Beta Lactam Antibiotics
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Beta lactam antibioticsDr. Suman Jain
Beta lactam antibioticsBeta lactam antibiotics Classes These antibiotics have beta lactam ring. 1. Penicillins 2. Cephalosporins 3. Carbapenem (e.g. imipenem) 4. Monobactam (e.g. aztreonam) in addition lactamase inhibitors (clavulanic acid, sulbactam )also have lactam structure but are not antibacterial. 1. The Penicillins Chemistry These are derivative of 6 amino penicillanic acid. 6APA nucleus is essential for biological activity. Penicillin G (benzyl penicillin) is the only natural penicillin used clinically. Semisynthetic penicillins are prepared from penicillium chrysogenum. Unit of penicillin 1 international unit = 0.6g of penicillin G sodium. 1 million units= 0.6 gm Semisynthetic penicillins are prescribed by weight.
PenicillinsMechanism of action They are bactericidal. They inhibit cell wall synthesis. The peptidoglycan is composed of glycan chains which are linear strands of two alternating amino sugar (N acetylglucosamine and N acetylmuramic acid) that are crosslinked by peptide chains. Penicillins bind to PBPs which catalyse transpeptidase reaction. The interaction between penicillin and PBP is covalent. They inhibit transpeptidation (final stage in the synthesis of cell wall). The lysis of bacteria that usually follow the use of beta lactam antibiotic is dependent on cell wall autolytic enzymes. Autolysins or murein hydrolases usually work in the process of cell division. Penicillins activate autolysins.4
Penicillins: Mechanism of bacterial resistance
1. Structural differences in PBP due to mutation: e.g. Strep. Pneumoniae for penicillin G (called penicillin non-sensitive S. pneumoniae PNSP) Methicillin resistance in Staph. aureus. 2. Changes in porin structure- inability to penetrate, e.g E. coli, pseudomonas. 3. Production of beta lactamase (penicillinase) most important mechanism for development of resistance. e.g., Staph aureus, H. influenzae, bacteroids, enteric G-ve organisms (E. Coli, Pseudomonas). 4. Presence of efflux pump: gram negative organisms5 salmonella.
Name Benzyl penicillin G Penicillin V
Abs oral administrati on Variable Good
Resis.to Penicillinase No No
Useful antimicrobial spectrum Streptococcus species, Neisseria meningitidis, many anaerobes, spirochetes, actinomyces
High activity against gram positive bacteria, low activity against gram ve bacteria, acid labile, destroyed by lactamase.
Antistaphylococcal penicillins: Isoxzolyl penicillins: Oxacillin Cloxacillin Dicloxacillin Flucloxacillin Nafcillin Broad spectrum penicillins: Ampicillin Amoxicillin Good Yes
Highly protein bound >95%
Yes No Listeria monocytogenes, enterococci. Proteus mirabilis, Escherichia coli, salmonella, shigella, H. influenzae, and Helicobacter pylori.
Similar to isoxazolyl penicillin; resistant to staph. lactamase Similar to penicillin G, destroyed by lactamase but acid stable and more active against gram ve bacteria Similar to ampicillin but greater absorption, gives high blood concentrations, most effective of all lactams for penicillin resistant strep pneumoniae. Inferior to ampicillin, against gram positive cocci and L. monocytogenes
Antipseudomonal penicillins: i. Carboxypenicillins: Ticarcillin Ureidopenicillins: Extended spectrum penicillins: Piperacillin
Poor, not given orally
Above plus. Pseudomonas Enterobacter species, Proteus (indole positive)
Poor (not given orally)
Pseudomonas species, Enterobacter species, mainly Klebsiella and bacteroids.
Resembles ticarcillin against gram ve aerobes Piperacillin effective against gram positive cocci and monocytogenes (like ampicillin)
ADME of Penicllin GAbsorption Benzylpenicillin G- Only 1/3rd abs.from duodenum. Destroyed by gastric juice, Absorption better in achlorhydriac. Penicillin V- more stable in acidic medium and better absorbed orally. Benzylpenicillin G is administered IV. Penicillin G procaine, and Penicillin G benzathine (repository preparations- slowly release penicillin)- are adm.IM. Distribution Widely distributed 65% is reversibly protein bound. Therapeutic conc in most tissues except prostatic fluid. Penetration in CSF more if meninges are inflammed (normally 1% but in meningitis 5%adequate for susceptible organisms). Fever increases penetration. Excretion Through kidneys. 10% by GF and 90% by tubular secretion. Probenecid decreases excretion. T -30 minutes. Clearance low in neonates and infants and in renal failure.7
Uses of Penicillin GDrug of choice (DOC) for: N. meningitidis (meningococcal meningitis, septicemia). Bacillus anthracis- anthrax Clostridium perfringens (gas gangrene) C. diphtheriae (diphtheria) T. pallidum (syphilis) Leptospira (leptospirosis) Actinomyces israelii (actinomycosis). Borrelia burgdorferi (lyme disease) in children. Prophylactic uses of the penicillin: Recurrences of rheumatic fever - 1.2 million units of benzathine penicillin G once a month. Syphilis - prophylaxis for a contact with syphilis
The penicillinase resistant penicillinsantistaphylococcal penicillins.
Agents used for staphylococccal infection. No of isolates have developed resistance- MRS. Vancomycin is drug of choice for MRS. Resistance to methicillin is due to high molecular PBP which has very little affinity to beta lactam antibiotics. i. ii. Methicillin: may produce interstitial nephritis- no longer used.
Isoxazolyl penicillins - Dicloxacillin is the most active of all these. 30-80% absorption from GIT. Adverse reactions: with oxacillin- hepatitis. iii. Nafcillin. CSF concentration is adequate to treat Staph. meningitis. Adverse reactions: hepatitis, neutropenia Uses: eta-lactamase producing staph, also for penicillin susceptible strep
Aminopenicillins- broad spectrum penicillins
III. Aminopenicillins Examples: ampicillin, amoxicillin and their congeners. Destroyed by beta lactamase (produced by both gram-positive and negative organisms) Sensitive organisms are: The Meningococci, Pneumococci, Gonococci and Listeria monocytogenes. Gram ve bacilli- H. influenzae, enterobacteriaceae (E. coli, Proteus mirabilis, salmonella and Shigella). Gram ve cocci- Moraxella. catarrhalis Enterococci synergism with aminoglycoside Concurrent administration of a lactamase inhibitor such as clavulanate or sulbactam markedly expands the spectrum of activity of these drugs. Resistant organisms- Enterobacter species, less active against B. fragilis
Ampicillin and Amoxicillin
AmpicillinWell absorbed orally. Probenecid increases plasma conc. Appears in bile, undergoes enterohepatic circulation - excreted in feces and urine . T 80 minutes. Given 4 times daily. Adverse reactions of ampicillin Diarrhea. Macular rash- in patients with AIDS, EB virus infection (infectious mononucleosis) or lymphatic leukemia, and also in patients with renal failure, or taking allopurinol. Pseudomembranous enterocolitis (clostridium difficile diarrhea), secondary infection with candida
Amoxicillin Antimicrobial spectrum identical to ampicillin with the exception that amoxicillin appears to be less effective than ampicillin for shigellosis. Plasma conc. are 2-2.5 times more and also lasts twice as long than ampicillin when given in the same dose, half life is same. This is because it is more rapidly and completely absorbed from the gastrointestinal tract than ampicillin. Because of its more complete absorption, the incidence of diarrhea is also less. It is given three 11 times daily.
Upper respiratory tract infection: Effective for sinusitis otitis media, acute exacerbation of chronic bronchitis and epiglotitis. Amoxicillin is more effective against Strep. pneumoniae. Urinary tract infections: Most uncomplicated UTIs. Meningitis: Acute bacterial meningitis in children caused by H. influenzae, Strep. pneumoniae or Neisseria meningitides. Ampicillinexcellent activity against L. monocytogenes- common in immunocompromised patients. of suspected bacterial meningitis. Salmonella infections:A fluoroquinolone or ceftriaxone - drug of choice, but co-trimoxazole or high doses of ampicillin also effective. For carrier without gall bladder disease - ampicillin, cotrimoxazole or ciprofloxacin are effective. Bacillary dysentery: Infection due to Shigella responds to ampicillin, but quinolones are preferred. Gonorrhea: If organisms are sensitive then use ampicillin or amoxicillin Other infections: Ampicillin plus aminoglycoside or one of the newer cephalosporins to treat sepsis caused by gram-negative bacteria. Also for 12 subacute bacterial endocarditis- ampicillin + gentamicin.
Therapeutic indications broad spectrum (amino)penicillins
5. 6. 7.
IV. Antipseudomonal penicillinsCarboxypenicillin: example: ticarcillin disodium Active against pseudomonas aeruginosa and certain indole positive Proteus, enterobacter species resistant to ampicillin. Bacteroides fragilis is susceptible in high concentration. Currently preferred drug for Pseudomonas but is inferior to piperacillin for the treatment of serious pseudomonal infection. Has synergistic activity with aminoglycosides. Available in combination with clavulanic acid. Be careful in patients with cardiac and renal function impairment- sodium load due to use of Na+ salts. Therapeutic indications: Serious infections caused by gramnegative bacteria in patients with impaired immune system, aminoglycoside is usually added.13
Extended spectrum penicillins
Ureidopenicillins: Example: piperacillin. Active against Klebsiella in addition to the organis