Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to flavonoids and their use in medicaments for combating microbial infections.
• Microbial resistance to ⁇ -lactam antibiotics is usually achieved by the microbes producing the enzyme ⁇ -lactamase, which cleaves the ⁇ -lactam ring of the antibiotic destroying its ability to prevent microbial growth.
• MRSA methicillin-resistant Staphylococcus aureus
• WO 95/23607-A1 discloses an antibacterial agent containing tea extract or active fraction thereof and a ⁇ -lactam antibiotic. The combination is said to act synergistically in the treatment of MRSA infections.
• the tea is extracted using water and contains polyphenols such as catechins of the following formula:
• Ri is a hydrogen atom or a hydroxy group and R? is a hydrogen atom or a 3.4.5-trihydroxybenzoyl group.
• R 2 is a hydrogen atom.
• flavonoids may have activity against MRSA.
• Six different types of compound may have activity: (a) flavones, (b) flavonols, (c) catechins, (d) isoflavones (e) flavanones and (f) flavanonols.
• Particularly interesting compounds are baicalein, myricetin, datiscetin, quercetagetin, (-)-epigallocatechin and (-)-epigallocatechin gallate.
• the present invention therefore provides a product comprising, for simultaneous, separate or sequential administration: (a) a flavonoid of formula:
• each group R 3 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , R d and R e represents independently hydrogen or a group OZ;
• Z is hydrogen, lower alkyl, a glycosyl group or a leaving group which in vivo is transformed into a hydrogen group
• X and Y are each hydrogen or X and Y together represent a double bond; or a pharmaceutically acceptable salt thereof;
• the invention includes within its scope: products in which the flavonoid is a flavone of formula:
• R a , R b , R c , R d and R e are as defined as above, and pharmaceutically acceptable salts thereof.
• Z represents a glycosyl group
• a wide variety of such groups may be employed, either those formed from simple sugars or from derivatives thereof such as uronic acids.
• glycosyl groups i.e. groups formed by removal of the anomeric hydroxyl group in a sugar or a derivative thereof, are easily metabolised to the corresponding hydroxy compound.
• sugar moiety is of secondary importance.
• Commonly occurring glycosides that fall within the scope of the present invention include the monosaccharide derivative apigetrin/cossmetin (apigenin 7-glucoside), the disaccharide derivatives apiin (apigenin 7-(apiosylglucoside)) and acaciin (apigenin 7-(rhamnosylglucoside)), and the uronic acid derivative baicalin (baicalein 7-glucuronoside).
• a preferred glycosyl group is that of formula:
• each group R 3 , R ⁇ R 6 , R 8 represents independently hydrogen or an OH group and R 7 represents a group OZ in which Z is hydrogen or a group of formula:
• the above two groups are glucosyl and glucuronosyl, respectively.
• compounds such as baicalin may be used in the present invention:
• Baicalin is the glucuronide of baicalein and may be isolated from the Chinese herb Xi-nan Huangqin. However, especially useful are the compounds galangin, luteolin and apigenin of formulae:
• the compounds are mostly polyphenols and are weakly acidic.
• Pharmaceutically acceptable salts include phenolic salts with bases. However, they are particularly suitable for administration as salts when there is a C0 2 H group present such as in the glucuronic acid residue mentioned above. This can be converted to CO 2 M. where M is a metal, especially an alkali metal such as sodium or potassium.
• M is a metal, especially an alkali metal such as sodium or potassium.
• the glucuronic acid residue also helps solubility of the compound.
• the flavonoid would normally be present in such an amount so as to potentiate the action of the antibiotic, so that the combination is synergistic in the treatment of microbial infections.
• suitable compositions include those in which the ratio of flavonoid to antibiotic is in the range of from 2:1 to 1 :25 by weight (this might also be expressed as 'from 1 :0.5 to 1:25 by weight'), preferably from 1 :1 to 1 :25 by weight.
• the flavonoid may be present in such an amount so as to give plasma concentrations in the range of 0.1-100 ⁇ g mL "1 , preferably 1-10 ⁇ g mL "1 .
• the antibiotic may be effective against fungi, protozoa or viruses, but preferably the antibiotic is an antibacterial agent.
• the term 'antibiotic' is intended to include synthetic agents such as 4-quinolones, a family of antibacterial agents including ciprofloxacin.
• Other suitable antibiotics may comprise aminoglycosides and tetracyclines, but a ⁇ -lactam antibiotic is especially preferred.
• Suitable ⁇ -lactam antibiotics include penicillins (including penicillin G, penicillin V and others), methicillin, ampicillin, cefotaxime, amoxicillin, cloxacillin. cefoperazone and piperacillin.
• compositions of the present invention may comprise other ingredients. Mention may be made of inter alia antimicrobial agents, viscosity adjusting agents, osmolarity adjusting agents, buffers. pH adjusting agents, flavourings, stabilisers, colourings, preservatives, solubilisers and the like. Delayed release or controlled release formulations are also included in the present invention.
• compositions of the present invention may be formulated for administration by any suitable means. Particular mention may be made of oral, enteral, parenteral, subcutaneous and nasal routes of administration.
• the compositions may be prepared as a spray, solution, suspension, colloid, concentrate, powder, granules, tablets, pressed tablets, capsules (included coated and uncoated tablets and capsules), suppositories and the like. Delayed release or controlled release formulations are also included.
• compositions will be sterile and suitable for medical use.
• the present invention provides the use of a flavonoid of formula:
• R d and R e represents independently hydrogen or a group OZ;
• Z is hydrogen, lower alkyl, a glycosyl group or a leaving group which in vivo is transformed into a hydrogen group; and
• X and Y are each hydrogen or X and Y together represent a double bond; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for combating microbial infection, said medicament comprising an antibiotic.
• the flavonoid would normally be used in such an amount so as to potentiate the action of the antibiotic, so that the combination is synergistic in the treatment of microbial infections.
• suitable compositions include those in which the ratio of flavonoid to antibiotic is in the range of from 2:1 to 1 :25 by weight.
• the flavonoid may be present in such an amount so as to give plasma concentrations in the range of 0.1-100 ⁇ g mL "1 , preferably 1-10 ⁇ g mL "1 . It will be appreciated that the ranges may also be expressed as '0.1-100 mg L "1 , preferably 1-10 mg L "1 '.
• the antibiotic may be effective against fungi, protozoa or viruses, but preferably the antibiotic is an antibacterial agent.
• the term 'antibiotic' is intended to include synthetic agents such as 4-quinolones. a family of antibacterial agents including ciprofloxacin.
• Other suitable antibiotics may comprise aminoglycosides and tetracyclines, but a ⁇ -lactam antibiotic is especially preferred.
• Suitable ⁇ -lactam antibiotics penicillins (including penicillin G, penicillin V and others), methicillin, ampicillin. cefotaxime, amoxicillin, cloxacillin. cefoperazone and piperacillin.
• the flavonoid compound and antibiotic it is not essential, although it may be convenient, for the flavonoid compound and antibiotic to be mixed together and administered in a single formulation. Simultaneous or sequential administration of two separate formulations is also suitable and falls within the scope of the invention. Optionally, where two separate formulations are to be administered each formulation may be administered by a different route.
• the composition of the present invention is particularly useful in treating or preventing bacterial infections or infections by other micro-organisms which are at least partially resistant to treatment by a ⁇ -lactam antibiotic alone. However, the composition of the present invention may also be used to treat any microbial infection and may be used to prevent further spread of resistance to ⁇ -lactam antibiotics.
• the present invention is particularly useful against ⁇ -lactam resistant bacteria such as Staphylococcus spp., in particular Staphylococcus aureus.
• baicalin in antimicrobial tests, the results obtained showed that baicalin, baicalein, apigenin, galangin and others significantly enhanced the activity of ⁇ -lactams against MRSA.
• baicalein as the example, the following results were obtained. MICs were reduced from 125 to 4 ⁇ g mL "1 for methicillin, 125 to 4 ⁇ g mL “1 for cefotaxime, 250 to 8 ⁇ g mL "1 for ampicillin and 250 to 16 ⁇ g mL "1 for penicillin G. The compound also significantly enhanced the activity of penicillin G and ampicillin against penicillin- resistant S.
• 16 ⁇ g mL "1 of baicalin reduced the MIC of ampicillin to 8 ⁇ g mL "1 .
• 16 ⁇ g mL “ 1 of baicalin reduced the MIC of methicillin to 4 ⁇ g mL "1 against MRS A respectively.
• aureus 9968 cells in 4 h (Figs. 6 and 7). Furthermore, ampicillin at 12.5 ⁇ g mL "1 was active enough to kill 99.9% of S. aureus 1 1561 cells in 4 hours in combination with baicalin. Penicillin G in combination with baicalin also showed similar bactericidal activity to ampicillin against S. aureus 1 1561 even though it was slightly less at the concentration of 12.5 ⁇ g mL *1 but greater at 50 ⁇ g mL "1 than the corresponding concentrations of ampicillin.
• baicalin combined with ⁇ -lactams had significant synergistic activity.
• the role played by baicalin as an enhancer of ⁇ -lactams was found to be strong enough to inhibit and to kill MRSA and/or penicillin- resistant Staphylococcus aureus at a relatively low ranges of concentrations (2 to 16 ⁇ g mL "1 ) in vitro. This concentration was regarded as being a breakpoint for clinical susceptibility (Livermore, D. M., 1993).
• baicalin baicalein is a main constituent of the Chinese herb Huangqin with a content as high as 4% (Chinese Pharmacopoeia Committee 1985). This herb has been in use for more than one thousand years in China and Japan (Huang. H-C, el al. 1994) with no toxicity recorded in the literature (Chinese Pharmacopoeia Committee 1985). Literature reports indicate that oral administration of aqueous extract of the herb 4 or 5 g kg "1 to dogs thrice daily for 8 weeks did not produce any significant abnormalities in the routine blood tests and histology of internal organs.
• baicalin has a wide range of bioactivity such as aldose-reductase inhibitory, anti-inflammatory, antiallergic (Williamson, E. M. and Evans, F. J. 1988) and anti- anaphylactic activity (Abe, K-I. Inoue, O.. and Yumioka, E., 1990).
• the anti-thrombotic activity Harborne. J. and Baxer. H.
• the present invention also provides the use of a medicament containing a flavonoid of the above formula, or a pharmaceutically acceptable salt thereof, and an antibiotic to combat a microbial infection.
• the invention further provides a method of treatment of a microbial infection by administering a medicament containing a flavonoid of the above formula, or a pharmaceutically acceptable salt thereof, and an antibiotic to a patient afflicted with such an infection.
• Fig. 1 shows the potentiation of ⁇ -lactams selected from penicillin G, ampicillin, cefotaxime and methicillin by baicalin against methicillin-resistant Staphylococcus aureus NCTC 11940 (Fig. la), penicillin-resistant NCTC 11561 (Fig. 1 b) and penicillin-resistant NCTC 9968 (Fig. 1 c);
• Fig. 2 shows the effect of methicillin combined with baicalin on the viable counts of methicillin-resistant Staphylococcus aureus (NCTC 11940), the values plotted being the means of 4 observations, and the vertical bars indicating the standard errors of the means;
• Fig. 3 shows the effect of cefotaxime combined with baicalin on the viable counts of methicillin-resistant Staphylococcus aureus (NCTC 11940), the values plotted being the means of 4 observations, and the vertical bars indicating the standard errors of the means;
• Fig. 4 shows the effect of ampicillin combined with baicalin on the viable counts of methicillin-resistant Staphylococcus aureus (NCTC 11940), the values plotted being the means of 4 observations, and the vertical bars indicate the standard errors of the means;
• Fig. 5 shows the effect of penicillin G combined with baicalin on the viable counts of penicillin-resistant Staphylococcus aureus (NCTC 9968), the values plotted being the means of 4 observations, and the vertical bars indicating the standard errors of the means;
• Fig. 6 shows the effect of ampicillin combined with baicalin on the viable counts of penicillin-resistant Staphylococcus aureus (NCTC 9968), the values plotted being the means of 4 observations, and the vertical bars indicating the standard errors of the means;
• Fig. 7 shows the effect of ampicillin combined with baicalin on the viable counts of penicillin-resistant Staphylococcus aureus (NCTC 1 1561), the values plotted being the means of 4 observations, and the vertical bars indicating the standard errors of the means; and
• Fig. 8 shows the effect of penicillin G combined with baicalin on the viable counts of penicillin-resistant Staphylococcus aureus (NCTC 11561), the values plotted being the means of 4 observations, and the vertical bars indicate the standard errors of the means.
• Example 1 Enhanced activity of ⁇ -lactams by baicalin against ⁇ -lactam-resistant Staphylococcus aureus
• NCTC 1 1940 and NCTC 11561 were obtained from The National Collection of Type Cultures. Colindale, London. Strain NCTC 9968 and NCTC 1 1561 are penicillin-resistant and the latter is also a ⁇ -lactamase producer. Strain NCTC 1 1940 is methicillin-resistant. ⁇ -Lactam antibiotics were obtained from Sigma, Poole. England. Iso-sensitestTM broth and agar, nutrient broth were obtained from Oxoid. Basingstoke. England. Ammonia solution (NH 4 OH) and lecithin were obtained from BDH, Poole, UK. TweenTM 80 was obtained from ICI, Leatherhead. UK. Microtiter plates were obtained from Bibby Sterilin Ltd., Stone. UK.
• the subcultures of the organisms to be tested were incubated in 20 mL of Iso-sensitestTM broth for 18 hours at 37 °C.
• the cell cultures were centrifuged and the cell pellets were washed with saline, recentrifuged, and resuspended in saline.
• the cell concentrations were adjusted with saline using a spectrophotometer at 500 nm to contain 10 CFU mL " . This cell suspension was then diluted with double strength broth to 10 6 CFU mL "1 .
• MIC Determinations MIC determinations were carried out using a modified microtiter method according to that described in the literature (American National Standards Institute, 1991). Test solution, 100 ⁇ L, was added to the first row of wells then two-fold serial dilutions were performed by transferring 50 ⁇ L with a microtiter pipette to the wells of the next row containing 50 ⁇ L of sterile water and so on until the seventh row. A 50 ⁇ L inoculum (10 6 cells mL "1 in double strength medium) was inoculated into each of the wells of the plates. The final concentration of the inoculum in all the wells was 5 x lO 3 cells mL "1 .
• the plates were covered with a plastic cover and then incubated at 37 °C for 18 hours.
• the microdilution plates were examined from below with a reflective viewer or read visually from the top. The MIC was taken as the lowest concentration of chemical at which the micro-organism tested did not show visible growth. Controls were performed using the corresponding concentrations of solvents.
• Dilution for solution B was carried out by the same method but beginning with the first row along the y-axis and continuing until the last row. Above dilutions of A and B in the microtiter plates were combined by transferring the dilution in each well of plate (B) to the well at the same column and row of plate (A) respectively to make a checkerboard, and duplicate plates were made.
• the inoculum (10 6 cells mL "1 in double strength medium) of 50 ⁇ L was inoculated into each of the wells. The final concentration of the inoculum in all the wells was 5 x 10 3 cells mL "1 . To prevent drying, the plates were covered with a plastic cover and then incubated at 37 °C for 18 hours. The microtiter plates were examined and MICs noted following the procedure described in MIC determinations.
• Viable cell counting was performed as previously described (Richards. R. M. E. and Xing. D. K. L. 1993) with modification. Compounds in test solutions were diluted alone or in combination with sterile water to the concentrations to be tested respectively. Cell suspensions of organisms obtained as described earlier were diluted with double strength medium to 10 6 cells mL "1 . A solution of 100 ⁇ L of each chemical singly or in combination was mixed with 100 ⁇ L of cell suspension in the first row of a microtiter plate to yield final concentrations of 5 x 10 3 cells mL "1 . At contact time of 0, 0.5.
• Baicalin was found active against all the strains of S. aureus with MICs of 64 ⁇ g mL " Overall, the MIC of baicalin did not differ among the Staphylococcus test strains whether they were susceptible or resistant to the ⁇ -lactams.
• MRSA methicillin-resistant strain of Staphylococcus aureus
• Baicalin at 16 ⁇ g mL "1 enhanced the activity of methicillin against MRSA (NCTC 11940), reducing the MIC of methicillin from 125 to 4 ⁇ g mL "1 .
• Baicalin at the same concentration also enhanced the activity of other ⁇ -lactams against MRSA, reducing the MIC of cefotaxime from 125 to 4 ⁇ g mL "1 , of ampicillin from 250 to 8 ⁇ g m "1 of baicalin with penicillin reduced the MIC of penicillin from 125 to 4 ⁇ g mL "1 against S. aureus 9968 and from 250 to 16 ⁇ g mL "1 against S. aureus 1 1561.
• Fig. 1 shows the synergistic activity for all the concentrations of the combinations of baicalin and ⁇ -lactams tested. A decrease of MICs for ⁇ -lactams is clearly indicated with the increase in the concentration of baicalin in the combination.
• Viable counts of MRSA were not only reduced from 5 x 10 3 to below 10 3 CFU mL "1 in 6 hours but also maintained under the detectable limit of 10 3 CFU mL "1 over 24 hours by 25 ⁇ g mL " of baicalin combined with 12.5 or 50 ⁇ g mL '1 of cefotaxime (Fig. 3).
• the same concentration of baicalin combined with ampicillin at 12.5 ⁇ g mL "1 reduced the viable counts of MRSA from 5 x 10 3 to 5 x 1 100 JJ CCFFUU mmLL ""11 oovveerr 66 hhoouurrss.. HHoowweevveerr,, tthhee counts recovered and increased to approximately 10 CFU mL "1 at 24 hours (Fig. 4).
• ampicillin at 50 or 12.5 ⁇ g mL "1 in combination with 25 ⁇ g mL "1 of baicalin reduced the viable counts of the bacteria from 5 x 10 3 to 10 J CFU mL "1 in 4 hours and continued to keep the counts under the detectable limit at 24 hours (Fig. 7).
• Bacterial strains, culture medium, antibiotics and microtiter plates were obtained from the same sources as those detailed in the Example 1.
• Clinical isolates of staphylococci ⁇ -lactamase producing, coagulase negative, 426805 and 426895
• Cloxacillin- resistant MRSA was induced by the following method.
• Methicillin-resistant Staphylococcus aureus 1 1940 was tested for MIC of cloxacillin and then subcultured with Iso-sensitestTM broth containing one half of the MIC of cloxacillin at 32 °C.
• the grown inoculum was cultured in the fresh media containing various concentrations of cloxacillin.
• the bacteria grown in culture containing the highest concentration of cloxacillin were subcultured in the higher concentrations of cloxacillin respectively. This process was repeated for about ten generations till the MIC of cloxacillin against the strain reached 1000 ⁇ g/mL.
• the flavonoids were purchased from Aldrich, Lancaster Synthesis or Sigma. Ammonia solution (NH OH) was obtained from Koch-Light Laboratory Ltd., Colinbrook. Berks., England. Dimethyiformamide (DMF) was obtained from Hopkin & Williams. Chadwell Heath, Essex. England.
• the cell cultures were centrifuged and the cell pellets were washed with saline, recentrifuged, and resuspended in saline.
• the cell concentrations were adjusted with saline under a spectrophotometer at 500 nm to a concentration of 10 CFU mL •
• This cell suspension was then diluted with double strength broth to 5 x 10 3 CFU mL " '.
• Calibration curves of absorbency readings versus colony counts of inoculum suspensions for each of the organisms had previously been plotted according to the method described in the literature (Richards, R. M. E. and Xing, D. K. L. 1993) to ensure the final CFU values were valid.
• MIC determination was carried out with a microtiter method according to a modification of that described in the literature (American National Standards Institute, 1991). Antibiotic application solution of 100 ⁇ L was added to the first row of wells then two-fold serial dilutions were performed by transferring 50 ⁇ L sequential dilutions with a microtiter pipette to the wells of the next row containing 50 ⁇ L of sterile water till the eleventh row. The inoculum (5 x 10 " cells mL in double strength medium containing 50 ⁇ g mL " flavonoid) of 50 ⁇ L was inoculated to each of the wells on the plates.
• the final concentration of the inoculum in all the wells was 2.5 x 10 " mL and the final concentration of flavonoid was 25 ⁇ g mL "1 or as otherwise specified.
• the plates were covered with a plastic cover and then incubated at 32 °C for 24 hours for MRSA (Hewitt, J. H. et al. 1969) and 37 °C for the rest of the strains.
• microdilution plates were examined from below with a reflective viewer or read visually from the top.
• the endpoint of MIC was taken as the lowest concentration of chemical at which the micro-organism tested did not show visible growth. Controls were set using corresponding solvents and water.
• R 3 OH.
• clavulanic acid when tested against MRSA reduced the MICs from 149-354 ⁇ g mL "1 to 106 ⁇ g mL "1 for cefotaxime and methicillin, and to 11 and 23 ⁇ g mL "1 for amoxicillin and ampicillin.
• This evidence suggested that the most active flavonoids tested, such as galangin (13) and luteolin (10), had several hundred times stronger activity than clavulanic acid in enhancing the activity of ⁇ -lactams against MRSA.
• the order of potency for the flavonoids was galangin (13) > luteolin (10) > apigenin (9) > 3',4',7,8-tetrahydroxyflavone (11) > baicalein (6) > baicalin (7).
• Other flavonoids such as kaempferol (14), quercetin (15), morin (16), myricetin (17) and taxifolin (20) showed some activity.
• Table 4 Minimum inhibitory concentration (MIC* ⁇ g mL "1 ) of ⁇ -lactams used alone and in combination with clavulanic acid (25 ⁇ g mL "1 ) and flavonoids (25 ⁇ g mL "1 ) against methicillin-resistant Staphylococcus aureus NCTC 11940
• Galangin, apigenin and baicalein also enhanced the activity of cloxacillin and penicillin V against cloxacillin-resistant MRSA 1 1940 by bringing down the MICs up to more than a thousand times (Table 11).
• Table 1 1 Minimum inhibitory concentrations (MICs) of ⁇ -lactams in combination with flavonoids against cloxacillin-resistant MRSA (induced from NCTC 11940)

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