Penicillins PDF

7/8/2024 Beta-lactum antibiotics: 1  7/8/2024 β-Lactam Antibiotic have four classes Penicillins Cephalosporins Carbapenems Monobactams...

7/8/2024 Beta-lactum antibiotics: 1  7/8/2024 β-Lactam Antibiotic have four classes Penicillins Cephalosporins Carbapenems Monobactams A β-lactam (beta-lactam) ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl Why Called β-Lactam Antibiotics? 1.The presence of β-lactam ring 2.This ring can be cleaved by β-lactamase enzymes produced by bacteria 3.This class of antibiotics kill bacteria by inhibiting bacterial cell wall synthesis 2  7/8/2024 Beta-lactum antibiotics: Penicillins 3  7/8/2024 History 1928 : a Penicillium mold in a petri dish culture of staphylococci colonies -clear zone free of growth. 1929 : Alexander Fleming – Characterized penicillin 1940- penicillin isolated and develop systemic antibacterial agents 1945 : Cephalosporium acremonium was isolated from raw sewage. The first cephalosporin, cephalosporin C, was derived from this fungus. All other cephalosporins are semisynthetic antibiotic derivatives of cephalosporin C. Potency of penicillin: Units The international unit (IU) for penicillin = amount of activity present in 0.6 µg of the international pure crystalline standard sodium salt of penicillin G 1 IU= 0.6µg of Na-penicillin G 1 mg of sodium salt contains=(1000/0.06)= 1667 units (U). 1g Potassium salt is equal to= 1595 U 1g procaine= 1050 U 1g benzathine= 1272 U The dose of more recent β-lactam antibiotics (semisynthetic penicillin) is expressed in milligrams per unit of weight rather than in international units. 4  7/8/2024 Penicillins Obtained from fungus Penicillium notatum Active moiety of Penicillin structure is 6-Amino penicillanic acid (6- APA) Now-a-days 6-APA is produced from Penicillium chrysogenum (mold containing large amount of fungal amidases) Basic structure of penicillin Sulfur containing 5 member Thiazolidine ring (A) connected to a Beta – lactum ring (B) having secondary Amino grp (-NH) is 6 attached at 6 position Side chain (R) at position 6 β Active moiety of Penicillin structure is 6- Amino penicillanic acid (6-APA) 5  7/8/2024 Structure activity relationship of penicillin Chemical alteration of any portion of the molecule (6PA) loss of antibacterial activity. The side chain - antibacterial and pharmacokinetic characteristics of a particular type of penicillin. Hydrolysis is the main cause of penicillin degradation - Syringe when penicillin is mixed with another drug. 11 Stability: 5.5-7.5 pH Some penicillin's are rapidly hydrolyzed by gastric acid, making them unsuitable for oral administration Prolong exposure with water- hydrolysis (water and crystal powder separate vial) Aqueous solutions of the alkaline sodium salt of sulfonamides inactivate penicillin. Penicillin is incompatible with heavy metal ions, oxidizing agents and strong concentrations of alcohol- decreases solubility (decrease activity). Na & K ion addition to natural penicillin increases solubility (used parenterally) Tri-hydrated form semi-synthetic penicillin's have higher solubility (use: oral+ parental) 6  7/8/2024 Natural penicillin (Penicillin-G) – R in the side chain- Benzyl group Semi-synthetic penicillin - R in the side chain- Other than Benzyl moiety Penicillins available as Na+ or K+ salts Penicillin-G- Na salt Classification of penicillin Penicillins are sub-classed based on Chemical structure (eg, penicillins, monobactams, and carbapenems), Spectrum (narrow, broad, or extended) Source (natural, semisynthetic, or synthetic) Susceptibility to β-lactamase (penicillinase) destruction. Note: All penicillins are ineffective against cell wall-deficient microorganisms such as Mycoplasma or Chlamydia spp. 7  7/8/2024 Classification Narrow Spectrum Narrow spectrum β-lactamase sensitive β-lactamase resistant (Natural penicillins) (Antistaphylococcal penicillins) Acid stable Acid labile Acid stable Acid labile Penicillin-G/ Penicillin-V Cloxacillin Methicillin benzyl penicillin (oral) (Oral, IM) (IM, IV) (IM, IV) Phenethecillin Procaine Dicloxacillin Nafcillin Penicillin-G Flucloxacillin (IM, IV) (IM depot) (Oral, IM) Biliary excretion Benzathine Oxacillin Temocillin Penicillin-G (IM depot) 8  7/8/2024 Penicillin G- Protype -Sodium -Potassium -Procaine -Benzathene Acid labile Beta lactamase sensitive Narrow spectrum Rapid excretion Poor penetration Hypersensitivity reaction Broad spectrum Amino penicillin’s Ampicillin, amoxycillin Ampicillin precursor Hetacillin, bacampicillin, pivampicillin, talampicillin Other antibiotics Mecillinam Pro-drug of ampicillin- Hetacillin, Pivampicillin, Becampicillin, talamicillin Half life - approximately 60-90 minutes. 9  7/8/2024 Extended spectrum / antipseudomonal penicillin's Carbenicillins, ticarcillin, mezlocillin, azlocillin, piperacillin Potentiated penicillins/ beta-lactamase protected penicillins Amoxycillin-clavulanic acid, Ampicillin-sublactum Ticarcillin-clavulonic acid Piperacillin-tazobactum Factor influencing the activity of beta-lactam antibiotics Most active against fast multiplying/ growing bacteria (logarithmic growth phase) It produces concentration dependant effect (plasma conc. must be above MIC constantly) Good activity in hypotonic environment and less in hypertonic medium to bacteria (fast movement of fluid inside bacterial cell, causes osmatic lysis) Chronic cases effect decreases due to slow growth, resistance develop Beta-lactam antibiotics don’t have significant post antibiotic effect 10  7/8/2024 Bacterial resistance Beta-lactamase (penicillinase enzymes) activity more (most common) β-lactamases are specific for penicillins (penicillinases), and some are specific for cephalosporins (cephalosporinases), while still others have affinity for both groups Decrease permeability to drugs Altered penicillin binding proteins -PBP (eg, methicillin-staph) Quiescent organism (during antibiotic exposure don’t grow) Tolerant organism (do not lysed at normal dose rate) Activation of antibiotic efflux mechanism β-lactamases  These are enzymes produced by penicillin resistant bacteria  attack the penicillins at –CO-N- bond of beta lactum ring  break the antibiotic into inactive penicilloic acid.  β lactamases are two types. – Penicillinase and cephalosporinase. 11  7/8/2024 PK Penicillin G - benzathine, procaine, potassium or sodium salt. Penicillin V - potassium and sodium salts - water soluble. Orally – destroy by Gastric pH or acidity (not given orally) – absorption occur in upper GIT Absorption decrease by food Sc/IM- absorption- well absorbed---peak PC in 15-30 min Depot preparation (procaine/benzathine penicillin) ……. prolong absorption/prolong excretion Ampicillin with water or glucose solution is quickly absorbed through oral route than when added to milk or milk replacer.  Amoxicillin- better absorbed than ampicillin. Distribution: Readily achieved in body tissue/fluid Penetration is poor in eye, prostrate & CNS During inflammation more penetration: meningitis, pleuritis, peritonitis (normally not penetrate in these tissue) Protein binding 20-80% Ampicillin – therapeutic concentration- inflammation of CSF Metabolism: Do not metabolized significantly- excreted unchanged Metabolism 20%: aminopenicillin, penicillin Excretion: Urine (20% glomeruli filtration & 80% tubular filtration) good for UTI; Probenecid blocks tubular secretion- increases plasma half life Broad spectrum: also in biliary; milk 12  7/8/2024 Side effects/ adverse effects Hypersensitivity/ cross allergic reaction GI disturbances- broad spectrum antibiotics Platelets dysfunctions (eg. Antiseudomonal penicillins)- thrombocytopenia and decrease platelets agglutination, bleeding Organ toxicity: Neuronal irritation- seizures (intrathecal inj), Ataxia-in dogs, Kidney damage: Methicillin- declined use – nephrotoxicity- MRSA strains – susceptible to vancomycin,/fluoroquinolones Drug interaction Aminoglycosides – synergistic/additive activity Salicylates, sulphonamides, phenylbutazone- displaces penicillins from plasma protein binding site (decrease half life) Probenecid blocks tubular secretion of penicillins - increase blood concentration (increase half life) 13  7/8/2024 Contraindications Patients hypersensitive to penicillins Pregnant animals Oral administration – septicemia & shock Increase doses of K+ & Na+ penicillins not recommended in pre existing electrolyte imbalance, renal diseases & CHF- precipitate the condition High dose sodium salt of penicillin G may also contribute to the sodium load in congestive heart failure Potassium penicillin G contains approximately 1.7 mEq/million units of penicillin and should be administered IV with some caution, especially in the case of hyperkalemia. Antimicrobial spectrum Narrow spectrum Gram positive and few gram negative, non-penicillinase producing bacteria Effective – Gram +ve: cocci & bacilli (Streptococci spp., bacillus) Gram-ve: bacilli (Corynebacterium, Listeria monocytogenes, Pasteurella multocida, and Haemophilus influenzae) spirochetes Moderately active gram-ve cocci (Neiserria), Actinomyces and anaerobic bacteria, including Fusobacterium, Leptospira and Borrelia burgdorferi. 14  7/8/2024 Clinical uses  Thoracic and abdominal abscess/ surgical operation  Staph. Skin infection  Osteomyelitis  Septicemia/bacteremia  Endocarditis  Catheterization  Endoscopies Narrow spectrum (beta-lactamase resistant ) Cloxacillin Skin, bone, soft tissue infections Septicemia Mastitis (milking animal) Oxacillin ophthalmic use Dicloxacillin Reserved for above Floxacillin - GIT infection (oral preparation) Nafcillin - mastitis 15  7/8/2024 Broad spectrum penicillin G+ve and G-Ve (non-beta lactamase producing strains-Enterobacteriaceae) They are all destroyed by beta lactamases Mostly Acid stable, hence given orally Eg. Ampicillin, amoxicillin, hetacillin Amoxicillin- better absorbed than ampicillin. Ampicillin – therapeutic concentration- inflammation of CSF  Ampicillin is used to treat certain infections that are caused by bacteria such as meningitis (infection of the membranes that surround the brain and spinal cord); Not effective in cold and flue Antimicrobial spectrum Effective Gram -ve bacteria (hydrophilic character): Bordetella, Haemophilus, E.coli, Salmonella, Shigella Amoxicillin: Helicobacter pylori Clinical uses UTI, Septicemia, burns, immuno-compromized patients Enteritis, mastitis, metritis, septicemia, pneumonia, respiratory infection Pyelonephritis, 16  7/8/2024 Extended spectrum penicillin/ anti-pseudomonal Eg. Carbenicillin, ticarcillin Pseudomonas aeruginosa, proteus Clinical uses Burn, urinary tract infection, septicemia, Carbenicillin is used for the treatment of urinary tract infections when oral therapy is needed and other antibiotics are ineffective High doses Na-carbencillin cause Na over load leads to the fluid retention and CHF ticarcillin is FDA approved for veterinary use as an intrauterine infusion in horses. Mechanism of action 17  7/8/2024 Penicillin have structural similarity with D-Ala – D-Ala terminus of the pentapeptide side chain of transpeptidase enzymes 18  7/8/2024 PB: A1&1B (Transpeptidase enzyme) Penicillin have structural similarity with D-Ala – D-Ala terminus of the pentapeptide side chain of Transpeptidase enzymes -occupy active site D-Ala and inactivate it. -Also inhibit the D-alanyl- carboxypeptidase =inhibition transpeptidation and carboxylation of peptide chain -inhibit cell wall synthesis -result in loss of rigidity Events: -induction autolysin-latter Entry of drug….. Binding to D-ala-D-ala- residue…… inhibition trans-peptidation & stage carboxy- peptidation ……cell wall collapse…. Activation of autolysin……. Cell lysis -cell suicide 19  7/8/2024 Mechanism of action Penicillins and other beta-lactum antibiotics interfere primarily with the synthesis of bacterial cell wall. Cell wall: shape, normal morphology, cell integrity, cell division These antibiotics produce their antibacterial effects by binding to a family of proteins called penicillin-binding proteins (PBPs). PBP are of 7 types based on mol weight (high and low) High weight PBP- 1A, 1B, 2 & 3 (Cell morphology) 1A & 1B –performed the role of transpeptidase enzyme responsible for cross-links between peptidoglycan strands Low weight PBP-4, 5, 6 Enzymatic hydrolysis of penicillins 20  7/8/2024 Resistance to penicillins Produce penicillinase/ beta lacatmase enzymes Altered Penicillin binding proteins (PBP) Drugs to be used in resistance are : Vancomycin Streptogramin Linezolid β-lactamase inhibitors Clavulinic acid Source: Streptomyces clavuligerus Has no activity antibacterial activity alone Stable in Gastric pH Potassium Clavulanate+ Amoxicillin trihydrate (2.5 mg+10mg/Kg oral BID) Clavulinic acid+Ticarcillin (1:4) Sulbactam synthetic penicillanic acid sulfone Chemically: Sulbactam sodium is sodium penicillinate sulfone Tazobactam Synthetic penicillanic acid sulfone containing a beta lactam ring derived from 6- aminopenicllanic acid. 21  7/8/2024 Suicidal inhibition Suicide inhibition, also known as suicide inactivation or mechanism-based inhibition. Clavulanic acid, which inhibits β-lactamase: Clavulanic acid covalently bonds to a serine residue in the active site of the β-lactamase. (acetyl-beta-lactamase complex) 1st step: binding of clavulanic acid molecule with enzyme & restructuring the - temporarily inhibition activity 2 step: Creating a much more reactive species that attacks another amino acid in the active site enzyme--permanently inactivating enzyme (irreversible inactivation of β- lactamase.) Potentiate the action of penicillin's 2 1 22  7/8/2024 Amoxicillin-Clavulanic acid (Co-Amoxiclav; 4:1) Potentiated the activity of amoxicillin by C. acid Earlier resistant, now susceptible Staph aureus, E.coli, proteus, klebsiella, salmonella, shigella Co-amoxiclav is still not effective against MRSA (methicillin-resistant Staph aureus) and Pseudomonas Pk is similar to amoxicillin C. acid metabolised but Amoxicillin not 23  7/8/2024 Clinical uses Skin and soft tissue infection Infection UTI, respiratory tract, biliary Peritonitis Small animals: peritonitis, RT (kennel cough)- dog UTI, skin and soft tissue infect- cats Enteritis and navel ill- calf RT, metritis, agalactia- pig Prednisolone+ Co-amox-CA for mastitis (intra mammary) Ampicillin- Sulbactam Sulbactam is semisynthetic beta-lactamase inhibitor Made for parental administration 7:1……. 14-1 or 16:1 Spectrum activity: ampicillin-resistant strain also susceptible Pasteurella spp, Staph aureus, haemophilus pleuropenumoniae Gram negative aerobes except Pseudomonas Use: aerobic + non-aerobic bacterial infection Surgical abdominal, surgical and skin & soft tissue infection Dog and cat: 20-50 mg/kg, im or iv x tid Cattle: 10 mg/kg od 24  7/8/2024 Ticarcillin sod.+ clavulanic acid 30:1 Treat drug resistant bacteria Use: IV administration Dog & cats: 15-25 mg/kg IV infusion x tid Horses: 50 mg/kg IV x tid / qid Piperacillin + tazobactam broadest activity; 8:1 Encompassing most Gram-positive and Gram-negative aerobic bacteria anaerobic bacteria, including many pathogens producing beta-lactamases. Broadest activity: Increase spectrum of activity Ampicillin + flucloxacillin 25  7/8/2024 Why penicillins and related drugs are called as beta-lactam antibiotics? What is difference between 6-aminopenicillanic acid and penicillioic acid? What is the source of natural penicillin? What is commercial source of penicillin? What is the dose Unit of natural penicillin and semi-synthetic or synthetic penicillin? 1 gm of penicillin G-Na and K salt contains how much unit of penicillin? Acid unstable penicillin's are not suitable by oral route, why? Reconstitution of penicillin salt with water for longer duration should be avoided done, why? Do not reconstitute the penicillin salts with alcohol, why? Name the penicillin salts suitable for parenteral administration. Why trihydrated for penicillin good for oral and parenteral administration? Why the penicillin is not effective against the mycoplasma? Name the pro-drug of ampicillin and why they have long half life than the ampicillin? How hypotonic environment increases the antibacterial effect of penicillin? State true/false-Beta-lactam antibiotics don’t have significant post antibiotic effect. Beta-lactam antibiotics are more effective in which stage of bacterial growth? What are the most common pathways of penicillin resistance development? 26  7/8/2024 What is another name of beta-lactamases enzyme and state the site of their action? Why penicillin is good for UTI infection? What is the effect Salicylates /phenylbutazone during penicillin treatment? How it affects? What is the effect Probenecid during penicillin treatment? How it affects? Why increase doses of K+ & Na+ penicillins are not recommended in pre existing electrolyte imbalance condition? Why most of the broad spectrum penicillins are given orally? What is target site of penicillin action? What is another name of PBP? What do you mean by potentiated penicillin? Why the name is beta lactamase protected penicillin? Why Clavulanic acid is a suicide inhibitor? Thank you 27  7/8/2024 Break of amide bond by Amidase- semisynthetic penicillin Essential Destroy by penicillinase Addition of Na, K, procaine i.e ester formation increases stability and solubility & PK 28