Safe and effective beta-lactamase dosing for microbiome protection

1. A method of protecting a human patient's gastrointestinal microbiome, comprising administering an effective amount of a pharmaceutical composition comprising a beta-lactamase to a patient in need thereof, wherein:

the patient is undergoing treatment or has recently undergone treatment with a beta-lactam antibiotic, optionally selected from a penicillin and a cephalosporin;

the patient is undergoing treatment with a proton pump inhibitor, wherein the proton pump inhibitor is esomeprazole;

the beta-lactamase comprises the amino acid sequence of SEQ ID NO: 1 and

the amount of beta-lactamase is 75 mg or 150 mg.

2. The method of claim 1 , wherein the beta-lactam antibiotic is a penicillin.

3. The method of claim 1 , wherein the beta-lactam antibiotic is a cephalosporin.

4. The method of claim 1 , wherein the beta-lactam antibiotic and beta-lactamase are administered simultaneously.

5. The method of claim 1 , wherein the beta-lactam antibiotic and beta-lactamase are administered sequentially.

6. The method of claim 1 , wherein the beta-lactamase is administered orally.

7. The method of claim 1 , wherein the beta-lactam antibiotic is administered parenterally, optionally selected from intravenously and/or by infusion.

8. The method of claim 1 , wherein the protection of the patient's microbiome comprises treatment or prevention of a microbiome-mediated disorder selected from an antibiotic-induced adverse effect, C. difficile infection, and a C. difficile -associated disease.

9. The method of claim 8 , wherein the antibiotic-induced adverse effect and/or CDI or C. difficile -associated disease is one or more of: antibiotic-associated diarrhea, C. difficile diarrhea (CDD), C. difficile intestinal inflammatory disease, colitis, pseudomembranous colitis, fever, abdominal pain, dehydration and disturbances in electrolytes, megacolon, peritonitis, and perforation and/or rupture of the colon.

10. The method of claim 1 , wherein the protection of the patient's microbiome comprises maintenance of a normal intestinal microbiota selected from a healthy microbiota balance and a healthy ratio or distribution.

11. The method of claim 1 , wherein the pharmaceutical composition comprising the beta-lactamase administered to the patient is in the form of an enteric-coated pellet or capsule.

12. The method of claim 11 , wherein the enteric-coated pellet or capsule is a delayed-release capsule.

13. The method of claim 1 , wherein the pharmaceutical composition comprising the beta-lactamase is administered to the patient at between 1 to 4 doses per day.

14. The method of claim 13 , wherein the pharmaceutical composition comprising the beta-lactamase is administered to the patient for between 4 and 7 consecutive days.

15. The method of claim 11 , wherein the enteric-coated pellet or capsule further comprises a sucrose sphere.

16. The method of claim 1 , wherein the method comprises administering one or more enteric-coated pellets or capsules comprising:

10-20% by weight of the beta-lactamase;

15-25% by weight of a sucrose sphere;

25-35% by weight of a binder excipient;

10-25% by weight of an enteric polymer;

1.5-2.5% by weight of a plasticizer;

0.5-1.5% by weight of a glidant;

0.1-1.0% by weight of an emulsifier; and

1-2% by weight of buffer salts;

wherein the amount of beta-lactamase is 25 mg or 75 mg, and wherein the total amount of beta-lactamase administered is 75 mg or 150 mg.

17. The method of claim 16 , wherein the one or more enteric-coated pellets or capsules comprise:

15.8% by weight of the beta-lactamase;

23.3% by weight of the sucrose sphere;

35% by weight of the binder excipient;

20.8% by weight of the enteric polymer;

2.1% by weight of the plasticizer;

1.0% by weight of the glidant;

0.4% by weight of the emulsifier; and

1.6% by weight of the buffer salts.

18. The method of claim 17 , wherein the binder excipient is hydroxypropylcellulose, the enteric polymer is EUDRAGIT L 30 D-55 (poly(methacrylic acid, methylmethacrylate), the weight plasticizer is triethyl citrate, the glidant is glyceryl monostearate, and the emulsifier is polysorbate-80.