Beta lactam antibiotics - penicillins

penicillins history ,chemistry ,classification ,dosage level ,limitation and adverse affects and general treatment algorithm for bacterial infection .

1. Beta- Lactam Antibiotics PENICILLINS Ashok kumar A I - MDS Dept of Orthodontics

2. Antibiotics Greek words anti = against ; bios = life Antibiotics are the substances produced by microorganisms , which suppress the growth or kill microorganisms at very low concentrations.

3. Beta- Lactam Antibiotics Inhibit the cell wall synthesis - bactericidal drugs

4. PENICILINS - History 1928-Alexander Fleming 1938-Florey & Chain 1941- Antibiotic first used clinically 1945-Noble Price

5. Classification Natural - penicilin G Semisynthetic - 1)Acid-resistant - Phenoxymethyl penicillin (Penicillin V). 2) Penicillinase -resistant - Methicillin , Cloxacillin . Extended spectrum penicillins 3) Aminopenicillins : Ampicillin , Bacampicillin , Amoxicillin. 4) Carboxypenicillins : Carbenicillin , Ticarcillin . 5) Ureidopenicillins : Piperacillin , Mezlocillin . β- lactamase inhibitors Clavulanic acid, Sulbactam , Tazobactam .

6. Mechanism of action

7. Chemistry of Penicilins PnG is highly water soluble , thermo labile and acid labile. It is stable in the dry state, but solution deteriorates rapidly at room temperature, though remains stable at 4°C for 3 days. Therefore, PnG solutions are always prepared freshly. 1 U of crystalline sod. benzyl penicillin = 0.6 μg of the standard preparation. 1 g = 1.6 million units or 1 MU = 0.6 g.

8. Penicillin G (Benzyl Penicillin) Antibacterial spectrum – Penicillin G ( PnG ) has a narrow antibacterial spectrum and is effective against gram-positive cocci and bacilli and a few gram-negative cocci . Resistance – 1) Many organisms like staphylococci produce a penicillinase which is a beta- lactamase ,which opens the β lactam ring and inactivates penicillins . 2) Altered target proteins on the bacterial cell which reduces affinity for penicillins also lead to resistance.

9. Preparations and dose PnG is mainly given parenterally ,though orally effective form-potassium PnG is also available. Benzyl penicillin is short-acting, repository forms like procaine penicillin and benzathine penicillin, which are longer-acting are made available. Given deep IM they release penicillin slowly from the site. Procaine penicillin is given 12-24 hourly while a single injection of benzathine penicillin is effective for 3-4 weeks

10. General Medical Uses a. Streptococcal infections: pharyngitis , tonsillitis , otitis media, rheumatic fever, etc. b. Meningococcal meningitis and other infections. c. Pneumococcal infections only if the infecting strain is found to be sensitive to PnG . d. Syphilis: benzathine penicillin is the drug of choice for all stages because T.pallidum has not developed penicillin resistance. e. Diphtheria , tetanus and other infections like gas gangrene, anthrax, actinomycosis .

11. Dental infections Sequelae of carious lesions and are caused by both aerobic and anaerobic bacteria such as Streptococci, Peptostreptococci , Eubacterium , Prevotella , Porphyromonas , Fusobacterium . It can be used for periodontal abscess, periapical abscess, pericoronitis, acute suppurative pulpitis, ANUG, oral cellulitis , also be employed prophylactically . In dental practice, use of PnG is very much restricted now

12. Prophylactic uses of PnG To prevent recurrence of rheumatic fever : benzathine penicillin is the preparation of choice. To protect agranulocytosis patients (an aminoglycoside may be given in combination). Gonorrhoea and syphilis - Sexual contacts are effectively protected against these diseases when treated with penicillin within 12 hours of exposure. In Valvular heart diseases - 25% cases of bacterial endocarditis are seen following dental extractions. Surgical prophylaxis (in combination with gentamicin ).

13. Adverse effects 1.Anaphylaxis (in approximately 1 in 100 000 injections); 2. Rashes (3–5% of patients) can, rarely, be severe ( e.g. Stevens Johnson syndrome , Jarisch-Herxheimer reaction) 3. Serum sickness – type III hypersensitivity; 4. I diosyncratic reactions including haemolytic anaemia and thrombocytopenia ; 5. In renal failure, high-dose penicillin causes encephalopathy and seizures.

14. History of allergy to penicillins should be taken before prescribing; incidence of allergy is higher among atopic individuals. A scratch test or intradermal sensitivity test with 2-10 units should be done. Even if this is negative, it does not completely rule out allergy. Penicillin should be given cautiously and a syringe loaded with adrenaline to treat anaphylaxis should be kept ready.

15. Limitations of benzyl penicillin include: 1. It is acid labile and so must be given parenterally (inactivated in gastric acid). 2. It has a short half-life, so frequent injections are required . 3. Development of resistant β- lactamase -producing strains can occur. 4. It has a narrow antibacterial spectrum . 5.Hypersensitivity reactions .

16. Procaine benzylpenicillin – This complex releases penicillin slowly from an intramuscular site, so a twice daily dosage only is required . Phenoxymethylpenicillin (‘penicillin V’) – A cid stable and so is effective when given orally ( 40–60% absorption ). Although it is useful for mild infections, blood concentrations are variable, so it is not used in serious infections or with poorly sensitive bacteria. Tablets are given on an empty stomach to improve absorption.

17. β- LACTAMASE-RESISTANT PENICILLIN Flucloxacillin was developed to overcome β- lactamase -producing strains. . It is effective against β- lactamase -producing organisms . It is used for the treatment of staphylococcal infections (90 % of hospital staphylococci are resistant to benzylpenicillin and 5–10% are resistant to flucloxacillin ).

18. EXTENDED-RANGE PENICILLINS Uses Haemophilus influenzae , E. coli, Streptococcus faecalis and Salmonella . They are used for a variety of chest infections ( e.g. bronchitis , pneumonia), otitis media, urinary tract infections, biliary infections and the prevention of bacterial endocarditis ( amoxicillin ). Amoxicillin is somewhat more potent than ampicillin , penetrates tissues better and is given three rather than four times daily . Both are susceptible to β- lactamases .

19. Adverse effects Diarrhea Rashes are common and may appear after dosing has stopped. There is an especially high incidence in patients with infectious mononucleosis or lymphatic leukaemia . Pharmacokinetics The half-life of each drug is about 1.5 hours and they are predominantly renally excreted . Probenecid blocks the renal tubular secretion

20. Beta- Lactamase Inhibitors It extends the antibacterial spectrum of amoxicillin and the combination inhibits organisms like betalactamase producing staphylococci, gonococci , E.coli and H. influenzae . The combination is used for mixed aerobic anaerobic infections including oro dental infections , gonorrhoea and nosocomial infections . Adverse effects are similar to those of amoxicillin, but abdominal discomfort is more common.

21. ANTIPSEUDOMONAL PENICILLINS Pseudomonas infection is important in neutropenic patients (e.g. those undergoing cancer chemotherapy) and in patients with cystic fibrosis . - Piperacillin , - Azlocillin - Ticarcillin .

22. Uses These expensive intravenous penicillins are not used routinely. They are useful against Gram-negative infections, particularly with Pseudomonas and they are also effective against many anaerobes. These drugs have a synergistic effect when combined with aminoglycosides in Pseudomonas septicaemias . Combinations of ticarcillin or of piperacillin with β- lactamase inhibitors designed to overcome the problem of β- lactamase formation by Pseudomonas are commercially available.

23. Adverse effects These drugs predispose to super infection . Rashes , sodium overload, thrombocytopenia and platelet dysfunction can occur Pharmacokinetics Absorption of these drugs from the gut is inadequate in the life-threatening infections for which they are mainly indicated. They are given intravenously every 4–6 hours. Their half-lives range from 1 to 1.5 hours and they are renally excreted.