Practices and Trends in the Prescription of Probiotics: A Detailed Analysis in an Eastern European Region

Abstract

The lack of clear prescribing protocols in the field of probiotics creates difficulties for physicians in the uniform application of these adjuvant therapies. Although there are guidelines that evaluate existing studies and provide different levels of evidence for the efficacy of probiotics, they do not offer specific prescribing strategies. The present study explores how this gap influences the prescribing behavior of physicians, analyzing the diagnoses associated with prescribed probiotics, the duration of treatment, and the associations with antibiotics. Additionally, the study addresses potential omissions in prescribing strategies, exploring discrepancies and possible errors in doctors’ recommendations. Through this research, an attempt is made to understand correctly how probiotics are integrated into treatment protocols, with the aim of improving prescribing directions and effective use in the future.

1. Introduction

The probiotic market has seen a considerable expansion in recent years due to the increasing interest of people in their health and the growing awareness of probiotics’ health benefits [1,2]. In addition, probiotic therapies have been more prevalent in the last decade, being widely recommended and prescribed during antibiotic therapy in order to avoid intestinal imbalance. According to the International Probiotic Association (IPA), the EU probiotic market was valued at EUR 9.5 billion in 2022, approximately 25% of the global sales of probiotics, including probiotic supplements, yogurts, and sour milk. Probiotic supplements accounted for 17% of the total probiotic market, with Italy representing the lead consumer of this kind of product in Europe [3].

Innovation in the field of probiotics is challenging due to a lack of efficacy proofs, competition with already on-the-market probiotic products that are not supported by evidence, and a complex regulatory approval process that must be gone through. Insufficient fundamental knowledge and poor investment in research and development result in inadequate and underpowered clinical trial designs [4]. Most randomized controlled trials are effectively just pilot studies, too limited to foster any meaningful probiotic-specific clinical advancements. More extensive clinical studies (phase III) are required to demonstrate efficacy to health authorities and improve the health practitioners’ confidence in probiotics efficacy [5]. While many probiotic products lack evidence, some particular strains showed efficacy depending on the type of disease and mode of administration (for prevention or treatment) [6].

At the global level, there are few guidelines based on scientific evidence intended to support healthcare professionals in incorporating probiotics into their daily patient care practice. The most recent guidelines issued by the World Gastroenterology Organisation (WGO) include probiotics for prophylaxis and the treatment of targeted conditions like diarrhea (in the acute phase or associated with Clostridium difficille infection, antibiotics, etc.), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) among other gastrointestinal disorders and infections. This guidance offers probiotic options, doses, and routes of administration for targeted diseases based on clinical evidence [7]. Other guidelines, like the one released by the American Gastroenterological Association (AGA), are not that optimistic and do not recommend the ingestion of probiotics for most digestive diseases (IBS, IBD, Clostridium difficile infection) due to the heterogeneity of studies and inconsistency in the probiotic strains studied [8]. For the prevention of antibiotic-associated diarrhea (AAD) in children, ESPGHAN recommends the administration of Lactobacillus rhamnosus strain GG and Saccharomyces boulardii (no specific strain). This guidance does not deny the efficacy of other probiotic strains but requires future studies to establish their beneficial effect [9]. Although guidelines for probiotic use exist, there is a lack of consensus among them, indicating that universal guidelines for probiotic use are still not established but are needed for the accuracy of medical acts and the correctness of patients’ therapy.

Due to the variety of probiotic supplements, the multitude of strains, the lack of general clinical guidelines, and the absence of proper regulation over these products, it is complex and confusing for healthcare practitioners to decide on a specific probiotic product for their patients [10]. Also, making educated decisions about probiotic usage is challenging due to insufficient scientific data on their effectiveness. Therefore, the decision to choose a bacterial supplement is often left to the patient [11].

The present study aims to evaluate the types of probiotics most widely used by Romanian physicians, the treatment period recommendations, the possible correlation with medical diagnosis, types of concomitant dispensed antibiotics, and patient demographics. Novel insights into the current practice of probiotic prescription and its implications for patient care are expected.

2. Materials and Methods

2.1. Data Collection

The present study on probiotic prescription patterns was conducted from January 2022 to February 2024 and included collecting a comprehensive set of data from medical prescriptions containing probiotics from multiple pharmacies located in Bucharest, Romania.

For inclusion in the study, medical prescriptions were required to contain at least one probiotic supplement and to accurately include all the relevant data necessary for our analysis. Exclusion criteria included prescriptions without a probiotic recommendation and those that were incomplete or illegible. The data extracted from each prescription included the probiotic product, medical diagnosis, primary treatment duration, probiotic treatment duration, gender, age, and any concomitant antibiotic prescriptions, including the type of antibiotic. All these data were organized into a structured table to facilitate a clear overview of the data and to prepare for further statistical analysis. Our research was approved by the Ethical Committee for Scientific Research of the “Carol Davila” University of Medicine and Pharmacy Bucharest, Romania (approval no. 2684/02.02.2024), and all the data protection regulations were followed during this investigation.

All the probiotics dispensed under their commercial brand name were reviewed and categorized according to the bacterial or yeast genus, species, and strain contained. Information regarding the composition of each probiotic product was obtained from the manufacturer of the specific commercial probiotic supplement.

2.2. Analysis

We categorized probiotic prescribing patterns by (i) antibiotic class association, (ii) condition, and (iii) probiotic therapy duration concerning the primary treatment by focusing on the identification of probiotic prescription models or inconsistencies. To simplify the statistical analysis, the probiotic strains from commercial supplements, listed in the recipes, were categorized by their genus and species. The resulting data were analyzed using Microsoft Office Excel (Windows 10) version 2403 and GraphPad Prism Version 9.3.0 (463). The statistical significance of the data was calculated using the chi-square test and Fisher’s test for small data samples for a 95% confidence interval, with a statistical significance being considered for a p-value lower than 0.05.

3. Results

Within this study, a dataset of 560 medical prescriptions containing probiotics was collected. In

Table 1. Classification of probiotics found in medical prescriptions.

Genus	Species	Strain
Bacillus	B. clausii	N/A
	B. mesentericus	TO-A
	B.coagulans	N/A
Bifidobacterium	B. bifidum	HA-132
		BB-01
		W-23
		BB-G90
	B. breve	BR-03
		BB-G95
	B. infantis	N/A
	B. lactis	BL-G101
		DSM 15954 (BB-12)
		BI-04
		W-52
		HN-019
		Lafti B-94
	B. longum	BB-536
		W-11
		BL-986
		N/A
Clostridium	C.butyricum	TO-A
Enterococcus	E. faecium	N/A
Lactobacillus	L. acidophillus	LA-G80
		LA-14
		LA-1063
		LA-02
		HA-122
		DSM 13241 (LA-5)
		Rosell-52
	L. casei	HA-108
		R-0215
		LC-03
	L. paracasei	431
		LPC-12
		LPC-G110
		Lafti L-26
		CNCM I-1572
	L. fermentum	LF-26
	L. gasseri	LG-G12
	L. helveticus	LH-43
		Lafti L-10
		Rosell-52
	L. plantarum	CECT 7484
		CECT 7485
		R-1012
		LP-09
		LP-G18
	L. reuterii	DSM 17938
	L. rhamnosus	GG
		R-0011
		LR-02
		LRH-10
		HN-001
		LR-G14
		Rosell-11
Lactococcus	L. lactis	LL-02
		W-58
Pediococcus	P. acidilactici	CECT 7483
Saccharomyces	S. boulardii	CNCM I-745
		Lesaffre CNCM I-3799
		N/A
	S. cerevisiae	CNCM I-3856
Streptococcus	S. faecalis	T-110
	S. salivarius	K-12
	S. thermophilus	TH-4
		ST-30
		YA-08

N/A: strain not defined by the manufacturer.

, microorganisms included in physician-recommended supplements are described according to their taxonomic grouping by genus, species, and strain of origin. Thus, we found 8 genera, 25 species, and 70 strains, of which 64 are defined, and 6 are undefined probiotics.

3.1. Distribution of Probiotic Recommendations by Age and Gender

The probiotic product recommendations found in the present study were made for 350 women and 210 men in various age categories, according to Figure 1. Notably, the highest proportion of probiotic recommendations is among women aged 18–60. The distribution for the younger and over 60 age groups is lower but follows a similar distribution between the genders. There was a significantly larger tendency of doctors to recommend probiotics to middle-aged people (18–60 age group) than to young (under 18 years old) or elderly people (over 60 years old), as confirmed using the Fisher exact statistical test, which revealed a significant difference between the groups (p < 0.0001).

Applying the statistical chi-square test indicated no statistically significant difference between the distribution by gender and age groups regarding the recommendation of probiotics (p > 0.05). This suggests that gender does not influence the recommendation of probiotics according to age.

3.2. Diagnostics Associated with Probiotic Recommendation

Regarding the pattern of probiotic recommendation depending on the associated therapies, it was found that approximately 99% of the studied probiotic prescriptions contained an antibiotic recommended as prophylaxis or treatment. Only 1% of medical prescriptions associated probiotics with other medical treatments, as shown in Figure 2.

According to the biological kingdoms represented in Figure 3, doctors recommended probiotics mainly including bacteria, listing about 76% of prescriptions, while only 19% recommended taking probiotics of fungal (yeast) origin. The remaining 5% are represented by recommendations of combined probiotics (bacteria and yeast).

It is worth noting that probiotics containing yeasts have only one species of yeast in their composition, such as Saccharomyces boulardii, which is a typical example representing over 90% of the content of probiotics of this type. On the other hand, probiotics containing bacteria primarily include a mixture of different species of the same genus or different genera, such as combinations of Lactobacilli and Bifidobacteria. Thus, bacterial probiotics generally offer a wider variety of beneficial species, while yeast probiotics focus on a single species. From the point of view of the biological kingdoms found in the medical prescriptions included in the present study, 24 bacterial species and 2 fungal species are distinguished, as seen in Table 1.

3.3. Prescribed Probiotic Genera

From the 560 recipes collected, Lactobacilli strains were the most frequently recommended in commercial probiotic products, with 369 occurrences, as shown in Figure 4. Bifidobacteria followed, with 294 occurrences in the recipes. Saccharomyces, a fungal probiotic genus, was the next most frequently recommended after the two bacterial genera.

The following probiotic genera appear in doctors’ prescriptions less frequently, are not present in many commercial products, and therefore are not recommended as often as the previously mentioned genera. For example, Enterococcus is included in only one probiotic supplement and hence represented by a single strain. Pediococcus also appears in a single prescription. Streptococcus and Bacillus are two other genera that vary in recommended species or strains, and Clostridium is represented by a single strain included in two commercial products.

3.4. Prescribed Probiotic Species

Figure 5 reveals that the most recommended probiotic species are the bacteria Lactobacillus acidophilus (24.5%) and Bifidobacterium lactis/B. animalis subsp. lactis (17.1%), and the yeast Saccharomyces boulardii (12.4%). The strain DSM 13241 (LA-05) of the species L. acidophilus is the most recommended within this species (78%), followed by the strain HA-122 in a much smaller proportion (12%). In the case of B. lactis (B. animalis subsp. lactis), strain DSM 15954 (BB-12) is the primary recommendation of doctors. S. boulardii is recommended explicitly in the case of the CNCM I-745 strain (76%), and a relatively high percentage of recommendations (21%) for this species include strains not specified by the manufacturer. The rest of the strains are rarely included in prescriptions and are associated with uncommonly recommended commercial products.

In terms of frequency, these three are followed by B. bifidum and B. infantis, E. faecium, L. casei, L. reuterii, and L. rhamnosus, each of which appear in approximately 5% of the recommendations.

The high number of recommendations for bacterial species belonging to the Lactobacillus and Bifidobacterium genera is due to the wide variety of species that constitute these two taxonomic groups and also to the complex content of certain commercial probiotic supplements, which are not limited to a single probiotic species but contain up to nine bacterial species. The general belief is that several strains combined in a single probiotic product may have a broader spectrum of activity and may result in a synergism of potentiating the beneficial action or at least an additive effect. However, there is insufficient evidence to support the use of combination probiotic products over single-strain ones [12,13,14].

Much less frequently, probiotic species such as Bacillus spp., Clostridium spp., Lactococcus spp., Pediococcus spp., and Streptococcus spp. are recommended, as are some representatives of Bifidobacteria (B. breve, B. longum), Lactobacilli (L. paracasei, L. fermentum, L. gasseri, L. helveticus, L. plantarum), and Saccharomyces (S. cerevisiae). S. boulardii continues to be disputed as either a different species or a variant of S. cerevisiae. The genetic characteristics are similar in both species, so it is still difficult to classify this highly marketed probiotic strain [15]. Given this fact, the present study included the two species as different in the analysis.

3.5. Physicians’ Approach Regarding the Importance of Probiotic Product Specificity

As shown in Figure 6, a significant proportion of probiotic recommendations (92%) was tailored to particular commercial products. Conversely, 8% of physicians opted to abstain from making specific recommendations and instead deferred to patients in selecting probiotics.

3.6. Analysis of Antibiotic–Probiotic Associations

As shown in Figure 7, of the 554 antibiotic and probiotic prescriptions, penicillins accounted for approximately 47% of physician recommendations, followed by a similar recommendation percentage (15%) for cephalosporins and fluoroquinolones. Macrolides are also recommended in a moderate percentage (12%). The remaining 11% of recommendations (Other antibiotics) comprise antibiotics from multiple classes: tetracyclines, lincosamides (clindamycin), rifamycins, aminoglycosides, sulfonamides/dihydrofolate reductase inhibitors (sulfamethoxazole/trimethoprim combination), and nitroimidazoles (metronidazole). Given that prescriptions containing a combination of antibiotics represented a minor proportion—approximately 7% of the total dataset—we decided to treat each antibiotic in these combination prescriptions as a separate entity. This approach is justified by the need to maintain the clarity and consistency of the analysis, allowing for a more straightforward interpretation of trends and usage patterns of probiotics associated with individual antibiotics.

Table 2. Recommended antibiotics and probiotics for the treatment or prophylaxis of different infections.

Class of Antibiotics	Antibiotics Associated with Probiotics	%
Penicillins	Amoxicillin/clavulanic acid	43.1
	Amoxicillin	3.9
	Other penicillins	0.5
Cephalosporines	Cefuroxime	9.5
	Cefixime	4.6
	Other cephalosporines	0.7
Macrolides	Azithromycin	6.1
	Clarithromycin	5.6
	Other macrolides	0.5
Fluoroquinolones	Ciprofloxacin	6.8
	Levofloxacin	5.7
	Other fluoroquinolones	2.0
Other classes	Lincosamides	2.9
	Tetracyclines	2.4
	Nitroimidazoles	3.2
	Others	2.7

illustrates that most antibiotic prescriptions alongside probiotics were made for the amoxicillin/clavulanic acid combination (43.1% recommendations), followed by cefuroxime, the third-generation cephalosporin (9.5% recommendations), ciprofloxacin (6.8% recommendations), and in approximately equal percentages of azithromycin, clarithromycin, and levofloxacin (~6% recommendations). The rest of the antibiotics are recommended in less than 5% of cases.

3.7. Physicians’ Recommendations for Probiotic Genera Associated with Antibiotic Therapy

Data were collected and organized into a table comprising the frequency of probiotic genera recommendation by antibiotic class. The variations can be observed in Figure 8. For meaningful statistical analysis, we combined probiotic genera with less than 25 recommendations (Bacillus, Clostridium, Lactococcus, Pediococcus) into a single column (Other probiotics). In this way, we avoided the appearance of unreliable or irrelevant results due to a small amount of data.

The statistical analysis started from the null hypothesis that physicians make probiotic recommendations randomly with no specific association with the class of antibiotic prescribed. This hypothesis suggests no statistically significant correlation exists between the antibiotic type and the recommended probiotic genus. We used the chi-square test to test this hypothesis, based on which the null hypothesis cannot be rejected (p > 0.05). Therefore, insufficient statistical evidence suggests that probiotic prescribing is not associated with the antibiotic class.

3.8. Physicians’ Recommendations for Probiotic Species Associated with Antibiotic Therapy

Data were collected and organized into a table displaying the frequency of antibiotic class recommendations for probiotic species. The variations are illustrated in Figure 9. For relevant statistical analysis, we combined recommended species numbering less than 50 in the Other probiotics column.

We started from the null hypothesis that probiotic recommendations are made randomly by physicians with no specific association with the class of antibiotic prescribed. This hypothesis suggests no statistically significant correlation exists between the antibiotic type and the recommended probiotic species. To test this hypothesis, we used the chi-square test, based on which the null hypothesis is rejected (p < 0.05), meaning that there is a statistical difference between the classes of antibiotics and the species contained in the recommended probiotic products.

3.9. Diagnoses for Which Probiotics Are Associated with Antibiotics

Figure 10 highlights the type of infections for which antibiotics are recommended alongside probiotic strains by doctors. Interestingly, second in the dual therapy recommendations is prophylaxis (22%), right after respiratory tract and medium ear infections (34%). This indicates that a significant portion of antibiotic prescriptions are given to prevent infections rather than to treat them, contributing to the spread of antimicrobial resistance [16,17]. Figure 11 highlights the large proportion of penicillins administered for respiratory tract and medium ear infections, dental infections, and prophylaxis. Cephalosporines are used especially for respiratory tract and medium ear infections, urogenital tract infections, and prophylaxis. Fluoroquinolones are particularly prescribed for the treatment of urogenital tract infections, and macrolides are used for respiratory tract and medium ear infections.

3.10. Duration of Probiotic Treatment Versus Duration of Antibiotic Therapy

The duration of probiotic treatment provides information on physicians’ perceptions of the role of probiotics in relation to primary treatment (Figure 12a) and diagnosis (Figure 12b). We divided this duration into three categories: 0 days, 1–7 days, more than 7 days. We chose the intermediate value of 7 days, taking into account that antibiotic therapies with a duration of 7 days were the most recommended in the present study. Extending the probiotic treatment duration to twice the initial antibiotherapy interval might be an effective approach for the majority of patients whose prescriptions were included in the study. Also, according to the literature, the administration of probiotics for seven days post-antibiotic therapy appears to be a strategy used in many studies investigating the activity of probiotics after the administration of antibiotics [18,19,20]. There is a statistically significant difference, as revealed using Fisher’s exact test, between medical prescriptions where doctors recommended administering probiotics for the same duration as antibiotics versus those where probiotics were recommended for either 1–7 days longer or more than 7 days after stopping the antibiotic treatment (p < 0.0001).

Using the chi-square test, no statistical differences (p > 0.05) were observed to reveal a relationship between the recommended duration of probiotic consumption and antibiotic class. This result suggests that the type of antibiotic chosen does not influence the recommended duration of probiotic administration, as shown in Figure 12a.

We further investigated whether the duration of probiotic therapy depends on the type of infection patients suffer from. Using the chi-square test, no statistical differences (p > 0.05) revealed a relationship between the recommended duration of probiotic consumption versus antibiotic therapy and the type of infection, as shown in Figure 12b.

4. Discussions

No studies exist regarding the pattern of prescription and clinical use of probiotics in Romania. Also, up to date, there are no available guidelines or protocols locally or abroad to support doctors in prescribing probiotics in conjunction with antibiotic treatments or other therapies. Several studies have assessed doctors’ perceptions of probiotics’ importance and recommendation level via surveys, but no research has been conducted on the actual prescribing practices. We analyzed medical practice by attentively scrutinizing the doctors’ released prescriptions arriving in community pharmacies from Bucharest.

Probiotics are living microorganisms that, when given in sufficient quantities, provide a positive effect on the host’s health [21,22]. The consumption of probiotics in Romania is increasing due to growing interest in digestive health and the benefits of probiotics, but it remains at a lower level compared to other European countries and globally. In Europe, countries like France, Germany, and the UK have a longer tradition of probiotic use, reflected in higher consumption volumes and a greater variety of available products [3,23]. Globally, Asian markets, particularly Japan, China, and South Korea, lead in probiotic consumption due to their long-standing dietary cultures that include naturally probiotic-rich fermented foods like miso and kimchi [24].

Yet, not everything about probiotics is auspicious as there are negative sides that are often overlooked by health practitioners and patients. One example is the regulatory process of probiotics, which is currently inadequate and may influence the decision-making process regarding the correct probiotic to choose in therapy. Probiotics are mostly promoted for the benefit of health as over-the-counter dietary supplements and not drugs and, therefore, do not have official prescribing guidelines. They cannot be advertised for clinical purposes without solid scientific evidence, and the disclosure of any potential negative effects is not necessary for probiotic supplements. Therefore, probiotics can be overestimated as beneficial by patients or consumers, and the potential risks of their administration, like allergic responses and opportunistic infections, are often overlooked [25]. As long as probiotics do not claim to treat or prevent specific disorders (in which case EFSA must assess whether the health claims are legitimate), they are not subject to the same accurate testing and approval processes as drugs and are treated as dietary supplements [26]. So far, no health claims have been accepted by EFSA and nor is the word “probiotic” allowed to be added on the food supplement labels [27,28]. Thus, the manufacturing process, quality, effectiveness, and safety of the bacterial product are not the focus of authorities [26]. To address this issue, the International Scientific Association for Probiotics and Prebiotics (ISAPP) is working towards standardizing the regulatory framework across different countries. ISAPP’s efforts aim to implement stringent regulations that ensure all probiotic products meet high standards of quality and efficacy, increasing healthcare professionals’ confidence in prescribing probiotics and enhancing patient outcomes [22]. However, probiotic supplements are widely considered safe and are consumed by healthy and ill individuals worldwide, with or without a prescription. There are potential safety risks, including the development of bacteremia and fungemia, but particularly in patients with weakened or impaired immune systems (such as critically ill children, patients who have undergone surgery, hospitalized individuals, and those with compromised immune functions) who are at greater risk [29]. Moreover, common probiotics such as Bifidobacteria and Lactobacilli could potentially carry antibiotic-resistance genes to normal or pathogenic microbiota from the intestinal lumen, skin, or mouth [30].

Based on the analysis of collected data, the probiotic recommendations for populations between 18 and 60 years old were significantly higher than for those under 18 and, respectively, over 60 years. Studies such as that of Palleja et al. [31] demonstrate that the recovery of the intestinal flora is affected following the short-term administration of a cocktail of powerful antibiotics that takes place about a month and a half after the end of antibiotic therapy, in the case of young and healthy individuals (18–40 years). These results were obtained without using stimulatory probiotic therapy, and it is believed that the rapid recovery of the microbiota or resistance of some commensal species is due to intrinsic antibiotic resistance genes [31]. Thus, for adults over 18 years old, probiotics may be largely unmotivated, as the dynamic of gut microbiota is stable over that age and the commensal microorganisms have their way of returning to their original pre-antibiotic status. On the other hand, other studies claim that changes in intestinal microbial populations during and after antibiotic therapy can be drastic and long-lasting or even permanent, with the microbiome being irreparably affected. These microbial changes are capable of generating serious repercussions for health outcomes, such as increased susceptibility to pathogenic infections [32,33]. For the elderly population, the gut microbiota undergo compositional changes with the advancement of the aging process, so probiotic therapy might be a powerful weapon in holding this microbiota aging process in place and decreasing the susceptibility of linked diseases like Parkinson’s and Alzheimer’s diseases [34,35]. However, in children under three years of age, the gut microbiota is still developing, which requires special attention to therapies that have the potential to alter the diversity and abundance of gut bacteria, such as antibiotics [36]. Moreover, the disturbances of the intestinal microbiome in the first part of life seem to be involved in the establishment of metabolic diseases, such as diabetes and obesity, or allergies later in life [37,38]. In the case of the younger and older population categories, the use of probiotics, especially as part of antibiotic therapies, should be much more targeted by doctors. Nonetheless, women between 18 and 60 received a much higher recommendation for probiotics than men. This may be due to women’s tendency to seek healthcare and complementary and alternative medicine more frequently than men, especially at their reproductive age [39,40].

Moreover, 98.9% of probiotics prescribed by doctors were recommended in the context of a concomitant administration with antibiotics in order to treat or prevent an infection. This indicates a widespread practice of using probiotics to counteract the adverse effects of antibiotic therapy on the gut microbiota and to prevent complications such as antibiotic-associated diarrhea or C. difficile infection and associated abdominal cramps [41,42]. Indeed, according to the percentages, doctors are aware of the benefits of probiotics and try to prevent or counterbalance the adverse effects potentially induced by antibiotics. Similarly, in an international study by Fijan et al., it was highlighted that more than 90% of health professionals believe that probiotics are useful, especially in antibiotic courses. Still, relatively high percentages (over 50%) also consider them effective for treating allergies and depression. Few, however, consider liver disease and cancer a target for probiotics [43]. Another survey conducted in Japan found that only 63% of health professionals recommend probiotics during and after a course of antibiotics [44], a percentage much lower than what we found during our study, which observed the practical patterns of doctors. In another investigation that followed the general practitioners’ perceptions of probiotics across European countries, it was also found that 63–64% of them would prescribe probiotics for antibiotic-associated diarrhea and infectious diarrhea (which is mainly associated with antibiotherapy) [42].

The concomitant administration of probiotics and antibiotics is an essential problem due to the sensitivity of most beneficial bacterial strains to antibiotic therapy, even when the two are administered with a temporary separation. In an in vitro study, probiotic bacteria demonstrated sensitivity in approximately 70% of the cases of association with antibiotics frequently included in therapeutic regimens [45]. In this case, the dose and mode of administration of the probiotic can be decisive for maintaining the effectiveness of the probiotic therapy during antibiotic therapy. Most probiotics are administered to reach the colon, the target organ where they can exert their beneficial effects [46]. Typically, probiotics should reach the gut intact, unaltered by the simultaneous administration of antibiotics or other drugs. The most effective probiotic in terms of viability when co-administered with antibiotics is Saccharomyces boulardii, a probiotic yeast on which antibiotic treatments have no negative impact, being only susceptible to antifungal therapies [47]. Studies like the one carried out by Hammad and Shimamoto showed that, although the lack of antibiotic resistance genes in probiotics is a good safety criterion and encourages their consumption, most probiotics are destroyed by the antibiotics they are co-administered with, and the potential demonstrated benefits of probiotics are negated. Thus, the combination of antibiotic and probiotic therapies may be very limited in beneficial effects [48].

The remaining approximately 1% of the prescriptions represented probiotic recommendations outside the co-administration of antibiotics, respectively, for cases of influenza (treated with antivirals), obesity, liver protection, dyspeptic syndrome, and viral enterocolitis. This fact suggests that doctors consider probiotics to be primarily involved in the prevention or treatment of antibiotic-induced gut dysmicrobism without considering the potential benefits that probiotics could bring to the overall health of the body. Indeed, probiotics are well-known for their potential effect in regulating the composition of the gut microbiota in the context of antibiotic therapy [49], but their additional effects are conspicuously neglected by health professionals. Probiotics have been shown to improve the host’s health by acting on multiple levels. Probiotics can alleviate, prevent, or even treat specific gastrointestinal diseases, such as IBS [50], IBD [51], Helicobacter pylori infection, and lactose intolerance [52]. Growing evidence suggests a strong bond between healthy gut microbiota and the functional central nervous system (known as the microbiota–gut–brain axis) [53], which has lead to the various testing of probiotics for the prevention or ease of some neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease [54], anxiety and depression [55], autism spectrum disorders, and multiple sclerosis [56]. Studies found that beneficial bacteria have favorable effects on cardiovascular diseases [57], diabetes [58], obesity [59], cancer [60], and diseases with an allergic component [61]. Probiotics act in these conditions through various mechanisms, such as inducing digestive health [62], stimulating immunity, and decreasing inflammation [63]. All these recent clinical interventions with probiotics emphasize that their beneficial effects extend beyond intestinal health, impacting a broad spectrum of diseases. Therefore, probiotics support various bodily functions by regulating the gut microbiome.

Most probiotics recommended in medical practice are of bacterial origin, probably due to the expansion of studies that support the benefits of probiotic bacteria for human health. Probiotics of yeast origin, represented entirely by species of the Saccharomyces genus, are also recommended, but to a much lesser extent than bacterial ones, possibly due to the smaller variety of constituent species compared to probiotic bacteria that include both diverse genera and species. Although some probiotic prescriptions combine bacterial and fungal probiotics to optimize benefits, they are still relatively underused compared to the other two categories. Physicians could further explore the potential of fungal and combined probiotics, which studies show may prove more effective in treating antibiotic-induced diarrhea than bacterial strains alone. For example, S. boulardii has advantages over bacterial probiotics, being a non-pathogenic yeast that does not acquire resistance genes like Lactobacillus strains [15]. In addition, its viability is not affected by antibiotic treatments, and it does not colonize the intestine, being completely eliminated within a maximum of 5 days after administration, unlike various species of Lactobacilli [64]. Duysburgh et al. demonstrated, using an in vitro simulator of the colonic microbiota, that the combination of the probiotics L. rhamnosus GG and S. boulardii is synergic and superior to the two probiotics alone, reversing amoxicillin/clavulanic acid adverse effects on microbiota [65].

The probiotic supplements recommended in the present study mostly contain Lactobacillus spp., Bifidobacterium spp., and Saccharomyces spp. yeasts. All other probiotic genera are either poorly represented on the Romanian market or not promoted enough for doctors to acknowledge their benefits and recommend them accordingly. Indeed, globally, the most recommended probiotics belong to the genera Lactobacillus, Bifidobacterium, and Saccharomyces [66]. Also, these three genera, along with Lactococcus, are considered safe to add to probiotic supplements. Instead, the genera Enterococcus, Streptococcus, Bacillus, and Clostridium are present in physician recommendations, although these types of probiotics have a questionable safety profile given the composition of multiple pathogenic strains in all of these bacterial genera [14].

Figure 5 illustrates that certain probiotic species are preferred by physicians and included in medical prescriptions more frequently, possibly due to their significant presence in the probiotic supplement market or their known effectiveness in treating or preventing certain conditions. Thus, Lactobacillus acidophilus, Bifidobacterium lactis, and Saccharomyces boulardii could be considered more effective or better documented compared to other species. An international scientific questionnaire addressed to health professionals demonstrated that L. acidophilus is also one of the most recognized probiotic species. However, the same study showed that the species S. boulardii is not regarded as a probiotic species by approximately 70% of respondents [43].

However, at present, the most supported probiotic strains in the specialized literature for the prevention and treatment of AAD and infectious diarrhea, also having a remarkable safety profile, are Saccharomyces boulardii CNCM I-745 [67,68] and Lactobacillus rhamnossus GG [69,70]. Although several commercial products contain S. boulardii, the clinically supported strain CNCM I-745 is contained in only one commercial probiotic product in the present study. On the other hand, Lactobacillus rhamnosus GG is not a frequently prescribed probiotic strain. Supplements recommended by doctors often contain strains unknown or not declared by the manufacturer, as is the case of B. infantis, E. faecium, S. boulardii, and others, as seen in Table 1. Although the trust in this type of probiotic product is questionable, the rate of recommendations for such products is considerable. In the European Union, there is no specific regulation for probiotic products; they are included in the legislative framework of food supplements (Law 178/2002/EC and Directive 2000/13/EU) [26]. Therefore, the manufacturer’s lack of obligation to describe the type of probiotic through all three taxonomic categories—genus, species, and strain—is explained. As such, among the commercial products recommended by doctors are probiotics for which the bacterial or fungal strain contained is not specified. Transparency about the probiotic strain included in a dietary supplement is important because it informs consumers about the types of microorganisms they are ingesting and the specific health benefits they might provide. In addition, accurate labeling can support health professionals in considering scientific research on the effects of different strains and making more informed and personalized recommendations for their patients.

In 8% of the cumulative prescriptions, physicians avoided recommending a specific probiotic, leaving the final choice to the patient or pharmacist. These types of recommendations highlight the fact that there is a concern among doctors about supporting the intestinal microbiota and protecting it in the case of antibiotic treatments, but it may also mean a lack of information regarding the specific effects of different probiotic strains. The favorable effect and safety of probiotic supplements can be both strain and disease-specific and should not be generalized to all probiotic bacteria existing on the market [6]. Personalized probiotic prescriptions should be carried out based on scientific evidence from strain-specific studies, which take into account disease-specific patient stratification. A study in the USA that surveyed 632 doctors about their probiotic prescribing practices found that 40% leave the choice of probiotic supplement up to the patient [10], a much higher percentage than in our current medical practice study. However, recommending a probiotic without specifying a brand name or probiotic strain still means that doctors recognize their general health benefits. Given the variable and often conflicting scientific evidence regarding various probiotic strains, it is not surprising that physicians are nonspecific and avoid suggesting a particular probiotic to accompany primary treatment. The multitude of probiotic products on the Romanian market makes it challenging to choose a product associated with antibiotic therapy. Prescribers should choose the probiotic based on the efficacy and safety proven by randomized clinical trials of the probiotic contained in the commercial product [6]. Additionally, ensuring that the probiotic strain contained in the commercial product is the same as that supported by clinical trials and is useful for the condition being treated is a critical factor that can lead to maximum probiotic effectiveness [67].

In the medical practice analyzed in the present study, probiotics are recommended for the prevention or treatment of intestinal dysmicrobism induced by antibiotics, and the most common clinical form of microbial imbalance is diarrhea associated with the consumption of antibiotics. This health problem occurs in 5–35% of patients taking antibiotics and may begin during treatment or several weeks after stopping therapy [71]. Penicillin is the class of antibiotics most intensively recommended by doctors next to probiotics. For the rest of the antibiotic classes, the recommendation of probiotics is lower, with similar percentages for cephalosporins, macrolides, and fluoroquinolones. These data primarily reveal the very high prevalence of beta-lactam antibiotic recommendations (especially penicillins) in the case of antimicrobial treatments of infections, but also the high tendency of doctors to counteract the damage caused by antibiotics of this type on the enteric microbial flora. Indeed, according to studies, penicillins, cephalosporins, and lincosamides are considered to be the most significant disruptors of the intestinal microbiota, causing most cases of diarrhea associated with antibiotic treatment. However, digestive disorders of this type are rare when using low-risk antibiotics such as macrolides and fluoroquinolones [71]. Any antibiotic can be the source of diarrhea, but the culprits are usually broad-spectrum antibiotics that act on anaerobic microbes and reach the intestinal level due to incomplete oral bioavailability. Such antibiotics include the duo amoxicillin/clavulanic acid, third-generation cephalosporins (cefixime and ceftriaxone), and clindamycin [71]. The data contained within this study confirm that doctors’ probiotic recommendations follow current scientific findings that certain antibiotics have a more significant potential to affect gut microbial populations and cause adverse digestive effects. Therefore, adding live strains to patient prescriptions is a step toward preventing or treating these effects. However, the statistical analysis results demonstrate that although doctors generally recommend probiotics alongside high-risk antibiotics, there is no pattern or logic in prescribing specific probiotics according to the antibiotic administered. Statistically, it has been shown that there is no association between the class of antibiotic used and the genus of probiotics recommended. In terms of the probiotic genus associated with certain classes of antibiotics, medical prescriptions lack consistency, which is not surprising considering that, to date, no guidelines have been developed for the correct and specific association of probiotics with antibiotics. According to WGO [7], only two probiotic strains are classified as evidence grade I for effectiveness in diarrhea caused by antibiotics, these being L. rhamnosus GG and S. boulardii CNCM I-745. However, this guideline, like others, does not directly recommend the ingestion of probiotics but emphasizes the evidence provided by randomized clinical trials in favor of probiotics [7]. Cochrane meta-analyses also support the effectiveness of the same two probiotic species in preventing the onset of antibiotic-associated diarrhea in the pediatric population. The authors categorized the effect of reducing the incidence of diarrhea as moderate. However, these studies proclaim the need for large clinical trials to test the effectiveness of these probiotics, as current evidence is insufficient to fully support their use [72,73,74].

On the other hand, the results suggest that doctors do not recommend probiotic species randomly but instead based on the classes of antibiotics used. It is important to note that such statistical associations do not prove causality or clinical efficacy and that prescribing a probiotic with an antibiotic may be based on the more intensive marketing of a particular probiotic product, recommendations from probiotic supplement representatives, or personal physician preferences. The conclusion that doctors associate probiotics with antibiotic therapy, taking into account the probiotic species but not the gender, is unlikely to happen in practice. According to studies, when prescribing probiotics, doctors do not prioritize scientific literature as their primary source of information but instead rely on educational materials from manufacturers, media, and information directly communicated to them by representatives of probiotic supplements or through symposia [41,75,76]. While several scientific studies provide strong, peer-reviewed evidence, others have limitations in terms of scope or methodological precision [77]. This disparity gives rise to ethical concerns, such as the possibility of partiality, bias, and conflicts of interest. As a result, prescribing practices may be impacted in manners that are not evidence-based, as their sources frequently highlight the advantages of certain probiotic products while neglecting their potential hazards or restrictions. Many doctors are unaware that probiotics can also have adverse effects, including antibiotic interaction or increased antimicrobial resistance [1]. Thus, the statistical associations in the present study do not guarantee that medical prescriptions are always based on deliberate and informed choices regarding the best combination of probiotics for each antibiotic. Conversely, there may be a general tendency to prescribe certain probiotics with specific antibiotics without this being necessarily the most effective for the patient. Doctors may follow publicized recommendations instead of choosing based on a detailed analysis of each case. Moreover, personalized probiotic therapy is a desired approach in practice, but there is insufficient evidence to use it in an informed manner [78]. Thus, official guidelines for choosing probiotics during antibiotic therapy would be an excellent arsenal for physicians when their patients require antimicrobial therapy.

A key issue that physicians must consider when combining probiotics with antibiotics in patient therapy is the potency of the probiotics concerning the administered antibiotics, specifically their resilience in the presence of these antibiotics. Lactobacilli, the most recommended probiotic species alongside antibiotic treatment, is a very varied taxonomic group, and the multitude of species has not yet allowed the characterization of antibiotic susceptibility or resistance. Various studies show inconsistent results regarding the viability of these probiotics in contact with antibiotics, with only the global intrinsic resistance of Lactobacilli to vancomycin being certain. Otherwise, the susceptibility or resistance of Lactobacilli to antibiotic treatments depends both on the species and, more specifically, on the tested strain [79,80,81,82]. Given that researchers have not reached a consensus regarding the susceptibility of bacterial species to the antibiotics with which they are co-administered, the recommendation of probiotics containing bacterial strains is not strongly supported.

Diarrhea following antibiotic treatments occurs mainly due to antibiotics that pass through the enterohepatic circuit, regardless of whether they are administered orally or intravenously. Also, it can begin just one day after the initiation of antibiotic therapy, as well as several weeks after its cessation [71,83]. Our investigation found that the conventional physician advised administering probiotics for the same duration as the antibiotics. This may suggest the suboptimal use of probiotics, as the administration of probiotics during and after antibiotic treatment is recommended to protect or restore gut flora. Multiple studies have demonstrated the effectiveness of probiotics when used for several days after stopping the antibiotic treatment [18,84,85,86]. The recommendation to administer probiotics for a longer period than the antibiotic therapy may reveal physicians’ confidence in the ability of live strains to help restore the intestinal microbiota, which may be disrupted by antibiotics. Additionally, this suggests a deeper understanding that the modulation of the microbiota is a chronic process, requiring the administration of probiotics for a long period, ranging from several days to weeks [87].

According to studies [18,49,84,85,86], the most effective probiotic administration scheme extends seven days beyond the duration of antibiotic therapy. This strategy is also the least used in current research. In the present study, the recommended duration for probiotics administration is not optimal for most cases included in this study, and it is unlikely that the probiotics will manifest effects sufficient to alleviate the digestive discomfort associated with antibiotic therapy. Also, medical strategy neglects the potential of probiotics in fighting infections and pathogens in general. Some studies suggest that probiotics may help reduce the severity or duration of certain diseases, such as respiratory infections [88,89] or urogenital ones [90,91] if administered for a longer timeframe. In such cases, tailoring the posology of probiotics according to the infection could maximize these benefits. For some infections, probiotics can also help prevent recurrences. For example, in urogenital infections, specific Lactobacillus strains could reduce the risk of urinary tract infection recurrence [92,93]. In addition, probiotics can modulate the body’s inflammatory response, which can be beneficial in certain infections where excessive inflammation can be harmful [94]. An optimal approach should consider both the type of antibiotic and the specific infection being treated. For instance, in treating bacterial vaginosis with metronidazole, using Lactobacillus spp. as a probiotic is a particularly inspired choice. This is not only attributed to the fact that Lactobacilli are naturally resistant to metronidazole but also because they have a beneficial effect on the vaginal flora [1,95]. Maintaining the viability of the probiotic strain in the presence of antibiotics and optimizing the therapeutic impact of the bacterial or fungal strain on the infection treated with antibiotics would maximize the benefits of probiotics in both protecting the microbiota and providing additional support in fighting certain infections.

Figure 13 illustrates the proposed directions for future research in the probiotics field, highlighting key areas where current information is lacking, according to our study.

Strengths and Weaknesses

The study’s strengths include collecting prescriptions through numerous pharmacies covering all districts in Bucharest. Bucharest is representative of probiotic and antibiotic consumption in Romania because it has a large population, vast demographics, well-developed medical infrastructure, and serves as an administrative and economic center. It also hosts many educational institutions and public health organizations, making it a key location for data collection and health studies [96]. Given the low physician recommendation for using probiotic products, collecting the 560 prescriptions required sustained effort over approximately two years. Most prescriptions containing antibiotics do not also include probiotics. However, comparing the total number of prescriptions containing only antibiotics versus those containing antibiotic–probiotic combinations was not the aim of our study.

The weak point is that the data are specific only to the Bucharest region, and the study does not have a national perspective but a local one. On the other hand, the present study could contribute as comparative data to future studies that will be conducted in Romania or abroad regarding the use of probiotics in medical practice.

5. Conclusions

The present study highlights the need for better scientific substantiation and rigor in the prescription of probiotics, considering individual factors such as patient diagnosis and associated treatment. While probiotics are not generally regulated as drugs, there is a need for comprehensive guidelines from regulatory agencies to inform healthcare professionals about their appropriate use based on existing scientific evidence. Since physicians recommend probiotics primarily as adjunctive therapy with antibiotics, accurately pairing the right probiotics with antibiotics is essential for an effective treatment. However, the benefits of probiotics extend beyond restoring the intestinal flora during antibiotic treatments, contributing to the therapy of various diseases. As doctors overlook this fact, guidelines that describe the beneficial effects of specific probiotic strains in treating various intestinal (IBS, IBD) and non-intestinal diseases (diabetes, cardiovascular diseases, cancer, neurodegeneration, and more) should be created. Until regulatory authorities issue official guidelines on probiotic usage, healthcare professionals should rely on clinical evidence from peer-reviewed studies, trials, meta-analyses, and systematic reviews. They should also consider expert consensus and recommendations from reputable organizations like WGO or AGA to guide their probiotic recommendations. Encouraging the ongoing education of doctors in probiotics and human microbiota could positively impact the quality of medical practice and patient care.