NL2036724B1

NL2036724B1 - Antibacterial composition for oral use comprising honey

Info

Publication number: NL2036724B1
Application number: NL2036724A
Authority: NL
Inventors: Johannes De Wolf Robertus; Ooms Pieter; Bruines Bastiaan
Original assignee: Fons Ip Rights B V
Priority date: 2024-01-02
Filing date: 2024-01-02
Publication date: 2025-07-18

Abstract

The present invention relates to honey, particularly to honey for use in preventing and/or treating an infection, preferably a bacterial infection by Streptococcus pneumoniae and/or Staphylococcus aureus, more preferably a respiratory infection by Streptococcus pneumoniae and/or Staphylococcus aureus. The present invention further relates to a composition suitable for oral administration and/or rectal administration and/or perineal administration, wherein the compositions comprise honey.

Description

P36563NLO0/MJO

Title: Antibacterial composition for oral use comprising honey

Technical field

The present invention relates to compositions comprising honey, particularly to therapeutic compositions comprising honey. The present invention particularly relates to preventing and/or treating respiratory infections, especially caused by bacteria such as (Methicillin-resistant)

Staphylococcus aureus and/or Streptococcus pneumoniae.

Background of the invention

Infections of the upper respiratory tract are among the most common diseases in all age groups. Such infections are typically characterized by inflammation of the mucous membranes lining the throat, leading to the classic symptoms of redness, swelling, and discomfort. Common symptoms include coughing, a sore throat and headache. Whereas most of the viral upper respiratory tract infections are cleared without any serious complications, viral infections may predispose patients to secondary bacterial infections, which are often associated with a more severe clinical course [Hanada, S., et al. Front

Immunol. 2018; 9: 2640." (2018)]. Among the common bacterial pathogens responsible for upper respiratory tract infections are Streptococcus pneumoniae and Staphylococcus aureus.

Given that bacterial colonization may aggravate disease and lead to prolonged recovery, effective antimicrobial agents are of great importance.

Among the known antibacterial agents, natural products such as honey are becoming increasingly more popular. Honey is not only valued as a nutritional product, but also for its medicinal properties. One of the most important findings relating to the medicinal use of honey, is its antibacterial activity against numerous bacteria, including Streptococcus pneumoniae and Staphylococcus aureus, which are among the most common causes of community-acquired and hospital-acquired pneumonia, respectively [Slupsky, Carolyn M., et al. Journal of proteome research 8.6 (2009): 3029-3036].

Despite its gained popularity in modern medicine, the use of honey is not yet widely applied and/or accepted in clinical setting. However, driven by its natural origin and its beneficial healing properties, honey has been subjected to a multitude of laboratory and clinical investigations during the past few decades. One of the challenges associated with using honey is related to its consistency, particularly to its stickiness and viscosity, which make it difficult to use. For this reason, several research efforts have been focusing on better delivery and application procedures of honey, such as described in US11154578B2, which provides a composition comprising honey in the form of a semi-solid cream and US9044489B2 which relates to diluted honey-comprising compositions. Other efforts that are widely reported on are aimed at better understanding honey’s bioactivity and/or enhancing the bioactivity of compositions comprising honey, for example by exploring synergistic effects between ingredients, as described in EP3856219A1.

While the beneficial properties of honey are recognized, optimal application of honey in treatment, as well as its comparative efficacy with existing therapies, remains insufficient.

This is not only related to above-mentioned factors such as its challenging consistency and lack of understanding its bioactive properties, but also to a lack of evidence and guidance on how and when to use honey in clinical setting.

Therefore, there is a need for better guidance on optimal use of honey in treating bacterial infections, particularly respiratory tract infections.

Summary of the invention

The present inventors have identified a composition comprising honey that exhibits antibacterial effects, particularly bacteriostatic effects against (Methicillin-resistant)

Staphylococcus aureus and/or Streptococcus pneumoniae. Surprisingly, it was found that the composition can be used in a surprisingly advantageous dosage scheme, leading to an immediate and prolonged protective and/or treatment efficacy against Staphylococcus aureus and/or Streptococcus pneumoniae, without periods of suboptimal efficacy.

More specifically, it was surprisingly found that both in the case of administering the composition comprising honey as well as in the case of administering commonly used antibiotics such as penicillin, there are periods of suboptimal protection. Importantly, it was found that these periods (to be seen starting from the moment of administration) do not overlap, offering the possibility of administering a combination according to a surprisingly advantageous dosage scheme, wherein first the composition comprising honey is administered, and afterwards, in case infection is still present, suitable antibiotics are administered. Apart from the surprisingly advantageous dosage scheme, the current invention further relates to reducing the use of antibiotics and/or to preventing resistance to antibiotics, especially to preventing resistance to antibiotics in an early stage of treatment.

Accordingly, in first aspect the present disclosure relates to honey for use in preventing and/or treating an infection by Streptococcus pneumoniae and/or Staphylococcus aureus.

In another aspect, the present disclosure relates to a composition suitable for oral administration and/or rectal administration and/or perineal administration.

Detailed description of the invention

The present disclosure relates to honey for use in preventing and/or treating an infection, preferably a bacterial infection, more preferably an infection by Streptococcus pneumoniae and/or Staphylococcus aureus, wherein the use comprises: a) providing the honey to a subject, preferably providing the honey by oral administration; b} within 1-48 hours after starting step a), determining if the subject has a(n) (bacterial) infection, preferably an infection by a Streptococcus pneumoniae and/or

Staphylococcus aureus; c) if a (bacterial) infection is determined in step b), preferably if an infection by

Streptococcus pneumoniae and/or Staphylococcus aureus is determined in step b), (further) administering an antibiotic drug, preferably a single compound antibiotic drug, to the subject; wherein step b) and/or step c) of the use are preferred steps.

In the present disclosure, traditional use is also envisaged.

Herein, with the term ‘honey’ is meant a viscous substance produced by honeybees and other insects from the nectar of flowers. Whereas the composition of honey may vary due to factors such as floral source, origin and purity, generally honey has a content of 80-85% carbohydrates, 15-17% water, 0.3% proteins, 0.2% ashes and minor quantities of amino- acids, phenols, pigments and vitamins [Khan, Shahid Ullah, et al. Saudi journal of biclogical sciences 25.2 (2018): 320-325]. Herein, diluted honey compositions and/or compositions comprising honey in addition to other components, are also encompassed. Honey can also be described as a hypertonic sugar solution. In an embodiment, the present disclosure may also relate to other hypertonic sugar solution for use according to the present disclosure.

In a preferred embodiment, the honey for use according to the present disclosure, relates to honey for use in preventing and/or treating any bacterial infection, preferably bacterial infections of the respiratory tract, which herein refer to bacterial infections affecting the nose, mouth and/or airways. The honey for use may be used in preventing and or treating bacterial infections by any of the bacteria from the list consisting of, but not limited to: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chiamydophila pneumoniae, Legionella pneumophila, Staphylococcus aureus, Klebsiella pneumoniae,

Pseudomonas aeruginosa, Moraxella catarrhalis, Bordetella pertussis, or any combination thereof.

In another preferred embodiment, the honey for use according to the present disclosure is provided at least 1 time daily, preferably 2 times daily, even more preferably at least 3 times daily, yet even more preferably at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 times daily in step a). In addition and/or alternatively, the honey is provided as often as appropriate, preferably at most 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,9, 8,7, 6, 5, 4, 3, 2 times daily. In addition and/or alternatively, the honey may be provided every 2, 3,4, 5,6, 7, 8,9, 10, 11, 12 hours. In addition and/or alternatively, the honey may be provided for as long as desired in step a), preferably for at least 6, 12, 18, 24, 30, 36, 42, 48, 54, 80, 66, 72 hours in step a). In addition and/or alternatively, the honey may be provided for at most 14, 12, 10, 8, 6, 4 days, preferably for at most 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 66 hours. It is preferred that in step a), no single compound or other antibiotic (other than honey) is administered.

In another preferred embodiment, the subject of step a) of the present disclosure may be a carrier i.e. the subject of step a) of the present disclosure may be harboring a potential pathogen e.g. bacteria, preferably Streptococcus pneumoniae and/or Staphylococcus aureus, but not showing signs and/or symptoms of (bacterial) infection. In a particularly preferred embodiment, the subject of step a) of the present disclosure may be a farmer, preferably a pig farmer.

In another preferred embodiment, it is determined (diagnosed) in step b) of the present disclosure if the subject has a bacterial infection, wherein step b) may be performed within 2 weeks after step a), preferably within 1 week after starting step a), more preferably within 8, 5, 4, 3 days after starting step a), even more preferably within 6-48, 8-48, 10-48, 12-48, 14- 48, 16-48, 18-48, 20-48, 22-48, 24-48 hours after starting step a). The determination or diagnosis of step b) of the present disclosure may be performed using any method known in the art and known to the skilled person, which typically involves a combination of clinical evaluation and laboratory tests. The subject may for example undergo a physical examination, which may reveal signs associated with bacterial infections. Examples of such signs are fever, swelling, redness and localized pain. In addition to this, the subject may undergo blood tests, urine tests, cultures of samples from the infected site, wherein the infected site is preferably the nose, mouth and/or airways.

In yet another preferred embodiment, if a (bacterial) infection is determined in step b) of the present disclosure, an antibiotic drug is administered to the subject, wherein the antibiotic drug can be any antibiotic drug known in the art to prevent and/or treat infection with the bacteria (potentially) causing the infection. Preferably, the antibiotic drug is selected from the 5 list comprising penicillin, amoxicillin, ceftriaxone, macrolides (e.g., azithromycin, clarithromycin), ampicillin, ciprofloxacin, tetracyclines (e.g., doxycycline), fluoroquinolones (e.g., levofloxacin), vancomycin, clindamycin, linezolid, piperacillin-tazobactam, cefepime, meropenem, amoxicillin-clavulanate, cefixime, cefuroxime, rifampicin, cephalosporins and trimethoprim-sulfamethoxazole. In another preferred embodiment, the antibiotic drug is a single compound antibiotic drug, preferably selected from the group consisting of vancomycin, daptomycin, linezolid, penicillin, macrolides, clindamycin, cephalosporins, rifampicin. Preferably, the antibiotic drug is administered for as long as typically prescribed to prevent and/or appropriate to treat infection with said bacteria, according to any suitable dosing regimen. More preferably, the antibiotic drug is administered for at least 1, 2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 15, 18, 17, 18, 19, 20, 21 days. In addition and/or alternatively, the antibiotic drug is administered for at most 30, 29, 28 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 days. In addition and/or alternatively, the antibiotic drug is administered at least once every other day, preferably at least daily, more preferably at least twice daily, even more preferably at least three times daily. In addition and/or alternatively, the antibiotic drug is administered at most 4, 3, 2, 1 time(s) daily. In a preferred embodiment, the antibiotic drug may be administered via any administration route known in the art, preferably via oral administration, via intravenous administration, topical administration and/or by inhaling. Preferably, if a (bacterial) infection is determined in step b) of the present disclosure, the antibiotic drug of step c) replaces the honey of the present disclosure i.e. the subject discontinuous to be provided with the honey. More preferably, if a (bacterial) infection is determined in step b) of the present disclosure, the antibiotic drug of step ¢) is further administered to the subject i.e. while the subject continuous to be provided with the honey of the present disclosure.

In addition and/or alternatively, the honey according to the present disclosure is used in preventing and/or treating bacterial infections of Streptococcus pneumoniae and/or

Methicillin-resistant Staphylococcus aureus (MRSA).

Also foreseen in the present disclosure is a use wherein in step a) of the present disclosure an antibiotic drug is provided instead of honey, and/or in step c) of the present disclosure honey is administered instead of an antibiotic drug.

In a preferred embodiment, the honey for use according to the present disclosure is comprised in a composition, preferably in a composition (suitable) for oral administration. In an embodiment, the honey according to the present disclosure, when provided by oral administration in step a), preferably comprises administering a composition for oral administration comprising the honey to the oral cavity and/or throat of the subject. Herein, oral administration includes, but is not limited to, (oral) inhalation.

In a preferred embodiment, the composition according to the present disclosure has a pH of lower than 7, preferably lower than 6, more preferably lower than 5, most preferably lower than or equal to 4.5. In a preferred embodiment, the composition has a pH of at least 1, 2, 2.5, 2.75, 3, 3.5, 3.75, 4. In another preferred embodiment, the composition has a pH between preferably between 1-5, preferably between 2-4, more preferably between 2.5-4.5, most preferably between 3-4.5.

In an embodiment, the composition according to the present disclosure preferably further comprises agents with soothing and/or antibacterial properties, such as Althea officinalis

Glycyrrhiza glabra, Citrus aurantium, Foeniculum vulgare, Foeniculi aetheroleum, Illicium verum, Menthae piperitae aetheroleum, Pimpinella anisum, Salviae officinalis aetheroleum,

Malva sylvestris, Primula elatior, Angelica archangelica, Calendula officinalis, Cetraria islandica, Drosera rotundifolia, Echinacea purpurea, Eucalyptus globulus, Eucalypti aetheroleum, Hyssopus officinalis, Levomentholum, Marrubium vulgare, Menthae arvensis aetheroleum, Matricaria recutita, Pimpinella saxifrage, Pimpinella major, Plantago lanceolata,

Rosae x centifolia, Salvia officinalis, Thymus serpyllum, Thymus vulgaris, Thymus zygis, Tilia cordata, Tilia platyphyllos, Verbena officinalis, Verbascum denisiflorium, Verbascum phlomoides, Achillea millefolium, Alchemilla xanthochlora, Anisi aetheroleum, Hyssopus officinalis, Iris germanica, Limonis aetheroleum, Melissa officinalis, Mentha x piperita,

Menthae arvensis, Salvia triloba, Salviae lavandulifoliae, Angelica archangelica, Echinacea purpurea, Levomentholum, Matricaria recutita, Pimpinella major, Pimpinella saxifrage,

Pulmonaria officinalis, Rosae gallica, Rosae x centifolia, Salvia officinalis, Thymus zygis, Tilia cordata, Tilia platyphyllos, Verbascum denisiflorium, Verbascum phlomoides, Verbena officinalis, Veronica officinalis, Thymus serpyllum, Calendula officinalis, Cetraria islandica,

Eucalypti aetheroleum, Eucalyptus globulus, Marrubium vulgare, Papaver rhoeas, Plantago lanceolata, Thymus vulgaris, Thymus zigis Primula veris, Thymol crystals, Populus nigra-

Buds, Glycyrrhiza glabra-Roots, Verbascum thapsiforme, aloe vera, Grindelia robusta, chamomile, elderberry, and/or green tea and/or extracts thereof.

In a particularly preferred embodiment, the composition for aral administration according to the present disclosure preferably further comprises Althea officinalis and/or an extract of

Althea officinalis. Althaea officinalis is a plant belonging to the Malvaceae family and to the

Althaea genus, known for its soothing properties. In a preferred embodiment, the composition comprises between 20-70 wt.% Althea officinalis and/or an extract of Althea officinalis, preferably between 30-65, more preferably 35-60, even more preferably between 40-60, most preferably between 45-55 wt.% Althea officinalis and/or an extract of Althea officinalis, wherein the wt.% is drawn on the total weight of the composition. Preferably the composition comprises at least 20 wt.% Althea officinalis and/or an extract of Althea officinalis, preferably atleast 25, 30, 35, 40, 45, 50 wt.% Althea officinalis and/or an extract of Althea officinalis, wherein the wt.% is drawn on the total weight of the composition. Preferably the composition comprises at most 75 wt.% Althea officinalis and/or an extract of Althea officinalis, preferably at most 70, 65, 60, 55 wt.% Althea officinalis and/or an extract of Althea officinalis, wherein the wt.% is drawn on the total weight of the composition.

In an embodiment, the composition for oral administration according to the present disclosure preferably further comprises honey and Althea officinalis or extract thereof in a honey:Althea officinalis (or extract thereof) in a wt.% ratio between 4:1 and 1:4, preferably between 3:1 and 1:3, more preferably between 1:1 and 1:3, even more preferably between 1:1 and 1:2.

In an embodiment, the composition according the present disclosure preferably further comprise(s) one or more preservative(s). Preferably, the composition comprises less than 1 wt.% of preservative(s), preferably less than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.02, wherein the wt.% is drawn on the total weight of the composition. In addition and/or alternatively, the composition preferably comprises at most 1 wt.% of one or more preservative, preferably at most 0.5, 0.3, 0.1, 0.05, 0.03, 0.02, 0.01 wt.% of one or more preservative, wherein the wt.% is drawn on the total weight of the composition. Selection of specifically a composition with a pH lower than 7, preferably lower than 6, 5, 4.5, more preferably a pH between 2.5-4.5, may allow for less than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2,0.1, 0.05, 0.02 wt.% preservatives.

In an embodiment, the composition according to the present disclosure comprises one or more preservative(s) selected from the group consisting of benzoic acid, flavonoids, parabens, phenolic acids, abscisic acid, sorbic acid and pharmaceutically acceptable salts and combinations thereof, such as potassium sorbate. Preferably the composition comprises at least one preservative(s), wherein the preservative comprises potassium sorbate.

In an embodiment, the composition for oral administration according to the present disclosure can be in any form known to the person skilled in the art, such as in lozenges or troches, in the form of a spray, an inhalation liquid, a gargle, syrup, pastille, and/or dissolvable strips, but is preferably in liquid form, preferably in the form of a spray.

In an embodiment, the honey according to the present disclosure preferably further comprises in step a), providing the honey by rectal administration and/or perineal administration to the subject and/or administering a composition comprising the honey to the rectum and/or perineum of the subject. Herein, rectal administration preferably refers to administration on and/or around the rectum, preferably not to internal administration via and in the rectum (i.e. enteral rectal administration) of the subject of step a) of the present disclosure,

In an embodiment, the honey according to the present disclosure can be any honey, preferably selected from the group consisting of acacia honey, manuka honey, clover honey, wildflower honey, alfalfa honey, buckwheat honey, eucalyptus honey, orange blossom honey and/or any combination thereof, preferably any honey originated from the European Union and/or South-America.

In addition to the above, the present disclosure further provides for the following steps: a)providing the honey by oral administration and/or rectal administration and/or perineal administration to at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500 subjects; b)within 1-48 hours after starting step a), determining if the subjects have an infection by

Streptococcus pneumoniae and/or (Methicillin-resistant) Staphylococcus aureus; c) determining an infection by Streptococcus pneumoniae and/or (Methicillin-resistant)

Staphylococcus aureus in at least one subject; d}administering an antibiotic drug to the at least one subject determined to have infection by Streptococcus pneumoniae and/or (Methicillin-resistant) Staphylococcus aureus.

Also foreseen is a method for prevention or treatment of an infection, preferably a bacterial infection, more preferably an infection by Streptococcus pneumoniae and/or Staphylococcus aureus, e.g. for a subject in need thereof, the method comprising the steps as disclosed herein.

The present disclosure further relates to a composition suitable for oral and/or rectal administration and/or perineal administration, wherein the composition preferably comprises: — honey;

— one or more preservative(s) and/or; — One or more of the agents with soothing and/or antibacterial properties, preferably

Althea officinalis and/or an extract of Althea officinalis, more preferably a combination of Althea officinalis (and/or an extract of Althea officinalis) and Thymus vulgaris. Said composition may also be used in the form of a nasal spray.

Preferably, the composition suitable for oral administration and/or rectal administration and/or perineal administration according to the present disclosure comprises between 1-70 wt.% of honey, preferably between 2-65, more preferably between 3-60, even more preferably between yet even more preferably between 5-55, yet even more preferably between 10-50 most preferably between 20-40 wt.% of honey, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration. In another preferred embodiment, the composition suitable for oral administration and/or rectal administration and/or perineal administration comprises at least 10, 20, 25, 30, 31, 32, 33, 34, 35, 36 wt.% honey, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration. In addition and/or alternatively, the composition suitable for oral administration and/or rectal administration and/or perineal administration comprises at most 100, 90, 80, 85, 80, 75, 70, 65, 60, 55, 50, 45 wt.% honey, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration.

The composition suitable for oral administration and/or rectal administration and/or perineal administration according to the present disclosure may additionally and/or alternatively comprise one or more preservative(s). Preferably, the composition suitable for oral administration and/or rectal administration and/or perineal administration comprise(s) between 0.001-5 wt.% of one or more preservative(s), preferably between 0.005-3, more preferably between 0.01-2, most preferably between 0.01-1, most preferably between 0.01- 0.1 wt.% of one or more preservative(s). Preferably, the composition for oral administration and/or rectal administration and/or perineal administration comprise(s) one or more preservative(s) selected from the group consisting of benzoic acid, flavonoids, parabens, phenolic acids, abscisic acid, sorbic acid and pharmaceutically acceptable salts and combinations thereof, such as potassium sorbate. Preferably, the composition for oral administration and/or rectal administration and/or perineal administration comprises less than 1 wt.% of preservative(s), preferably less than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.02 of one or more preservative, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration.

In addition and/or alternatively, the composition for oral administration and/or rectal administration and/or perineal administration preferably comprises at most 1 wt.% of one or more preservative, preferably at most 0.5, 0.3, 0.1, 0.05, 0.03, 0.02, 0.01 wt.% of one or more preservative, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration.

The composition suitable for oral administration and/or rectal administration and/or perineal administration according to the present disclosure may additionally and/or alternatively comprise(s) one or more of the agents with soothing and/or antibacterial properties.

Preferably, the composition suitable for oral administration and/or rectal administration and/or perineal administration comprises between 20-70 wt.% of one or more of the agents with soothing and/or antibacterial properties, preferably between 30-85, more preferably 35-60, even more preferably between 40-60, most preferably between 45-55 wt.% of one or more of the agents with soothing and/or antibacterial properties, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration. Preferably the composition suitable for oral administration and/or rectal administration and/or perineal administration comprises at least 20 wt.% of one or more of the agents with soothing and/or antibacterial properties, preferably at least 25, 30, 35, 40, 45, 50 wt. % of one or more of the agents with soothing and/or antibacterial properties, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration. Preferably the composition suitable for oral administration and/or rectal administration and/or perineal administration comprises at most 75 wt. % of one or more of the agents with soothing and/or antibacterial properties, preferably at most 70, 65, 60, 55 wt.% of one or more agents of the with soothing and/or antibacterial properties, wherein the wt.% is drawn on the total weight of the composition for oral administration and/or rectal administration and/or perineal administration. In addition and/or alternatively, the one or more agents with soothing and/or antibacterial properties comprise(s) at least Althea officinalis and/or an extract of Althea officinalis.

Preferably, the composition suitable for oral administration and/or rectal administration and/or perineal administration has a pH of lower than 7, preferably lower than 6, more preferably lower than 5, most preferably lower than or equal to 4.5. In a preferred embodiment, the composition for oral administration and/or rectal administration and/or perineal administration has a pH of at least 1, 2, 2.5, 2.75, 3, 3.5, 3.75, 4. In another preferred embodiment, the composition for oral administration and/or rectal administration and/or perineal administration according the present disclosure has a pH between preferably between 1-5, preferably between 2-4, more preferably between 2.5-4.5, most preferably between 3-4.5.

In another embodiment, the compositions suitable for oral and/or rectal administration and/or perineal administration may further comprise additional ingredients, such as colorants or flavorings, preferably citrus and/or thyme (extract), which may further enhance the organoleptic properties of the compositions suitable for oral and/or rectal administration and/or perineal administration.

CLAUSES

1. Honey for use in preventing and/or treating an infection by Streptococcus pneumoniae and/or Staphylococcus aureus, wherein the use comprises: a)providing the honey by oral administration to a subject; b)within 12-48 hours after starting step a), determining if the subject has an infection by

Streptococcus pneumoniae and/or Staphylococcus aureus; c)if an infection by Streptococcus pneumoniae and/or Staphylococcus aureus is determined in step b), administering a single compound antibiotic drug to the subject. 2. Honey for use according to clause 1, wherein the Staphylococcus aureus is Methicillin- resistant Staphylococcus aureus (MRSA). 3. Honey for use according to any one of clauses 1 or 2, wherein the oral administration of step a) comprises administering a composition comprising the honey to the oral cavity and/or throat of the subject. 4. Honey for use according to any one of clauses 1 to 3, wherein the oral administration of step a) comprises administering a composition comprising the honey, wherein the composition has a pH of lower than 5, preferably between 2.5-4.5. 5. Honey for use according to clause 4, wherein the composition further comprises Althea officinalis and/or an extract of Althea officinalis. 6. Honey for use according to any one of clauses 4 or 5, wherein the composition comprises honey and Althea officinalis or extract thereof in a wt.% ratio between 3:1 and 1:3, preferably between 1:1 and 1:3, more preferably between 1:1 and 1:2, wherein the wt.% is drawn on the total weight of the composition. 7. Honey for use according to any one of clauses 4 to 6, wherein the composition further comprises one or more preservative(s), wherein the wt.% of preservative(s) is less than 1 wt.%, preferably less than 0.5 wt.%, wherein the wt.% is drawn on the total weight of the composition. 8. Honey for use according to any one of clauses 4 to 7, wherein the composition comprises one or more preservative(s), wherein the preservatives comprise potassium sorbate and/or sodium benzoate. 9. Honey for use according to any one of clauses 4 to 8, wherein the composition is in liquid form, preferably in the form of a spray and/or an inhalation liquid. 10. Honey for use according to any one of clauses 1 to 9 wherein step a) further comprises providing the honey by rectal administration and/or perineal administration to the subject and/or wherein step a) comprises administering a composition comprising the honey to the rectum and/or perineum of the subject. 11. Honey for use according to any one of clauses 1 to 10, wherein the honey is selected from the group consisting of acacia honey, manuka honey, clover honey, wildflower honey, alfalfa honey, buckwheat honey, eucalyptus honey, orange blossom honey and/or any combination thereof. 12. Honey for use according to any one of clauses 1 to 11, wherein the use comprises: a)providing the honey by oral administration to at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500 subjects; b)within 12-48 hours after starting step a), determining if the subjects have an infection by

Streptococcus pneumoniae and/or (Methicillin-resistant) Staphylococcus aureus; c) diagnosing an infection by Streptococcus pneumoniae and/or (Methicillin-resistant)

Staphylococcus aureus in at least one subject; d)administering a single compound antibiotic drug to the at least one subject determined to have infection by Streptococcus pneumoniae and/or (Methicillin-resistant)

Staphylococcus aureus. 13. Honey for use according to any one of clauses 1 to 12, wherein the single compound antibiotic drug is selected from the group consisting of vancomycin, daptomycin, linezolid, penicillins, macrolides, clindamycin, cephalosporins, rifampicin. 14. A composition suitable for oral administration and/or rectal administration and/or perineal administration comprising:

— 2-60 wt.% honey; — 0.01-1 wt.% preservative(s); — 40-80 wt.% Althea officinalis and/or an extract of Althea officinalis; wherein the composition has a pH of between 2.5 and 4.5; wherein the wt.% is drawn on the total weight of the composition.

Brief description of the figures

Figure 1. Box plots showing zone inhibition measurements of the disc diffusion test with the composition comprising honey and an antibiotic after 24 and 48 hours of incubation of

Streptococcus pneumoniae.

Figure 2. Box plots showing zone inhibition measurements of the disc diffusion test with the composition comprising honey and an antibiotic after 24 and 48 hours of incubation of

Staphylococcus aureus.

Examples

Example 1. The effect of the composition comprising honey on the bacteriostatic activity of Streptococcus pneumoniae and Staphylococcus aureus

The aim of this experiment is to evaluate the antibacterial (i.e. bacteriostatic) activity of the composition with regard to Streptococcus pneumoniae and Staphylococcus aureus.

Method

The composition for oral administration was prepared as described in Table 1. The bacteriostatic activity was evaluated using a disc diffusion test. More specifically, a bacterial culture of Streptococcus pneumoniae and Staphylococcus aureus was inoculated on an agar surface, after which a filter disk impregnated with either of the composition was placed on the agar surface. The agar plates were incubated for 24 and 48 hours, after which the zones of inhibition formed around each disk were measured. As a control, antibiotic penicillin was used.

Table 1.

Results

As can be seen in Figure 1, compared to penicillin, both the composition showed a clearly higher zone of inhibition for Streptococcus pneumoniae after 24 hours. After 48 hours, the zone of inhibition on the plates exposed to penicillin generally increased. The composition, although still showing a clear zone of inhibition {higher than for penicillin after 24 hours), had now a more narrow zone.

As can be seen in Figure 2, a similar trend was seen for the plates inoculated with

Staphylococcus aureus, wherein after 24 hours, the composition showed a higher zone of inhibition than when penicillin was used. After 48 hours, this trend was still visible.

As can been seen from this experiment, both the composition and the antibiotic result in zones of inhibition, both for Streptococcus pneumoniae and for Staphylococcus aureus.

Although the composition shows superior zones of inhibition compared to the antibiotic, the effect of the composition reduces over the time span evaluated, whereas the effect of the antibiotic increases. Overall, the shown data suggests that the composition comprising honey on its own (as it shows immediate effect and is superior to antibiotics), are ideal to use in the early phase of infection, after which it should be established in time whether (further) administration of antibiotics may be desirable.

Example 2. Effect of pH

The aim of this experiment is to evaluate the effect of pH on the antibacterial (i.e. bacteriostatic) activity of the composition.

Method

The composition is prepared as described in Example 1 and subsequently aliquoted for each pH condition to be tested. The pH of each composition is adjusted using citric acid or sodium hydroxide (under control of a calibrated pH meter). The bacteriostatic activity is evaluated using a disc diffusion test. More specifically, a bacterial culture of Streptococcus pneumoniae is inoculated on an agar surface, after which a filter disk impregnated with the composition is placed on the agar surface. The agar plates are incubated for 24 hours, after which the zones of inhibition formed around each disk are measured and translated to a score, wherein: - = suboptimal zone of inhibition + = acceptable zone of inhibition

++ = good zone of inhibition n.d. = will not be determined

Results

As can be seen from table 2, a pH between 2 and 6 results in acceptable to even good zones of inhibition. Based on the results, it seems that the composition performs best when having a pH between 3 and 5.

Table 2

PH |Ora a 4 |* 5 |* 8 |+

To

Fm + [re wna

Twa na

We

Example 3. Bacteriostatic effect of honey and/or antibiotics

The aim of this experiment is to evaluate the antibacterial (i.e. bacteriostatic) activity of the composition and/or an antibiotic with regard to Streptococcus pneumoniae over time.

Method

The bacteriostatic activity is evaluated using a disc diffusion test, for which a bacterial culture of Streptococcus pneumoniae is inoculated on an agar surface. The composition is prepared as described in Example 1. A filter disk, previously impregnated with either of the compositions (prepared as in experiment 1), or a suitable antibiotic (e.g. penicillin) is placed on the agar surface. As can be seen in table 3, a combination of the composition comprising honey and an antibiotic is also evaluated. The agar plates are incubated for 72 hours, after which the zones of inhibition formed around each disk are measured and translated to a score, wherein: - = suboptimal zone of inhibition + = acceptable zone of inhibition +++ = good zone of inhibition n.d. = will not be determined

Results

As can be seen from Table 3, both the composition (i.e. ‘Honey’) and the antibiotic (i.e. ‘Antibiotic’) alone result in suboptimal zones of inhibition (i.e. bacteriostatic activity).

Interestingly, the best results are obtained when combining both the composition comprising honey and the antibiotic. The results do not only show that it is the combination between the composition comprising honey and the antibiotic that result in superior results, but also that the timing matters. More specifically, when comparing dosing regimen number 2, 3, 5 and 6, it can be seen that acceptable results are obtained when the composition is administered first (i.e. from the start). Interestingly, when said composition is administered first, after which a switch is made to antibiotics within 12-48 hours from the start, even better results are obtained.

Table 3

Start Within 12- | Within 48- | inhibition 48 hours 72 hours from start | from start [Fae [arey [Fee 7 [Frey [Fene [ae |v 4 [Alie Aniete [Anton

B |e [Row |- 5 [Antie [Honey [es |-

Claims

P36563NLO0 - NL2036724 Conclusions

1. Honey for use in preventing and/or treating an infection by Streptococcus pneumoniae and/or Staphylococcus aureus, the use comprising: a) providing the honey by oral administration to a patient; b) determining within 12-48 hours after initiating step a), whether the patient has an infection with Streptococcus pneumoniae and/or Staphylococcus aureus; c) if an infection by Streptococcus pneumoniae and/or Staphylococcus aureus is determined in step b), administering, within 12-48 hours after initiating step a), a single compound antibiotic to the patient.

Honey for use according to claim 1, wherein the Staphylococcus aureus is Methicillin-resistant Staphylococcus aureus (MRSA).

Honey for use according to any of claims 1 or 2, wherein the oral administration of step a) comprises administering a composition comprising the honey to the oral cavity and/or throat and/or airways of the patient.

Honey for use according to any one of claims 1 to 3, wherein the oral administration of step a) comprises administering a composition comprising the honey, the composition having a pH less than 5, preferably between 2.5-4.5.

Honey for use according to claim 4, wherein the composition further comprises Althea officinalis and/or an extract of Althea officinalis.

Honey for use according to any of claims 4 or 5, wherein the composition comprises honey and Althea officinalis or extract thereof in a wt.% ratio of between 3:1 and 1:3, preferably between 1:1 and 1:3, more preferably between 1:1 and 1:2, the wt.% being calculated on the total weight of the composition.

Honey for use according to any one of claims 4 to 6, wherein the composition further comprises one or more preservative(s), the weight percentage of preservative(s) being less than 1 wt%, preferably less than 0.5 wt%, the wt% being based on the total weight of the composition.

Honey for use according to any one of claims 4 to 7, wherein the composition comprises one or more preservatives, the preservatives comprising potassium sorbate and/or sodium benzoate.

Honey for use according to any one of claims 4 to 8, wherein the composition is in liquid form, preferably in the form of a spray and/or an inhalation liquid.

Honey for use according to any one of claims 1 to 9, wherein step a) further comprises providing the honey by rectal administration and/or perineal administration to the patient and/or wherein step a) comprises administering a composition comprising the honey to the rectum and/or perineum of the patient.

Honey for use according to any one of claims 1 to 10, wherein the honey is selected from the group consisting of acacia honey, manuka honey, clover honey, wildflower honey, alfalfa honey, buckwheat honey, eucalyptus honey, orange blossom honey and/or a combination thereof.

Honey for the use according to any one of claims 1 to 11, the use comprising: a) providing the honey by oral administration to at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500 patients; b) within 12-48 hours after starting step a), determining whether the patients have an infection with Streptococcus pneumoniae and/or (Methicillin-resistant) Staphylococcus aureus; c) diagnosing an infection by Streptococcus pneumoniae and/or (Methicillin-resistant) Staphylococcus aureus in at least one patient; d) administering a single compound antibiotic to at least one patient confirmed to have an infection with Streptococcus pneumoniae and/or (methicillin-resistant) Staphylococcus aureus.

Honey for use according to any one of claims 1 to 12, wherein the single compound antibiotic is selected from the group consisting of vancomycin, daptomycin, linezolid, penicillins, macrolides, clindamycin, cephalosporins and rifampicin.

14. A composition suitable for oral administration, comprising: - 2-60 wt.% honey; - 0.01-1 wt.% preservative(s);

- 40-60 wt.% Althea officinalis and/or an extract of Althea officinalis; the composition having a pH between 2.5 and 4.5; the weight percentage being drawn from the total weight of the composition.