Beta-Lactam Antibiotics and Vancomycin PDF

𝛽 Lactam Antibiotics BY DR AHMED TAHA  𝛽 Lactam Antibiotics These antibiotics have a beta-lactam ring as the essential antibacterial component in their chemical structure. The antibiotics under this group consist of: I. Penicillins. II. Cephalosporins. III. Carb...

𝛽 Lactam Antibiotics BY DR AHMED TAHA  𝛽 Lactam Antibiotics These antibiotics have a beta-lactam ring as the essential antibacterial component in their chemical structure. The antibiotics under this group consist of: I. Penicillins. II. Cephalosporins. III. Carbapenems. IV. Monobactams.  Penicillins Chemistry: The essential constituents of the penicillin nucleus is a B-lactam ring. The basic chemical structure is 6-aminopenicillanic acid. Source: I. Natural: from molds (Fungi) only penicillin G and Penicillin V. II. Semisynthetic.  Penicillins Preparations of Penicillins: 1- Benzyl Penicillin (Penicillin G): It has the following disadvantages: a. Short duration of action = 4-6 Hours. b. Acid sensitive; NOT effective Orally. c. 𝛽 Lactamase (Penicillinase) sensitive. d. Narrow spectrum = NOT effective against Gram -ve Bacilli as Salmonella, Shigella, H. influenza, Helicobacter pylori & E. coli.  Penicillins Preparations of Penicillins: 2- Long-Acting Penicillins: (disadvantages b, c & d) a. Procaine penicillin G/ 12h. b. Fortified Procaine Penicillin G/ 24h and quick onset. c. Benzathine Penicillin G/ month. 3- Acid Resistant Penicillins:(disadvantages a, c & d) Phenoxy methyl penicillin (Penicillin V). 4- 𝛽 Lactamase (Penicillinase) Resistant: Methicillin (Obsolete as it is nephrotoxic). Used mainly to diagnose Methicillin-Resistant-Staph-Aureus (MRSA) infection.  Penicillins Preparations of Penicillins: 5- Acid & 𝛽 Lactamase Resistant Penicillins (Oxa): Effective ORALLY in treatment of Staph. infections. Oxacillin, Cloxacillin and nafcillin (IV in Severe Staph infections). 6- Broad-Spectrum Penicillins (Amino-penicillins): Effective against Gram +ve & -ve organisms including Gram -ve bacilli as Salmonella, Shigella, H. influenza, H. pylori- & E. coli. BUT NOT effective against Klebsiella, Proteus & Pseudomonas aeruginosa. Lactamase sensitive and they are acid resistant.  Penicillins Preparations of Penicillins: 6- Broad-Spectrum Penicillins (Amino-penicillins): a) Ampicillin: - Incomplete oral absorption& affected by food - Useful in enteritis and disturb intestinal flora. - Short duration of action/6 hours. b) Pro-drugs of ampicillin (esters of ampicillin) (Pivampicillin and Bacampicillin) These are prodrugs which de-esterified in the gut mucosa or liver to release ampicillin to the systemic circulation. They are better absorbed from the gut than ampicillin itself and have no effect on GUT flora.  Penicillins Preparations of Penicillins: 6- Broad-Spectrum Penicillins (Amino-penicillins): C) Amoxycillin Like ampicillin but differs in: - complete oral absorption& not affected by food - Less effective in enteritis and less disturb intestinal flora. - longer duration of action/8 hours. 7- ANTIPSEUDOMONAL PENICILLINS (Extended Spectrum): - Broad spectrum and effective against Pseudomonas aeruginosa & Proteus. - They are 𝛽 Lactamase sensitive.  Penicillins Preparations of Penicillins: 7- ANTIPSEUDOMONAL PENICILLINS (Extended Spectrum): -Combined with Aminoglycosides for Synergism & avoid resistance. 1- Carboxypenicillins (Carbenicillin IV,IM and oral). 2- Ureido-penicillin (Piperacillin IV and IM) Stronger than carboxypenicillins and effective against Klebsiella. 8- Reversed-Spectrum Penicillins (Amidino-Penicillins): Mecillinam (IV and IM) and Pivmecillinam (Oral). Effective against Gram -ve Bacteria e.g., Salmonella & Shigella but not Pseudomonas, Klebsiella or H. Influenza.  Penicillins Pharmacokinetics of Penicillins: - Routes of administrations. - Distribution: No passage across normal BBB. Pass easily inflamed meanings. Pass placental barrier; but NOT Teratogenic. - Active Renal tubular excretion which is inhibited by Probenecid. Readjust the dose in patients with impaired renal function, except Nafcillin is excreted in bile. - Metabolized by bacterial enzymes: Penicillinase~ Penicilloic acid ~ Inactive & Hapten causes allergic reactions. Amidase ~ 6-Amino-penicillancic acid.  Penicillins Antibacterial activity: - Action on bacteria: Bactericidal. - Mechanism of Action: a) Penicillins bind to specific penicillin binding proteins (PBPs) that inhibits transpeptidase enzyme leads to inhibition of cross linking between peptidoglycan layers causing inhibition of cell wall synthesis (Final step of cell wall synthesis). b) Penicillins activate bacterial autolytic enzymes (autolysins) leads to cell wall lysis. c) Bacteria imbibe water by its high osmotic pressure leading to rupture. (action mainly on growing bacteria more on resting). - Selectivity: Penicillins have selective toxicity, they act on bacteria but do not affect human cells due to the lack of peptidoglycan cell wall in human cells.  Penicillins Antibacterial activity: - Resistance: a) Natural: due to absence of peptidoglycan cell wall as in Mycoplasma. b) Acquired (plasmid-mediated) by: I. Synthesis of enzymes that destroy the β-lactam ring of penicillins, these enzymes are known as "β-lactamases" or penicillinases. II. Alteration in the binding site of PBP. III. Decreased permeability (influx) to penicillins. IV. Increased efflux of the antibiotic from the inside of the bacterial cells to the outside.  Penicillins Spectrum: I. Narrow spectrum penicillins: active Against a. Gram positive bacteria (cocci and bacilli). b. Gram negative cocci. c. Anaerobes except β-lactamase producing Bacteroides fragilis. d. Spirochaetes (Treponema pallidum). e. Actinomyces Israeli. II. Broad spectrum: active Against As narrow spectrum+ Gram negative bacilli Except Pseudomonas, Proteus, and Klebsiella. III. Extended spectrum: active against as broad + Pseudomonas, Proteus, and Klebsiella.  Penicillins Indications: I. Chemoprophylaxis: 1) Prophylaxis against streptococcal infections in rheumatic fever by benzathine penicillin. 2) Prophylaxis against endocarditis in patients with valve disease or prosthetic valves before dental procedures by Procaine penicillin. II. Treatment of: 1) Respiratory tract infections: pharyngitis, tonsillitis, otitis, sinusitis, bronchitis, and pneumonia. 2) Urinary tract infections. 3) GIT infections as typhoid fever and eradication of H.pylori in peptic ulcer. 4)Meningitis and Gonorrhea.  Penicillins Indications: II. Treatment of: 5) Pyogenic infections as abscess, osteomyelitis. 7) Endocarditis. 8) Diphtheria, tetanus, gas gangrene, anthrax. 9) Actinomycosis. 10) Syphilis.  Penicillins Adverse effects: I. Hypersensitivity (allergic reactions): 1) It is due to "penicilloic acid" which acts as a hapten. 2) It is manifested as rash, urticaria, angioedema, or anaphylactic shock (treated by adrenaline IM, cortisone IV, and antihistaminic). 3) It is prevented by asking the patient for previous history and by skin test. 4)The patient should never re-use penicillins. 5) There is "cross allergy" between penicillins and other β-lactam antibiotics as cephalosporins in about 10% of population , due to similarity in the chemical structure.  Penicillins Adverse effects: I. Hypersensitivity (allergic reactions): 6) Ampicillin causes "maculopapular rash" in case of: a) Allergy. b) Leukemia. c) Infectious mononucleosis (diagnostic test). d) Patients treated by allopurinol. II. Jarisch-Herxheimer reaction: due to release of toxins from dead Treponema in syphilitic patients treated by 1st dose of penicillin. The manifestations are similar to allergic reactions and are treated by cortisone. Penicillin therapy should be continued.  Penicillins Adverse effects: III. Diarrhea and superinfection. Due to monilia (candida) which is treated by Nystatin orally, or by endotoxin of Staph. or Clostridium difficile which is treated by oral Vancomycin or Metronidazole. IV. Seizures and epileptic fits in case of large doses or intrathecal injection. V. Penicillins are given in the form of Na+ or K+ salts, which may lead to hypernatremia or hyperkalemia especially in cardiac and renal patients. VI. Benzathine penicillin causes local pain and induration due to IM injection and thrombophlebitis after IV injection. VII. Carboxy penicillin causes platelet dysfunction. VIII. Methicillin causes Nephrotoxicity.  Penicillins Penicillins and 𝛽 Lactamase producing bacteria: - 𝛽 Lactamase producing bacteria are PEPSI organisms (Proteus, E. Coli, Pseudomonas, Staph, H. Influenza). - All generations of penicillins are 𝛽 Lactamase sensitive except Oxa group (discussed before). - Some generations of penicillins can overcome 𝛽 Lactamase by combinations with 𝛽 Lactamase inhibitors. (They have weak or no antibacterial activity). - 𝛽 Lactamase inhibitors ( Sulbactam, clavulanic acid and Tazobactam). 1. Ampicillin+ Sulbactam forms Unasyn ( oral, IM and IV). 2. Amoxycillin + clavulanic acid forms Augmentin and Hibiotic. 3. Piperacillin+ Tazobactam forms Tazocin.  Cephalosporins Source and chemistry: as Penicillin. Generations: a) 1st Generation: - Spectrum: (Broad) more on G+ve than G- ve bacteria. - Resistant to β lactamase. - Cannot pass BBB. - Routes of administrations: I. Oral: Cephalexin and Cephradine. II. Parenteral: Cefazolin and Cefapirin.  Cephalosporins Generations: b) 2nd Generation: - Spectrum: (Broad) more on G-ve than G+ ve bacteria. - More resistant to β lactamase than 1st generation. - Cannot pass BBB except Cefuroxime. - Routes of administrations: I. Oral: Cefuroxime and cefaclor. II. Parenteral: Cefuroxime, cefamandole and Cefoxitin (most active against anaerobes).  Cephalosporins Generations: c) 3 rd Generation: - Spectrum: (Broad) more on G-ve than G+ ve bacteria. - More resistant to β lactamase than 2nd generation. - Pass BBB except cefoperazone. - Routes of administrations: I. Oral: Cefixime. II. Parenteral: - Cefotaxime: Partially de-acetylated & partially excreted unchanged in urine. - Ceftriaxone: used Once/Day and excreted in bile.  Cephalosporins Generations: c) 3 rd Generation: - Routes of administrations: II. Parenteral: - Cefoperazone: active against P. aeruginosa, excreted in bile and not passing BBB. Cefoperazone + Sulbactam forms sulperazone. - Ceftazidime: active against P. aeruginosa and can pass BBB. - Moxalactam. d) 4 th generation: (Cefepime IV) Similar to Ceftazidime, BUT More resistant to β lactamase enzymes.  Cephalosporins Pharmacokinetics of cephalosporins: - Routes of administrations. - Distribution: BBB? - Active Renal tubular excretion which is inhibited by Probenecid, except: 1. Cefotaxime is Partially' de-acetylated & partially excreted unchanged in urine. 2. Ceftriaxone & Cefoperazone undergo Biliary excretion. Antibacterial activity: as penicillin.  Cephalosporins Indications: I. Respiratory tract infections. II. Urinary tract infections. III. Meningitis (3rd and 4th generations except cefoperazone). IV. Gonorrhoea. V. Typhoid fever (especially cefoperazone and ceftriaxone). VI. Anaerobic infections (oral, intra-abdominal, intrapelvic and gynaecological). VII. Pyogenic infections especially if due to penicillin-resistant bacteria. VIII. Prophylaxis against surgical wound infections.  Cephalosporins Adverse effects: 1. Hypersensitivity: as penicillin. 2. Diarrhea and superinfections: as penicillin. 3. Pain and induration after IM injection (add lidocaine) and thrombophlebitis after IV injection. 4. Never give ceftriaxone and Ca in same line as may form insoluble salt causing biliary stones. 5. Cefamandole, cefoxitin and cefoperazone cause: a. Disulfiram like action (alcohol intolerance). b. Hypoprothrombinaemia ( corrected by giving Vit k/ day). 6. Nephrotoxicity; especially if given with aminoglycosides (also nephrotoxic) and with loop diuretics (increase renal concentration of cephalosporins). 7. Moxalactam causes platelet dysfunction.  Carbapenems Members: Imipenem – Meropenem - Ertapenem. Imipenem Source: Synthetic. Chemistry: β Lactam antibiotics. Pharmacokinetics: I. Given IV and Pass BBB during meningitis. II. Imipenem is metabolized in renal tubular cells of PCT by "dihydropeptidase" into nephrotoxic metabolite. That is why imipenem should be combined with a dihydropeptidase inhibitor as cilastatin. the dose should be adjusted in renal impairment. Imipenem + Cilastatin forms Tienam.  Carbapenems Imipenem Action on bacteria: Bactericidal. Mechanism of action: as penicillins (PBP 2). Spectrum: very wide, active on Gram positive, Gram negative, aerobes and anaerobes growing or not. Indications: serious hospital acquired (Nosocomial) infections. Adverse effects: Allergy and partial cross-allergy with penicillin, GIT disturbances and seizures.  Carbapenems Meropenem Similar to imipenem BUT: a- Not metabolized by dihydropeptidase enzyme. b- Rare to produce seizures. Ertapenem Similar to meropenem but has longer half life so given parenteraly once daily  Monobactams Member: Aztreonam Source: synthetic. Chemistry: β lactam antibiotic. Pharmacokinetics: given IM, IV and excreted in urine. Action on bacteria and M. of action: bactericidal- inhibits cell wall synthesis (PBP3). Spectrum: Narrow active on Gram negative only (including Pseudomonas), inactive against Gram positive and anaerobes. Indications: in patients allergic to penicillins (No cross allergy with penicillin). Adverse effects: GIT disturbance.  Vancomycin Source: natural. Pharmacokinetics: I. Not absorbed orally but is given orally to act locally on GIT, given by IV infusion to treat systemic infection. II. Poorly penetrates BBB except in meningitis. III. Excreted unchanged in urine (useful in UTIs and dose should be adjusted in renal impairment). Action on bacteria and M. of action: bactericidal- inhibits cell wall synthesis. Spectrum: Gram positive bacteria (including MRSA, Clostridium difficile and Enterococci).  Vancomycin Indications: 1. Chemoprophylaxis against endocarditis in penicillin- allergic patients. 2. Treatment of pseudomembranous colitis (given orally). 3. Treatment of MRSA infections (given IV infusion). 4. Urinary tract infections (UTIs). Adverse effects: 1. Ototoxicity. 2. Nephrotoxicity. 3. Red man syndrome: rapid IV infusion leads to histamine release causing V.D. of cutaneous blood vessels and flushing may lead to shock. THANK YOU