Beta lactam antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives, cephalosporins and cephamycins, monobactams, carbapenems.

1. Beta Lactam Antibiotics Dr Mohit Kher Assistant Professor Pharmacology, ESIC

2. Antimicrobial agents Antibiotics Antivirals Antifungals Antiparasitic

3. Antibiotics

4. Beta Lactamase Inhibitors Amoxicillin is combined with clavulanic acid (Co- amoxy - clav ) Ampicillin is combined with sulbactam ( Sultamicin ) Piperacillin is combined with tazobactam Ceftazidime-avibactam combination is approved for complicated UTI (including pyelonephritis) and complicated intra-abdominal infections Meropenem- vaborbactam is a new combination approved for complicated UTI

5. PENICILLIN First Antibiotic to be used clinically Obtained from a fungus: Penicillium notatum Bacteriocidal drug MOA: Inhibit transpeptidase enzyme

6. Antibiotic Spectrum

7. Penicillin-G Oldest drug Other name: Benzyl penicillin Not used now commonly Problems with the drug: - Acid labile - Short acting drug - Resistance developed (penicillinase and beta-lactamase strains) - Narrow spectrum - Allergic reactions: Jarisch Herxheimer reaction

8. Penicillin-G is DOC for: B: Bacillus (Anthrax) L: Leptospira (Rat bite fever) A: Actinomyces S: Streptococcus T: Treponema pallidum (Syphilis) P: Pertunae (Yaws), Pasteurella multocida G: Gas gangrene

9. Newer Penicillin designed to overcome shortcomings Acid resistant Penicillin: Penicillin V, oxacillin, dicloxacillin, cloxacillin, amoxycillin and ampicillin. Benzathine and procaine group can be added to penicillin G to make it long acting. Probenecid can be administered with penicillins . Former inhibits the tubular secretion.

10. Recommended treatment for syphilis

11. Semi-Synthetic Penicillin

12. Anti-pseudomonal Penicillin C: Carbenicillin T: Ticarcillin M: Mezlocillin A: Azlocillin P: Piperacillin

13. Acid Resistant Penicillin Penicillin-V ( Phenoxymethyl Penicillin) Oral absorption is better But spectrum is just same as penicillin-G (Narrow spectrum: Mostly gram positive) It can not be dependent for more serious infections USES: Pharyngitis, sinusitis, otitis media, rheumatic fever

14. Aminopenicillins Ampicillin Prodrugs: Amoxicillin, Bacampicillin Active against all gram positive and many gram negative bacilli Eg. H. influenzae, E.coli, Proteus, Salmonella, Shigella & H. pylori Amoxycillin: More active, Better oral absorption Becampicillin : Less used now Acid resistant, penicillinase resistant But Beta-lactamase sensitive

15. USES Meningitis RTI Typhoid fever Bacillary Dysentry Cholecystitis Inhibits H.pylori UTI Gonorrhoea

16. Carboxypenicillins Carbenicillin Active against pseudomonas aeruginosa A/E: Fluid retention, CHF Ticarcillin Active against pseudomonas & proteus Less A/E

17. Ureidopenicillins Piperacillin Active against pseudomonas 8 times more active than carbenicillin

18. Resistance to Penicillins Beta lactamase production Alteration of penicillin binding protein (PBP) Decreased Porin production Drug efflux

19. Cephalosporins Obtained from fungus cephalosporium Bactericidal Same MOA as penicillin

20. Cephalosporins Spectrum

21. Cephalosporin Classification

22. Cephamycin (2nd generation): Cefoxitin Cefotetan Cefmetazole Cephamycin is effective against anaerobic bacteria (Bacteroides fragilis).

23. Cephalosporins secreted in bile Safe in Renal Failure : Cefoperazone Ceftriaxone

24. Anti-pseudomonal Cephalosporins Cefe p ime Cef p irome Cefo p erazone Ceftazidime (Most effective )

25. Decrease prothrombin time & Disulfiram like reaction Moxolactam Cefoperazone Cefotetan Cefomandole

26. USES Spectrum cover wide range of gram positive and gram negative bacteria. ENT, URTI, cutaneous infections: Alternative to penicillins DOC in: Typhoid Meningitis Septicemia Gonorrhea

27. Meningitis treatment Meningococcus → DOC: Penicillin-G → Resistance → Ceftriaxone Pneumococci → DOC: Penicillin-G → Resistance → Ceftriaxone + Vancomycin

28. Carbapenems Wide spectrum: Gram positive cocci, gram negative rods, pseudomonas as well as anaerobes. Imipenem is rapidly inactivated by renal dehydropeptidase I , so it is combined with cilastatin , an inhibitor of this enzyme. Cilastatin increases the half life of imipenem and also inhibits the formation of nephrotoxic metabolite. A/E: Seizures & GI distress

29. Other drugs (less likely to cause seizure): Do not require to combine with cilastatin Meropenem Ertapenem (very long acting) Doripenem Faropenem (oral)

30. All carbapenems are injectable ( Except faropenem , orally ) Carbapenems are β-lactamase resistant and are drug of choice for Enterobacter, Klebsiella and Acinetobacter species. Only β-lactams which are reliably efficacious against ESBL .

31. Drugs used in Typhoid Ceftriaxone: Injectable DOC Cefixime: Oral DOC Ciprofloxacin: DOC for carriers Cotrimoxazole/Amoxicillin/Ampicillin/Chloramphenicol: Widespread resistance

32. MONOBACTAMS Aztreonam Only effective against gram negative & pseudomonas Do not show any cross allergy Indications: Hospital acquired infections originating from urinary, biliary, GI and female genital tracts. S/E: Rashes & raised liver enzymes Only beta lactam antibiotic that can be used in patients having severe allergy to penicillin or cephalosporins.

33. Miscellaneous points Bactericidal drugs kill the bacteria whereas bacteriostatic drugs only inhibits bacterial growth. Bacteriostatic activity is adequate for the treatment of most infections, bactericidal activity may be necessary for cure in patients with altered immune systems like: neutropenias , HIV and other immunosuppressive conditions. Vancomycin resistance occurs due to altered binding site whose structure changes from Alanine-Alanine to Alanine-Lactate. Methicillin resistance occurs due to altered PBPs.

34. Combination of a bactericidal (ampicillin) and a bacteriostatic drug (chloramphenicol) is usually antagonistic in nature. This is because cidal drugs are usually acting on a fast multiplying organisms whereas static drugs decrease this multiplication. Beta lactamase break this ring between N and C=O group and can result in resistance. Beta lactamases are encoded by plasmids that can be transferred with the help of bacteriophage (transduction) in staphylococci and by transformation in Pneumococci.

35. Cefotaxime or amoxicillin-clavulanic acid and azithromycin : Effective in H. influenza infections. Cefuroxime has good CSF penetration. It can be used for meningitis, however ceftriaxone is superior. Cefuroxime is not effective against anaerobes. Fifth generation cephalosporins ( ceftobiprole and ceftaroline ) are the only beta-lactams active against MRSA.

36. Penicillins increase the bactericidal activity of aminoglycosides. Combination of penicillins /cephalosporins and aminoglycosides is the treatment of choice for pseudomonas infections. Meningococcal meningitis: DOC: Penicillin-G Empirical treatment: Ceftriaxone The only acceptable treatment for syphilis in pregnancy is penicillin. In penicillin allergy patients, DOC is doxycycline but it is C/I in pregnancy. Therefore, desensitization is done and penicillin is given.

37. Antibiotics Used in Empirical Therapy of Bacterial Meningitis and Focal CNS Infections

38. Frequent cause of mastitis is Staphylococcus aureus which may be penicillinase producing. Therefore, penicillinase resistant penicillins like cloxacillin are preferred for treatment of mastitis. Enterococcal endocarditis: DOC: Ampicillin + Gentamicin → if history of allergy → Vancomycin + Gentamicin

39. Extended spectrum beta-lactamases (ESBL) Beta-lactamases that breaks down: 3 Rd generation cephalosporins and monobactams DOC in ESBL: Carbapenems 2 nd gen is preferred over 4 th gen cephalosporins Beta lactams + beta lactamase inhibitors

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41. Glycopeptides Vancomycin is DOC for: MRSA Corynebacterium jeikeium Serious infections in penicillin allergic patients Rapid i.v. infusion of high doses of vancomycin can cause RED MAN SYNDROME. Vancomycin is used ORALLY to treat pseudomembranous colitis.