficient to eradicate Candida auris [4].
It is not known whether probiotic cleaning might be an adequate supplement to fill this gap as suggested by some trials analysing environmental samples [22, 28, 35], or whether additional procedures such as UV decontamination are required to safely remove MDROs.
Heavy and repetitive use of antiseptics and disinfectants are associated with reduced tolerances of clinical isolates to these agents, development of cross-resistance to antibiotics and other potentially detrimental effects on health and environment [1, 56, 57]. As an example, emergence of resistance to glutaraldehyde has been observed [58]. Another worrisome trend is the occurrence of cross-resistances among disinfectants and antimicrobials [59]. In addition, chemical disinfectants are harmful to the environment and their handling is potentially hazardous to health of cleaning staff and healthcare workers. More specifically, currently used chemical disinfectants such as glucoprotamin, aldehydes, and quaternary ammonium compounds may form phenolics and aldehyde toxic fumes that are problematic for health and the environment. Further, the use of glucoprotamin in its concentrated form requires specific carefulness and personal protective equipment by hospital staff [60].
Therefore, new technologies and compounds are required to add to the currently available disinfectants that are at least equally effective, but less harmful to the environment and wellbeing of healthcare workers and cleaning staff.
Advantages and disadvantages of three cleaning regimens – detergents, disinfectants and probiotics – identified by the expert group are summarized in Table 2. The most important priority is patient safety, but other aspects such as sustainability, costs, occupational safety, effects on the environmental microbiome and applicability must also be considered and weighed up against each other.
Defining knowledge gaps that need to be addressed by future research
This narrative review does not discuss bacteriophage preparations such as probiotic-phage sanitation (PCHSϕ) [61]. The latter contains probiotic detergents and bacteriophage preparations (e.g. a mixture of selected lytic phages directed against Staphylococcus spp., Streptococcus spp., Proteus spp., E. coli and Pseudomonas (P.) aeruginosa) that are commercially available by the Eliava Institute (Staphylococcal phage and Pyophage; GA, USA). This is beyond the scope of this work, as clinical outcome studies are not yet published.
Some trials showed the effect of probiotic cleaning products against enveloped viruses such as SARS-CoV-2 in controlled laboratory conditions, in hospital (emergency room of a children’s hospital) and non-hospital settings [37, 45, 62]. However, data on non-enveloped viruses, e.g. noroviruses, are lacking.
Another question concerns the best composition of probiotic detergents. Various in vitro studies show that probiotic species such as Bacillus and Lactobacillus spp. may be used for biofilm control of relevant pathogens in hospitals including Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, Enterobacter species, and Escherichia coli [63]. Molecular analyses revealed that probiotic-based products reduced the antimicrobial resistance (AMR) related gene expression in K. pneumoniae, but not in A. baumanii [1]. Another in vitro study compared hospital surfaces that were treated for eight months either with disinfectants (3.5% sodium hypochlorite), soap (saponified vegetable extract, essential oils, natural gum) or a probiotic cleaner (Bacterrorist non-toxic all-purpose cleaner) containing spores of Bacillus spp. [64]. Subsequently, in vitro experiments investigated whether the “resident microbiome” established during the 8-months-cleaning regimens with either disinfectants, soap or a probiotic cleaner could be overwhelmed by the pathogens E. coli, S. aureus and biofilm-generating P. aeruginosa. Resident microbiomes of surfaces treated with soap and probiotic cleaning but not disinfectants successfully outcompeted E. coli and S. aureus. At the same time, the resident microbiome overwhelmed P. aeruginosa on surfaces treated with soap, while the resident microbiome on surfaces treated with probiotic cleansers failed to completely replace P. aeruginosa. Thus, not only the mass of microbial cells but also a higher diversity of microbial species seems to be critical to outcompete certain pathogens including biofilm-forming P. aeruginosa. The resident microbiome on surfaces treated with disinfectants (sodium hypochlorite) were totally overwhelmed by biofilm-forming P. aeruginosa [64].
Routine and widespread application of probiotic cleaning products in hospitals require regulations, safety standards and quality controls that need to be determined, followed and monitored by public authorities to ensure patient safety. Such quality regulations and their clearance by public authorities are essential on the international, but also on the national level. They could represent a crucial step to overcome hurdles that currently prevent this novel option from achieving its breakthrough. These regulations must be realistic and safe, but flexible enough to enable further innovation. The European Union (EU) has already addressed products containing microorganisms, i.e. probiotics, in its “Proposal for a regulation of the European Parliament and of the Council on detergents and surfactants, amending Regulation (EU) 2019/1020 and repealing Regulation (EC) No 648/2004 (COM(2023)217) [65]. Herein, the authors determine that microorganisms intentionally added to detergents, “shall have an American Type Culture Collection (ATCC) number, belong to a collection of an International Depository Authority (IDA) or have had their DNA identified in accordance with a “Strain identification protocol” (using 16S ribosomal DNA sequencing or an equivalent method) […]” [65]. It should be noted that methods applied for strain identification in this context such as 16S ribosomal DNA sequencing must have sufficient accuracy to discriminate between bacterial species. It is not sufficient to aim at the genus level as different species of the same genus can be highly diverse. In general, all living organisms added to detergents that are used in healthcare environments including hospitals must be well characterized preferably by whole genome sequencing.
Despite the fact that some trials demonstrated the reduction of ARG in environmental samples after probiotic cleaning compared with disinfectants [22, 28, 35], there is no evidence for the reduction of newly acquired MDRO by patients after probiotic cleaning [32]. Thus, the potential of probiotic cleaning to reduce antimicrobial resistance genes in the environment, newly acquired MDRO and HAI among patients needs to be addressed in future research. Such trials need to be sufficiently powered, use a robust study design and should, if possible, also include conventional detergent as a control group [29].
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