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Betalactum antibiotics

The document discusses various classes of beta-lactam antibiotics, including penicillins and cephalosporins, detailing their mechanisms of action, antibacterial spectrum, resistance mechanisms, absorption, distribution, metabolism, excretion, and adverse reactions. It outlines the specifics of penicillin, its derivatives, semi-synthetic alternatives, and cephalosporins across generations with respect to their clinical uses and side effects. Additionally, the document highlights important pharmacological properties and challenges related to bacterial resistance.

Health & Medicine◦
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Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
What are they ? • Have Beta-lactam rings • Important groups are (PCcM) • Penicillin – the first antibiotic  Cephalosporins  Carbapenems  Monobactams
Penicillins  First ever antibiotic - 1941 – Flemming, Florey and Chain  Sources – Fungus Penicillium notatum and P. crysogenum  Penicillin G (PnG) – benzyl side chain (original Penicillin)  Sod. PnG is highly water soluble, thermolabile and acid labile Amide linkage - Split off by amidase to produce 6- aminopenicillanic Salt formation with Na+ or K+ Broken by ß- lactamase
Penicillin - MOA
MOA – Penicillin Image Essential of Medical Phamracology by KD Tripathi; Jaypee Brothers; 7th edition 2013
Mechanism of action  The principal bacteriocidal mechanism is inhibition of cell wall synthesis  The bacterial cell wall is a structure of highly cross-linked mucopeptide complex, in which peptidoglycan is a main component  Bacteria synthesize UDP–N-acetylmuramic acid pentapeptide (Park neucleotide) and UDP–N-acetyl glucosamine  They are linked together forming long strands and UDP splits off  The final step is cleavage of the terminal D-alanine  The energy released is utilized in cross-linking with adjacent peptide chains – by 5 glycine (Gly5)
Penicillin - MOA  Pencillin binding proteins (PBP) – enzymes and proteins – several PBPs and also different among species  ß-lactum antibiotics inhibit transpeptidase – cross linking prevented – defective cell wall  Results in Cell wall deficient (CWD) forms – hyperosmotic inside swells up and bursts  Also may be bizarre shaped and filamentous forms  Globular giant forms or protoplasts  Rapidly multiplying organisms – more victims  Gm+ve bacteria entirely peptidoglycan and gm-ve alternating with lipoprotein  Peptidoglycan cell wall unique in bacteria
MOA Penicillin - Video
Bacteria Vs Vertebrate
PnG – antibacterial spectrum  Narrow spectrum – mainly gm+ve and few gm-ve  Cocci: Streptococci, pneumococi, Staph. aureus  Gm-ve cocci – Neisseria gonorrhoeae, N. meningitidis, Gonococci  Bacilli: gm+ve bacilli – B. anthracis, C. diphtheriae, all Clostridia, Listeria, Spirochaetes (T. pallidum, Leptospira) – Fragilis  Gm-ve bacilli: Mycobacterium tuberculosis, rickettsiae, chlamydiae, protozoa, fungi, viruses – Not sensitive
Mechanism of Resistance 1. Inherently insensitive – PBP deeper 2. Penicillinase: Narrow spectrum ß-lactamase inactivates PnG – opens the ß-lactam ring • Gm+ve Staphylococci and gonococci, E. Coli, H. influenzae etc. – elaborate large amounts – diffuses to surroundings • Gm-ve bacteria in small quantity • Staphylococcal penicillinase – inducible by methicillin 3. Penicillin tolerant bacteria – low affinity for penicillin – altered PBP (pneumococci) • Methicillin resistant Staph. aureus (MRSA) – altered PBP 4. Less permeability to penicillin – low level penicillinase resistant gonococci and also H. influenzae – plasmid 5. Porins channels – gm-ve bacteria
PnG - Kinetics  Absorption: Acid labile – 1/3rd a dose absorbed orally  IM administration – good, rapid and complete absorption – peak 30 min.  Distribution: extracellularly and reaches most body fluids – serous cavities and CNS poor  In presence of inflammation – good penetration (meningitis, sinovitis)  Metabolism: Little metabolized – rapid excretion  Excretion: 10% glomerular filtration – tubular secretion – 30 min plasma half life  Longer tubular secretion in neonates – shorter during childhood – long for elderly and renal failure  Probenecid
Preparations and doses  Unitage: 1 U of CPPnG = 0.6µg of standard preparation; 1 g = 1.6 million unit  Sodium penicillin G (crystalline penicillin): dry powder in vial – also repository PnG injections  Repository penicillin G injections: deep IM  Procaine penicillin G injections: aqueous suspension – sustained effects 12 – 24 hours  Fortified procaine penicillin: 3 L U procaine penicillin + 1 L U Na+ penicillin  Benzathine penicilline G: 0.6 to 2.4 MU IM every 2 -4 weeks
PnG - ADRs  Upto 20 MU  Local irritancy and direct toxicity – Pain, nausea and thrombophlebitis; CNS toxicities – muscular twitching, convulsion, coma; also bleeding, arachnoiditis  Hypersensitivity (1-10%) – PnG – rash, itching, urticaria, fever; also wheezing, angioneurotic edema, serum sickness and exfoliative dermatitis – Anaphylaxis 1 – 4/10,000 – all penicillins may cause  Most common in parenteral administration – procaine  Also cross sensitivity  Scratch test (2 – 10 MU) intradermal  Negative intradermal test  Topical application – highly sensitizing - banned except freshly prepared solution  Superinfection – rare  Jarisch-Herxheimer reaction – fever, shivering, myalgia and exagerbation of lesions – vascular collapse
PnG - Uses Streptococcal infections – Pharyngitis, otitis media,, scarlet fever, rheumatic fever … SABE by Str. Viridans and fecalis – high dose 10 – 20 MU daily with gentamicin  Pneumococcal infections – lobar pneumonia, meningitis - rarely used now  Menigococcal infections: Mostly responsive - IV  Gonorrhoea – unreliable – Ophthalmia neonatorum – irrigation with saline and PnG  Syphilis: 1. 2 MU daily X 10 days Procaine penicillin, or 2.4 MU weekly; Late syphilis – Benzathine penicillin 2.4 MU weekly X 4 weeks  Diphtheria (carrier state), Tetanus and gas gangrene (adjuvant)  DOC in anthrax, actinomycetes, rat bite fever - PnG  Prophylactic: Rheumatic fever – Benzathine penicillin – 4 weekly upto 18 years; Bacterial endocarditis and aggranulocytosis
Semisynthetic penicillins  Produced chemically by altering side chain or incorporating precursors 1. Acid resistant Penicillin: Phenoxymethyl penicillin (Penicillin V) – 1 hour – 1/5th lower grade infections 2. Penicillinase resistant penicillin: Methicillin (MRSA) – penicillinase resistant but not acid resistant  Cloxacillin and dicloxacillin (acid resistant) – weaker than PnG but stronger than methicillin
Other penicillins 1. Extended spectrum: a) Aminopenicillins: Ampicillin, Becampicillin, Amoxicillin b) Carboxypenicillins: Carbanecillin c) Ureidopenicillins: Piperacillin, Mezlocillin 2. ß-lactamase inhibitors: Clavulanic acid, sulbactam and tazobactam
Ampicillin Active against organisms sensitive to PnG with additional H. influenzae, E. coli, Proteus, Salmonella, Shigella  More effective than PnG in Strep. Viridans, enterococci and gonococci  Not resistant to penicillinase and developed resistance  Not usefull against gm-ve - pseudomonas, Klebsiella, indole positive Proteus  Kinetics: acid stable, food interferes absorption, enterohepatic circulation  Uses: UTI, RTI (bronchitis, sinusitis, otitis media), Meningitis (1st line before), Gonorrhoea (1st line for non-penicillinase producing gonococci), Typhoid fever, Bacillary dysentery, Cholecystitis, SABE, H. pylori, Septicaemias  ADRs: Diarrhoea, alteration of gut flora, high incidence of rash – in AIDS patients … history of hypersensitivity  Becampicillin and Amoxicillin – similar drugs
Amoxcillin  Close congener of Ampicillin  Faster oral absorption, no food interference, lesser diarrhoea, more sustained effect and higher plasma conc.  Less effective against H. influenzae and Shigella  Effective against Penicillin resistant Strep. Pneumoniae  Uses: Bronchitis, UTI, SABE and gonorrhoea, H. pylori
Carboxypenicillins - carbenicillin Active against Ps. aeruginosa and indole positive Proteus  Less effective against Salmonella, E. coli, Enterobacter, Klebsiella and gm+ cocci  Resistance strains of Ps. Aeruginosa developed  Not acid resistant, not penicillinase resistant – given IM or IV – available as Na+ salt – CHF and renal failure, bleeding  Uses: seriuos infection caused by Pseudomonas e.g. burns, UTI, septicaemia - combined with gentamicin (1 -2 mg IM/IV 4 – 6 hrly)  Ureidopenicilins (Piperacillin): 8 times more active than carbenicillin, good against Klebsiella and many enterobacteriaceae. Used for treating seriuous gm-ve infectionsin immunocompromised and neutropenic patients
Beta-lactamase inhibitors  Enzymes produced by gm+ve and gm-ve bacteria – inactivate ß-lactum antibiotics by opening ß-lactum ring – Clavulanic acid, Sulbactum and Tazobactum  Clavulanic acid: Streptomyces clavuligerus; has a beta lactum ring but no antibacterial actuvity – inhibits a wide variety of lactamases (+ and -)  MOA: Progressive inhibitor; binds to ß-lactamases reversibly initially followed by covalent later – sucide inhibitor  Permeates the outer layer of gm-ve cell wall an inhibits periplasmically located ß-lactamases  Kinetics: Orally absorbed and can also be given parenterally; elimination half-life 1 hr – matches Amoxicillin - Coamoxiclav
Clavulanic acid  Uses: Clavulanic acid re-establishes activity of amoxicillin against resistant Staph. Aureus (but not MRSA), Influenzae, Gonorrhoea, E. coli, Proteus, Klebsiella, Salmonella and Shigella  Skin and soft tissue infections, intraabdominal and gynaecological sepsis, UTI, RTI and biliary infections  Gonorrhoea including PPNG – single dose Amoxicillin 3 gm – Clavulanic acid 0.5 gm and Probenecid 1 gm  ADRs: Same as amoxicillin but poorer GI tolerance, candida stomatitis/vaginitis and rashes
Sulbactum  Semisynthetic and related to Clavulanic acid  Progressive inhibitor of ß-lactamases  2-3 times less potent than clavulanic acid  Does not produce chromosomal ß-lactamases  Given parenterally – erratic oral absorption  Combined with ampicillin – Sultamicillin  Uses: PPNG, mixed aerobic and anaerobic infections, intra-abdominal, gynaecological, surgical and skin- soft tissue infections – hospital acquired
Tazobactum  ß-lactamases inhibitor – similar to sulbactum  Combined with Piperacillin  Used in Peritonitis, Pelvic/urinary/ respiratory infections caused by beta lactamase producing bacilli  Not useful against inducible chromosomal ß- lactamases produced by enterobacteriaceae and piracillin resistant pseudomonas
Cephalosporins  Obtained from Cephalosporium acremonium  The nucleus consist of a lactam ring + Dihydrothiazine ring  7-aminocephalosporanic acid  Same MOA as Penicillin  R1 and R2 – spectrum and pharmacokinetic activity respectively
Common features Excreted primarily by the kidney Exceptions Cefoperazone, Ceftriaxone ( Bile less in urine) Probenecid slows the tubular secretion CSF concentration good Cross the placenta High concentrations in synovial & pericardial fluids and aqueous humor
Resistance  Altering the PBPs reducing affinity  Impermeability to the antibiotic or its efflux  Elaboration of beta-lactamases  Individual cephalosporins differ  Antibacterial spectrum and potency  Susceptibility to beta-lactamases  Pharmacokinetic properties
First generation Parenteral: Cefazolin and Cephalothin Oral: Cephalexin, Cephradine, Cefadroxil Good activity against gram +ve bacteria Relatively modest activity against gram-ve bacteria Not effective against Enterococci, MRSA, S. epidermidis and B. fragilis Cefazolin: Surgical prophylaxis (2 hours half life) Cefadroxil has good tissue penetration
Second generation Parenteral: Cefuroxime, Cefotetan, Cefoxitin Oral: Cefuroxime axetil, Cefaclor Increased activity against gram -ve microorganisms Enterobacter spp., indole-positive Proteus spp., and Klebsiella spp. Cefuroxime & Cefoxitin: resistant to gram –ve β-lactamases Cefoxitin, Cefotetan also active against anaerobes (B. fragilis)
Third generation Parenteral: Cefotaxime, Ceftizoxime, Ceftriaxone, Ceftazidime, Cefoperazone Oral: Cefixime, Cefpodoxime proxetil, Ceftibuten, Cefditoren pivoxil Much more active against the Enterobacteriaceae Highly resistant to β-lactamases Antipseudomonal: Ceftazidime and Cefoperazone
Uses - Cefotaxime 1.Gram –ve meningitis 2.Hospital Acquired Infections 3.Septicemia in immunocompromised patients 4.Single dose therapy of Gonorrhoea (1 g Cefotaxime im + 1g Probenecid oral) Ceftizoxime inhibit B. fragilis
Ceftriaxone 1. Meningitis 2.Multiresistant typhoid fever 3.Complicated UTI 4.Abdominal Sepsis & Septicemia 5.Gonorrhoea & Chancroid
Third generation – contd. Ceftazidime Antipseudomonal Cause Neutropenia, thrombocytopenia, ↑ transaminase & ↑ blood urea Cefoperazone Antipseudomonal Cause Hypoprothrombinemia & Disulfiram like reaction
Fourth generation Parenteral: Cefepime, Cefpirome Extended spectrum of activity compared with the third generation Increased stability from hydrolysis by plasmid and chromosomally mediated β-lactamases Empirical treatment of serious infections in hospitalized patients when gram +ve microorganisms, Enterobacteriaceae, and Pseudomonas all are potential etiologies
Adverse effects - cephalosporins  Pain after IM and thrombophlebitis  Diarrhoea  Hypersensitivity reaction – like penicillin -10%  Nephrotoxicity  Bleeding – hypoprothombinaemia – cefoperazone, ceftriaxone  Neutropenia  Disulfiram like reaction - cefoperazone
Semisynthetic Penicillins are still usefull in various serious infections if used judiciously