B-lactam antibiotics

Basic Pharmacology of β-lactam Antibiotics

💊 Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based upon a shared structural feature, the beta-lactam ring.

Beta-lactam antibiotics include:
o Penicillins
o Cephalosporins
o Cephamycins
o Carbapenems
o Monobactams
o Beta-lactamase inhibitors - clavulanic acid

💊The original group of beta-lactam antibiotics is the penicillins, whose target is the cell wall
       💉They interfere with cross-linking of the cell wall in actively growing cells
     💉 The targets of the penicillins are called penicillin binding proteins (PBPs) and are enzymes involved in synthesis of the cell wall

Mechanism of Action of β-lactam Antibiotics
          The activity of antibiotics depends on three things:

🍔Affinity for the target (e.g. how well penicillin binds PBPs)
🍔 Permeability properties (e.g. through capsule, peptidoglycan)
🍔Stability to bacterial enzymatic degradation (e.g. beta-lactamases)
       Interferes with the last step of the bacterial cell wall synthesis peptidoglycan
💉After attachment to binding sites on the bacterium they inhibit the transpeptidation enzyme that cross-links the peptide chains attached to the backbone of the peptidoglycan
     💉 The final bactericidal event is the inactivation of an inhibitor of the autolytic enzymes
in the cell wall. This leads to lysis of the bacterium

Classification of Penicillins

💉There are 4 classes of penicillins, based upon their ability to kill various types of bacteria from narrow to broad range of effectiveness.

Natural Penicillins
          Include - Penicillin G, Procaine, Penicillin G, Penicillin V and Benzathine penicillin .
      💉 The natural penicillins were the first agents in the penicillin family to be introduced for clinical use.

       💉They are effective against gram-positive strains of streptococci, staphylococci, and some gram-negative bacteria such as meningococcal.

🍔Penicillin V is the drug of choice for the treatment of streptococcal pharyngitis. It is also useful for anaerobic coverage in patients with oral cavity infections.
Penicillinases-Resistant Penicillins
       Include - Cloxacillin, Dicloxacillin, Methicillin, Nafcillin and Oxacillin.
  💊 Methicillin was the first member of this group and it is rarely used because of its toxicity.
      The penicillinases-resistant penicillins have a narrower spectrum of activity than the natural penicillins.
     Their antimicrobial efficacy is aimed directly against penicillinases-producing strains of gram-positive cocci, particularly staphylococcal species and these drugs are sometimes
called anti-staphylococcal penicillins.
Broad-Spectrum Penicillins (Aminopenicillins)
       Include - Ampicillin, Amoxicillin, and Bacampicillin).
💊The aminopenicillins were the first penicillins discovered to be active against gram-negative bacteria (such as E. coli and H. influenza), which do not produce beta-lactamase enzymes.
       Aminopenicillins are acid-resistant so are administered orally.
💊Orally administered amoxicillin and ampicillin are used primarily to treat mild infections such as otitis media, sinusitis, bronchitis, urinary tract infections and bacterial diarrhea.
Extended Spectrum Penicillins

💊Extended Spectrum Penicillins
include both alpha-carboxypenicillins (carbenicillin and ticarcillin) and acylaminopenicillins (piperacillin, azlocillin, and mezlocillin).
     These agents have similar spectrums of activity as the aminopenicillins but with additional activity against several gram negative organisms of the family
Enterobacteriaceae, including many strains of Pseudomonas aeruginosa.
    Like the aminopenicillins, these agents are susceptible to inactivation by beta-lactamases.
💊These agents may be used alone or in combination with Aminoglycosides.

When given orally, different penicillins are absorbed at different degrees depending on their stability in acid and their adsorption to food.
💊 Penicillins can be given by intramuscular or intravenous injection.
💊Penicillins become widely distributed in the body fluids, passing into joints, into pleural and pericardial cavities, into bile, saliva, milk and across the placenta.
💉 Being lipid-insoluble, they do not enter mammalian cells.
💉They do not cross the blood-brain barrier (BBB) unless the meninges are inflamed, in which case they readily reach therapeutically effective concentrations in cerebro-spinal fluid (CSF).
💊Elimination of most penicillin is mainly renal and occurs rapidly. 90% occurs by tubular secretion.
• Tubular secretion of penicillins can be partially blocked by probenecid, which raises their plasma concentration and prolongs their action.

Resistance to Penicillin
      The production of β-lactamases:
🔗 β -lactamase production is particularly important in staphylococci, though other
organisms (Neisseria gonorrhoeae, Haemophilus spp.) also produce these enzymes.
🔗Streptococci do not produce β-lactamase enzymes.
🔗One solution is the concomitant use of β -lactamase inhibitors, such as clavulanic acid.
    A reduction in the permeability of the outer membrane and thus a decreased ability of the drug to penetrate to the target site.
    The occurrence of modified penicillin-binding sites. This is particularly important in methicillin-resistant staphylococci.

Clinical uses of penicillin
Penicillin can be used to treat:

1.Bacterial meningitis due to N. meningitidis, Strep. pneumoniae: Benzylpenicillin, high doses intravenously

2.Bone and Joint Infections (e.g. with Staph. aureus): flucloxacillin

3.Skin and soft tissue infections (e.g. with Strep. Pyogenes or Staph. aureus):
benzylpenicillin, flucloxacillin.

4.Animal bites (often mixed organisms): Co-amoxiclav.

5.Pharyngitis (from Strep. pyogenes): Phenoxymethylpenicillin orally.

6.Otitis Media (organisms commonly include Strep.pyogenes, H. influenzae): Amoxicillin

7. Bronchitis in patients with chronic obstructive airways disease (mixed infections
common): Amoxycillin orally.
8.Community-acquired Pneumonia, not severely ill (e.g. with Strep. pneumoniae):
amoxycillin orally.

9.Urinary Tract Infection
(e.g. with E. coli): Amoxycillin orally.

10.Gonorrhoea: Amoxycillin plus probenecid (orally), plus other antibiotics

11.Syphilis: Usually, benzathine penicillin and procaine penicillin intramuscularly is spared for neurosyphylis.

12.Endocarditis (e.g. with Strep. viridans or Enterococcus faecalis): Benzylpenicillin, plus an aminoglycoside.

13. Serious infections with Pseudomonas aeruginosa: piperacillin intravenously.

Unwanted Effects
Hyper-sensitivity reactions.
💊Skin rashes and fever are common.
💊Acute anaphylactic shock which may, in some cases, be fatal but is fortunately very rare.
💊Haematologic disturbances.
💊 Alteration of the bacterial flora in the gut, particularly the broad-spectrum type penicillin.

Cephalosporins
General Information
💊The cephalosporin ring structure is derived from 7-aminocephalosporanic acid
💊 While the penicillins are derived from 6-aminopenicillanic acid
💊Both structures contain the basic beta-lactam ring but the cephalosporin structure allows for more gram-negative activity than the penicillins and aminopenicillins.
💊 Cephalosporins are grouped into ‘generations’ by their antimicrobial properties.
💊 The first cephalosporins were designated ‘first generation.’ while later; more extended
spectrum cephalosporins were classified as second and third generation cephalosporins.
💊Three generations of cephalosporins are recognized and a fourth has been proposed.
        Significantly, each newer generation of cephalosporins has greater gram-negative
antimicrobial properties than the preceding generation.
        Conversely, the ‘older’ generations of cephalosporins have greater gram positive
(staphylococcus and streptococcus) coverage than the ‘newer’ generations (except
ceftriaxone/cefotaxime).
💊Gram-positive coverage diminishes as gram-negative coverage improves with each
successive generation of cephalosporins.
💊Because of this relationship, first generation cephalosporins are useful in treating skin
and urinary infections.
💊Total daily dosage of individual cephalosporins is similar within each generation.
💊Frequency of dosing decreases with increasing generation(s).
💊 Palatability improves (probably) with increasing generations.

Most second and third generation cephalosporins have not been approved for use in patients less than six months of age.

First generation cephalosporins have activity against staphylococcus and streptococcus,
along with Proteus, E. coli, and Klebsiella.

The second generation cephalosporins also have H. influenza activity

The third generations have greatly expanded gram negative coverage.

First Generation Cephalosporins
• Cefadroxil (Duricef-generic available)
• Cephalexin (Keflex-generic available)
• Cephradine (Velosef-generic available)

Second Generation Cephalosporins
• Cefaclor (Ceclor)
• Cefuroxime Axtel (Ceftin)
• Cefprozil (Cefzil)
• Loracarbef (Lorabid)

Clinical Uses
💊Active against beta-lactamase producing H. influenza and have been primarily been used in to treat sinusitis otitis or lower respiratory infections.
💊Can be used in mixed anaerobic infections.
💊Cefuroxime is the only second generation drug that crosses the blood-brain barrier (BBB)
but is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should not be used.

Third Generation Cephalosporins
  Ceftazidime
Ceftizoxime
Cefpodoxime
Ceftriaxone

Clinical Uses
💊Have expanded gram negative coverage and the ability of some to cross the blood-brain
barrier (BBB)
💊Used to treat meningitis caused by Pneumococci, meningococci and H. influenza.
💊Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin-resistant strains of pneumococci.
💊Should not be used to treat enterobacter infections even if the isolate appears susceptible
due to the emergence of resistance.

Adverse Effects
Allergic Manifestations
        The cephalosporins should be avoided or used with caution in individuals allergic to penicillins (about 5 to 7% show reactivity).
        In contrast, the incidence of allergic reactions to cephalosporins is 1-2% in patients without a history of allergy to penicillins.
Disulfiram-like Effect
             When cefoperazone is ingested with alcohol or alcohol-containing medications, a disulfiram-like effect is seen, because these cephalosporins block the second step in alcohol oxidation, which results in the accumulation of acetaldehyde.
Bleeding

Bleeding can occur with cefamandole or cefoperazone, because of anti-vitamin K effects.
Administration of the vitamin corrects the problem.

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