Penicillins Dr Reshmi Sameeth MBBS MD MBA Beta

+ Penicillins Dr. Reshmi Sameeth MBBS MD MBA

Beta lactams Penicillins Cephalosporins Monobactams Carbapenems

HISTORY

Penicillium notatum

STRUCTURE BETALACTAM RING

+ Mechanism of Action Cell wall synthesis inhibition

+ MOA n Cell wall synthesis inhibitors n Cell wall deficient forms produced n Hyperosmotic bacterium swell burst n BACTERICIDAL

+ Bacterial Cell Wall n Cell wall- Stability n Composed of Peptidoglycan layer

Peptidoglycan layer Parallel polysaccharide glycan chains crosslinked by peptide chains Prevents lysis and death of bacteria

NAc. M L-Ala D-Glu L-Lys + D-ALa D-Ala Pentapeptide side chain L-alanyl-D-glutamyl-L-lysyl-D-alanine

+ n Pentaglycine bridge extends from Llysine residue of one peptide chain to Dalanine residue of another NAG

+ Transpeptidation Reaction n Process of cross bridging n Catalysed by enzymes Penicillin Binding Proteins(PBPs) n Provide strength to bacteria

N A G N A G Transpeptidase N A G

N A G N A G Beta Lactams Transpeptidase N A G

+ Classification of Penicillins Ø Narrow spectrum Penicillins Ø Extended spectrum Penicillins Ø Acid labile (Parenteral) Ø Acid stable(oral) Ø Beta lactamase resistant Ø Beta lactamase sesnsitive

+ Narrow spectrum Penicillins Classification Pharmacokinetics Spectrum Uses

Acid stable Penicillin V Acid labile Penicillin G Procaine Penicillin G Benzathine Penicillin G Beta lactamase sensitive (Natural Pns)

Acid stable Cloxacillin Dicloxacillin Flucloxacillin Beta lactamase resistant (Antistaphylococcal) Acid labile Methicillin Nafcillin

+ Pharmacokinetics: Natural Pns Pn V acid stable given orally Pn G acid labile given im/iv Procaine Pn G and benzathine Pn G prolonged half life Pn G excreted by kidneys tubular secretion Probenecid blocks tubular secretion prolong DOA

+ Pk : Antistaphylococcal Pns n Cloxacillin, Dicloxacillin Acid stable Given orally n Food interferes with their absorption n Given 1 hour before food n Methicillin, Nafcillin acid labile im/iv

Acid stable Beta lactamase sensitive (Natural Pns) Acid labile Penicillin V Penicillin G Procaine Penicillin G Benzathine Penicillin G Spectrum and uses Gram positive cocci Gram positive bacilli Spirochetes Gram negative cocci Actinomyctetes Gram negative bacilli Bacteroides

+ Gram positive cocci n Streptococcus pyogenes: Pharyngitis, otitis n Streptococcus Pneumoniae: Pneumonia n Enterococcus: SABE n A single injection of Benzathine Penicillin G(1. 2 M units im) is used for treating Rheumatic fever as it prevents colonisation of beta hemolytic streptococci

+ Gram positive bacilli n Penicillin G DOC for infections caused by Gram positive bacilli n Clostridium tetani: Tetanus n Clostridium Perfringes: Gas gangrene n Corynebacteria diphtheriae: Diphtheria n Bacillus Anthracis: Anthrax n Listeria monocytogenes: Meningitis, listeriosis

+ Spirochetes n Treponema pallidum: Syphilis n Benzathine Pn G 2. 4 million units once a week for 2 -3 weeks n Or n Procaine Pn G 1 M units everyday for 10 days

Cloxacillin Acid stable Dicloxacillin Flucloxacillin Beta lactamase resistant (Antistaphylococcal) Acid labile Methicillin Nafcillin Spectrum and uses Additional activity against Staphylococci Staphylococcus aureus resistant to Nafcillin and Cloxacillin MRSA

Extended Spectrum Penicillins All are beta lactamase sensitive + Classification Pharmacokinetics Spectrum and uses

Acid stable Aminopenicillins Ampicillin Bacampicillin Talampicillin Amoxycillin Acid labile Antipseudomonial penicillins Carbenicillin Ticarcillin Piperacillin Mezlocillin Azlocillin

+ Pharmacokinetics n 1 gm Penicillin equivlent to 1. 6 million units n Amoxycillin and ampicillin similar Pk n Both adequate oral BA n Food decreases BA of Ampicillin hence given 1 hr before or after meals n Ampicillin achieve therapeutic conc in CSF hence used in meningitis( Amoxycillin not used) n Bacampicillin, Talampicillin Prodrugs of Ampicillin

+ Pk cont: n Carbenicillin, Ticarcillin, Piperacillin, Mezlocillin, Azlocillin Parenteral Pn as sodium salts should be cautious when used in CHF n Carbenicillin indanyl sodium salt acid stable given orally n Primary Route of elimination Kidney n Mezlocillin Hepatic metabolism dose adjustment needed in liver diseases

+ Aminopenicillins: Spectrum and uses n Ampicillin Lyophilic Penetrate porin channels of gram negative bacteria extended spectrum against Gram negative bacteria n Gram negative bacilli covered by Ampicillin: n Bordetella pertusis : whooping cough n Haemophilus influenzae: pneumonia, otitis, sinusitis n E. coli: UTI n Salmonella typhi

+ Contd: n H. pylori infection : Amoxycillin n SABE Ampicillin 2 g iv every 6 hrs n Listeria meningitis: Ampicillin : DOC n Gentamicin + Ampicillin Synergistic combination

+ Antipseudomonal penicillins n Activity n Used against Pseudomonas and Proteus for serious infections like: burns, septicemia, immunocompromised patients

+ Penicillin Resistance Inactivation of betalactam ring by betalactamase Modification of PBP Reduced permeability due to mutation of porin channels Activation of efflux mechanism

+ Betalactamase inhibitors n Betalactamases: family of enzymes produced by many gram positive and negative bacteria that inactivate betalactam antibiotics by opening the betalactam ring. n Betalactamase inhibitors are agents which bind irreversibly to the catalytic sites of susceptible betalactamases to prevent hydrolysis of penicillins

Clavulanic acid Sulbactam Tazobactam

+ Clavulanic acid n Obtained from Streptomyces clavuligerus n Has a betalactam ring but no antibacterial action n Inhibits a variety of betalactamases n It gets inactivated after binding to enzyme called suicide inhibitor n Orally absorbed

+ Amoxycillin+ Clavulanic acid n Extended spectrum against betalactamase producing bacteria like: n Methicillin Sensitive staphylococcus aureus( MSSA), H. influenzae, N. Gonorrhoeae, Klebsiella , Salmonella, Shigella n Fixed dose combinations available: Amoxycillin 500 mg+ Clavulanic acid 125 mg

+ Sulbactam+ Ampicillin n Sulbactam Parenteral n Mixed aerobic anaerobic infections, Gonorrhaeae, intraabdominal and gynaecological infections n FDC Ampicillin 1 g + sulbactam 0. 5 g im/iv n AE: Thrombophlebitis

+ Tazobactam+ Piperacillin n PK of Tazobactam matches with Piperacillin n Used in severe infections like: peritonitis, pelvic/urinary tract infections n FDC: Piperacillin 2 g+ Tazobactam 0. 25 g iv /im

+ Adverse effects of Penicllins Hypersensitivity reactions GI side effects Miscellaneous Effects

+ n Urticaria n Diarrhoea n Anaphylaxis n Glossitis n Stomatitis n Oxacillin SGOT, SGPT elevated n Methicillin interstitial nephritis n Jarisch Herxheimer reaction syphilis patients fever, shivering. colloapse due to breakdown of spirochetes

+ Drug interactions n Penicillin+ Gentamicin Antagonistic n Inactivate each other should not be mixed in the same syringe

+ SUMMARY

+ Penicillin G n Commercially obtained from Penicillium chrysogenum n Limitations in clinical use: n Not effective orally n Short DOA because it is rapidly excreted by tubular secretion n Narrow spectrum (gram positive mailnly) n Resistant (betalactamase , Alternative PBPs) n Hypersensitivity reactions

+ Penicillin G Acid labile n Newer Pn Acid n Given Orally n These are: n Penicillin stable V n Oxacillin n Dicloxacillin n Cloxacillin n Amoxicillin and Ampicillin

+ Pn G Short DOA n. Newer Pn Long DOA n Benzathine and Procaine groups are added to make it long acting. Benzathine Pn G longest acting Pn n Pn have wide Therapeutic index hence high initial dose can be used n Probenecid added to Penicillin

+ Probenecid administered along with Penicillins increases DOA Probenecid inhibits tubular secretion of Penicillin Increases plasma concentration Prolongs half life of Penicillins

+ Pn G Narrow spectrum n New Penicillins Extended Spectrum Penicillins Aminopenicillins Carboxypenicillins Ureidopenicillins Ampicillin Amoxycillin Carbenicillin Ticarcillin Mezlocillin Azlocillin Piperacillin A CT MAP Carboxy and Ureidopenicillins CT MAP Pseudomonas