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Beta lactam antibiotics (penicillin and cephalosporins)

Presented by

Jabeen Fatima

M pharmacy 1st year

Pharmacology.

G Pulla Reddy College Of Pharmacy.2/1/2017

2 Contents:

Introduction Mechanism of action Penicillins Cephalosporins

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3 INTRODUCTION:

Antibiotics: substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at low concentration.

Beta lactam antibiotics: beta lactam ring Penicillin Cephalosporins

Others Monobactam Carbapenems.

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4 Cont… Structures

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5 MECHANISM OF ACTION:

Interfere with the synthesis of bacterial cell wall. Bacteria synthesizes UDP-NAM and UDP-NAG. Peptidoglycan are linked- long strands (UDP splits) Cleavage of terminal D-Ala by transpeptidases Energy released is used for cross linkage between peptide chains. Inhibits the transpeptidases which constitute penicillin binding proteins

(PBPs) When bacteria divides in presence of beta lactam antibiotics-CWD-swell-

burst-lysis.

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6 GRAM POSITIVE BACTERIA

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7 GRAM NEGATIVE BACTERIA

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8 Cont..

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9 PENICILLINS: Introduction: First antibiotic, discovered by Alexander Fleming Obtained from Penicillium notatum, presently P. chrysogenum. Bactericidal Effective against gram positive bacteria, less against gram negative. Nucleus

Thiazolidine & beta- lactam ring Side chains via amide linkage

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10 CLASSIFICATION: Natural

Penicillin G (PnG ) Semisynthetic

Acid resistant –penicillin V penicillinase-resistant penicillins – methicillin, cloxacillin,

dicycloxacillon Extended spectrum penicillins

1. Aminopenicillins: ampicillin, bacampicillin, amoxicillin.

2. Carboxypenicillins: carbenicillin.

3. Ureidopenicillins: piperacillin, mezlocillin. Beta-lactamase inhibitors: clavulanic acid, sulbactam, tazobactam. 2/1/2017

11 NATURAL PENICILLINS (PnG):

Narrow spectrum Active against gram positive. Bacterial resistance: production of penicillinase. PENICILLINASE: beta lactamase

Opens beta ring – inactivates PnG. Ex: staphylococci, gonococci, B. subtilis, E. coli, H. influezae.

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12 Natural penicillin(cont..)

PHARMACOKINETICS: Acid labile, 1/3rd dose is absorbed, sod. PnG( i.m)- rapid and complete. Peak plasma level-30mins Distribution – extracellular, body fluids, CSF – poor. Plasma protein bound – 60% metabolism-little Excretion rapid renal. 105 – GF

Neonates – slow tubular secretion, t1/2 longer

Aged- slow2/1/2017

13 Natural penicillin (cont..)

Adverse effects: Local irriitancy & direct

toxicity Hypersensitivity Superinfections jarisch-Herxheimer reaction

Uses: Drug of choice (Allergic) Streptococcal ,

pneumococcal, meningococcal nfections.

Gonorrhea Syphilis Diphtheria Tetanus & gas gangrene Prophylactic uses: rheumatic

fever, bacterial endocarditis, agranulocytosis.

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14 SEMISYNTHETIC PENICILLINS:

Overcome shortcomings of PnG Poor oral efficacy Susceptibility to penicillinase Narrow spectrum of activity Hypersensitivity reaction

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15 Acid-resistant alternative to PnG (Pn V)

Acid stable Oral absorption – better t1/2 30-60mjn. USES

Streptococcal pharyngitis, sinusitis, otitis media rheumatic fever(prophylaxis).

Dose: 250-500mg/ 6 hourly. Infants 60mg, children 125-250mg.

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16 Penicillinase-resistant penicillins Side chains which protects the beta lactam ring from attack by staphylococcal penicillinase

( drug of choice ) METHICILLIN: highly penicillinase resistant, not acid stable.

Inducer of penicillinase production. MRSA: altered PBPs, no binding. Adverse effects: haematuria, albuminuria,reversible interstitial nephritis.

Replaced by cloxacillin CLOXACILLIN: isoxazolyl side chain. Highly penicillinase and acid resistant.

Absorbed – oral route, if taken empty stomach. 90% plasma protein binding, t1/2- 1hr Eliminated- primarily kidney, partly liver. Oxacillin, floxacillin- not marketed in india. 2/1/2017

17Extended spectrum penicillins

Active against gram negative bacilli as well. Grouped according to their spectrum of activity. Aminopenicillins: amino substitution.

Drug Pharmacokinetics Uses

Ampicillin: Developed resistance Active- strep. Viridans, enterococci, & listeria.

Acid resistant.Absorption incompleteFood interferesExcreted in bile (primary by kidney) & enterohepatic circulation occursdiarrhoea

UTIs, RTIs, MeningitisGonorrhoea, Typhoid fever, Bacillary dysentery, septicemia, cholecystitis,

Bacampicillin: ester Completely absorbs in g.i.t.Largely hydrolysed

Amoxicillin: congener Oral absortion betterFood does not interfereDiarrhoea(lower)

Bronchitis, UTIs, gonorrhoea, & SABE(sub acute bacterial endocarditis) 2/1/2017

18 Extended Spectrum Penicillins Cont.. Carboxypenicillins Carbenicillin:

Special feature- activity against Pseudomonus aeruginosa & indole positive proteus.

Neither penicillin resistant nor acid resistant. Absorption – inactive orally, excreted rapidly in urine Used as sodium salts- 1-2g i.m. or 1-5 g i.v. every 4-6hrs. High dose causes bleeding Uses: burns, UTIs, septicaemia. Combined with gentamycin but should not be mixed in same syringe. Carbenicillin indanyl: orally active ester.

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19 Extended Spectrum Penicillins Cont..

Ureidopenicillins: Piperacillin:

Antipseudomonal penicillin, 8 times more active than carbenicillin. Good activty against Klebsiella, Enterobacteriaceae, Bacteriodes. Treating gram negative infections in

neutropenic/iimmunocompromised or burn patients. t1/2 -1hr.

Mezlocillin- not available in India.

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20 Beta lactamase inhibitors Beta lactamase: opens beta lactam ring, inactivates antibiotics. Three inhibitors : clavulanic acid, sulbactam, tazobactam are for clinical use. Clavulonic acid:

Strep. clavuligerus. No activity of its own. Suicide inhibitors, gets inactivated after binding to enzyme. Permeates outer layer of cell wall of gram- bacteria. Used in combination with amoxicillin(coamoxiclav)

Pharmacokinetics: Rapid oral absortion, BA-60% Metabolism: hydrolysed and decarboxylated. Eliminated- GF(not effected by probenecid).

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21 Beta lactamase inhibitors Cont..

Uses: Skin and soft tissue infection, intraabdominal * gynaecological

sepsis, urinary, biliary and respiratory tract infection Gonorrhoea: 3g amoxicillin+ o.5g clavulonic acid+ 1g probenecid-

highly curative. Adverse effects: G.i. tolerance is poor. Candida stomatitis/vaginitis & rashes.

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22

CEPHALOSPORINS

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23 INTRODUCTION • Derived from Cephalosporin-C

obtained from a fungus cephalosporium.

• Nucleus:

• Beta lactam ring

• Dihydrothiazine ring

• Bactericidal

• Divided into 4 generations based on overall antibacterial spectrum and potency.

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24 CLASSIFICATION

Table

Generation Parenteral Oral

First generation cefazolin CefalexinCefadroxil

Second generation CefuroximeCefoxitin

CefaclorCefuroxime axetilcefprozil

Third generation CefotaximeCeftizoximeCeftriaxoneCeftazidimecefoperazone

Cefixime Cefpodoxime proxetilCefdinirCeftibutenCeftamet pivoxil

Fourth generation Cefepime Cefpirome

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25 First generation Cephalosporins

Developed in 1960s. High activity against gram positive, less against gram negative.

Drugs Properties

Cephazolin • prototype, parenteral, activity- streptococci, meningococci, gonococci, C. diphtheria, H influenza, actinomyces etc.

• i.m. & i.v. t1/2 – 2hrs• Surgical prophylaxis.

Cephalexin • Oral. • Less active H. influenzae, penicillinase producing staphylococci• T1/2- ~60mins.

Cephadroxil Good tissue penetration. More sustained action at site of injection (12hr)Dose reduced- creatinine clearance <50ml/min 2/1/2017

26Second generation Cephalosporins

Active against gram negative organisms, w None inhibits P. aeruginosa

Drug Properties

Cefuroxime Resistant to gram negatice beta lactamases and PNNG active to ampicillin-resistant H. influenzaTolerated well by i.m. High CSF levelsSingle dose i.m. for gonorrhea due to PNNG

Cefuroxim axetil Ester. Effective orally, absorption incompleteActivity- in vivo hydrolysis and release of cefuroxime (prodrug)

Cefaclor Significant Activity by oral route More active against H. influenzae, E.coli, and some anaerobes.

Cefprozil Good oral absorption(>90%)Activity against strep. Pyrogenes, Strep. Pneumoniae, staph. aureus, H. influenzae, Moraxella and klebsiella.Excreted by kidney, t1/2- 1.3 hrsBronchitis, ENT and skin infections. 2/1/2017

27 Third generation Cephalosporins

Developed in -1980s

Activity against gram negative Enterobacteriaceae and few Pseudomonus.

Highly resistant to beta lactamase

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28Drug Properties Uses Cefotaxime prototype.

Potent action on both.Not active on anaerobesDeacetylated in the body

Meningitis( gram- bacilli), hospital-acquired infections, septicemia

Ceftizoxime Similar.Inhibits B. fragilis.Not metabolized, excreted by kidney

Ceftriaxone Longer duration of action(t1/2- 8hrs).Crosses CSF. Elimination equally via bile and urine

Bacterial meningitis(children)Multiresistant typhoid fever, UTIs, abdominal sepsis and septicemia.

Ceftazidime Pseudomonas aeruginosa.Side effect: neutropenia, thrombocytopenia, rise in blood urea.

Febrile neutropenic patients with haematological malignancies, burns.

Cefoperazone Stronger activity on pseudomonas, B. fragilis, s. typhi, more to beta-lactamases.Excreted in bile.

Severe urinary, respiratory,biliary, meningitis, septicemias.

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29 Cont..Drug Properties Uses Cefixime Orally active.

Good activity against H. influenza, Enterobacteriaceae, strep. pyrogen Resistant to beta lactamases(not staph. Aureus)Longer acting

Respiratory, urinary and biliary infections.Side effects: stool changes & diarrhea.

Cefpodoxime proxetil

Orally active ester.Active against Enterobacteriaceae & streptococci, staph.aureus.

Respiratory, urinary, skin & soft tissue infection

Cefdenir Oral. Active against beta lactamase producing organism,respiratory pathogens

Pneumonia, chronic bronchitis,ENT & skin infections

Ceftibuten Oral. Active against gram positive,few gram negative(not staph. aureus) Stable to Beta lactamases

Respiratory and ENT infections

Ceftamet pivoxil

Ester. Gram negative bacteria- Enterobacteriaceae & N. gonorrhea

Respiratory & skin soft tissue infections2/1/2017

30 Fourth generation Cephalosporins

Distinctive feature- non Susceptibility to inducible chromosomal beta lactamase.

Cefipime: Developed in 1990s Highly resistant to beta lactamases(not MRSA) High affinity and broad spectrum. High concentration in CSF. Excreted via kidney.Uses: hospital-acquired pneumonia, febrile neutropenia, bacteraemia,

septicemia. 2/1/2017

31 Cont.. Cefpirome:

zwitter ion character-permits better penetration Resistant to many beta-lactamases.

Adverse effects: more toxic than penicillins.

1. Pain- i.m/i.v. –thrombophlebitis.

2. Diarrhoea

3. Hypersensitivity reactions

4. Nephrotoxicity

5. Bleeding- hypoprothrombinaemia2/1/2017

32 REFERENCES:

Essentials of medical pharmacology, 7th ed, KD Tripathi. http://

amrls.cvm.msu.edu/pharmacology/antimicrobials/effect-on-bacteria. http://tmedweb.tulane.edu/pharmwiki/doku.php/

beta_lactam_working_rough_draft_-_not_ready_for_prime_time.

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Thank you!!

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