Beta-Lactam Antibiotics and Penicillins

• Β-lactam antibiotics are named due to the four-membered Β-lactam ring chemical component
• They contain a Beta lactam ring in their molecular structure

Classes of Β-Lactam Antibiotics

• Penicillin derivatives
• Cephalosporins
• Carbapenems
• Monobactams

Penicillins

• In 1928, Alexander Fleming observed that a mould contaminating staphylococcus variants in a culture caused bacteria lysis
• The fungus belonged to the genus penicillium, so Fleming named the antibacterial substance penicillin
• The penicillin nucleus contains fused thiazolidine and Β-lactam rings to which side chains attach during amide linkage
• Penicillin is also known as Substituted 6-aminopenicillanic acid

Classification of Penicillins

• Naturally-occurring penicillins are original penicillins
• Penicillin-G (Benzyl penicillin) is the only naturally-occurring penicillin in clinical use
• Penicillin-G is not usually administered orally because it is acid labile
• Parenteral routes are used for Penicillin-G administration (IV or IM)
• Semi-synthetic penicillins are classified as acid-resistant alternatives to penicillin-G
• Phenoxymethyl penicillin (penicillin-V) is an example of a semi-synthetic penicillin
• Penicillinase-resistant penicillins include Cloxacillin, Oxacillin, Nafcillin, Dicloxacillin, and Methicillin
• These congeners have side chains protecting the Β-lactam ring against staphylococcus penicillase
• They are not resistant to Β-lactamases produced by gram-negative bacteria
• Extended-spectrum penicillins include Amino penicillins like Ampicillins, Bacampicillins, and Amoxicillin
• Carboxy penicillins include Carbenicillin and Ticarcillin
• Ureido penicillins include Mezocillin, Azlocillin, and Piperacillin
• Ureido penicillins are active against P. aeruginosa
• Extended spectrum antibiotics are sensitive to Β lactamase
• They are administered in combination with Β lactamase inhibitors like clavulanic acid, sulbactam, and tazobactam
• Penicillins vary in their resistance to gastric acid and therefore their oral bioavailability
• Parenteral formulations of ampicillin, piperacillin, and ticarcillin are available for injection
• Penicillins are polar compounds and are not metabolized extensively
• They are usually excreted unchanged in the urine via glomerular filtration and tubular secretion
• Nafcillin is excreted mainly in the bile, and ampicillin undergoes enterohepatic cycling
• The plasma half-lives of most penicillins vary from 30 minutes to 1 hour
• Procaine and benzathine forms of penicillin G are administered intramuscularly and have long plasma half-lives

Mechanism of Action of Β-Lactam Antibiotics

• Β-lactam antibiotics inhibit the synthesis of bacterial cell walls via interference
• They interfere with the transpeptidase enzyme that is responsible for cross-linking peptidoglycan cell walls
• The enzymes are associated with a group of proteins in gram-positive and gram-negative bacteria named Penicillin-binding proteins (PBPs)
• Different PBPs comprise the bacteria cell wall, and different Β-lactam antibiotics may target PBPs leading to variations in activity and resistance
• The cell walls of bacteria are essential for their normal growth and development
• Peptidoglycan consists of a heteropolymeric cell wall component
• It gives rigid mechanical stability by virtue of its highly cross-linked latticework structure
• Gram-positive microorganisms exhibit a thick cell wall that consists of 50-100 molecules thick, while Gram-negative bacteria have a wall thickness of 1-2 molecules
• Peptidoglycan composed of glycan chains are linear strands made of two alternating amino sugars N acetylglucosamine & N acetyl muramic acid, cross linked by peptide chains
• Transpeptidase inhibition causes spheroplast formation and rapid bacteria lysis
• Beta-lactam antibiotics are bactericidal drugs, inhibiting cell wall synthesis through:
  • Binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) in the bacterial cytoplasmic membrane
  • Inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall
  • Activation of autolytic enzymes that cause lesions in the bacterial cell wall

Penicillin G Pharmacokinetics

• Acid labile, and destroyed by gastric acid
• Absorption is rapid if given IM
• Distributes widely but penetration of cavities & CNS is poor
• Plasma half-life is 30 minutes
• Elimination is via kidney by tubular secretions
• Aged people and those with kidney failure excrete penicillins slowly
• Tubular secretion can be blocked by probenecid, achieving higher and longer-lasting plasma concentrations
• Probenecid decreases the volume of distribution of penicillin

Adverse Effects

• Pain at injection site
• Thrombophlebitis if given IV
• Bleeding in higher doses because of its interference with platelet function
• Hypersensitivity reactions like rash, itching, urticaria, fever
• Wheezing
• Angioedema
• Serum sickness
• Exfoliative dermatitis
• Clinical uses include therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes
• Allergy is worse with parenteral than oral administration

Ampicillin

• Active against all organisms sensitive to penicillin G
• Also effective against many gram-negative bacilli like H. influenza, E. coli, Proteus, Salmonella, H. pylori, Enterococci, L. monocytogenes, and Shigella

Amoxicillin

• This is a close congener of ampicillin and similar in all respects
• Used in the triple combination regimen for the treatment of PUD for H. pylori eradication
• The triple combination regimen is Amoxicillin/Protein-pump inhibitor/Clarithromycin

Clinical Uses of Penicillins

• Urinary tract infections (UTI)
• Respiratory tract infections (Bronchitis, sinusitis, otitis media)
• Meningitis
• Gonorrhea
• Typhoid fever
• Bacillary dysentery
• Cholera
• Septicemia

Cephalosporins

• Semisynthetic antibiotics derived from cephalosporium-c, obtained from the cephalosporium fungus
• Chemically related to penicillin
• Nucleus consists of a B-lactam ring fused to a dihydrothiazine ring (7-aminocephalosporamic acid)
• Cephalosporins are similar to penicillins but more stable to many bacterial B-lactamase & therefore have a broader spectrum of activity

Generations of Cephalosporins

• Five generations of cephalosporins
• The generations organized by their chronological sequence of development and spectrum & potency
• Gram-positive activity decreases from 1st to 5th generation, while gram-negative activity increases

1st Generation Cephalosporins

• Cefazolin is the prototype 1st generation cephalosporin and is given parenterally. The t½ is 2 hours
• Cephalexin is the most commonly used orally effective 1st generation, t½ is 1 hour and excreted unchanged in the urine
• Other 1st generation cephalosporins include Cefadroxil, Cefalotin, Cephradine, Cephapirin, and Cefaloridine

2nd Generation Cephalosporins

• Increased gram-negative coverage and is not active against P. aeruginosa
• Parenteral examples include Cefuroxime and Cefoxitin
• Oral examples include Cefaclor, Cefprozil and Cefuroxine axetil, Cefotetan and Cefamandole
• Cefuroxime and cefaclor are active against anaerobes but not B. fragilis
• Cefuroxime is resistant to gram-negative beta lactamases
• It is active against gram-positive cocci & certain anaerobes except B. fragilis

3rd Generation Cephalosporins

• Highly resistant to beta lactamases produced by gram-negative bacteria
• Active against gram-positive cocci and anaerobes
• Few can inhibit pseudomonas
• Parenteral examples include Cefotaxime, Cefoperazone, Ceftriaxone, and Ceftazidime
• Oral examples include: Cefixime, Cefdinir, Ceftibuten, Cefpodoxine, Ceptamet pivoxil, Ceftizoxine, Cefditoren pivoxil, and Moxalactam
• Cefotaxime is the prototype of 3rd generation
• Cefotaxime is not active against anaerobes esp. B. fragitis, S. aureus & P. aeruginosa
• It penetrates the CSF very well because it is lipid soluble
• T½ = 1 hour
• Excretion via kidneys
• Treats Meningitis, pneumonia, gonorrhea, pyelonephritis, UTI, septicemia, typhoid fever

Ceftriaxone

• It is very lipid soluble and penetrates the CSF
• Long half-life (8hrs) distinguishes it from other cephalosporins
• Eliminated in the urine and bile salt
• For bacterial meningitis, multi-resistant typhoid fever, complicated UTI, abdominal sepsis, and septicemia
• Side effects are Hypoprothrombinaemia, Bleeding, Haemolysis
• Ceftriaxone can be combined with sulbactam or tazobactam to overcome resistance

Ceftazidime

• Highly active against pseudomonas, but less active against S. aureus, Cocci and anaerobes like B. fragilis
• T1/2 = 1.5 - 1.8 hours
• For Neutropenic fever with harmatological malignancies and Burns
• Side effects are Neutropenia, Thrombocytopenia, Increased ALT, AST, Blood urea

4th Generation Cephalosporins

• Cefepime and Cefpirome: parenteral
• Similar activity to 3rd generation
• Highly resistant to B-lactamases
• Active against S. aureus, pseudomonas but not MRSA
• T1/2 - 2 hours
• Excretion via kidneys

5th Generation Cephalosporins

• Ceftaroline, Ceftolozane, Ceftobiprole
• Ceftolozane is combined with tazobactam
• Active against most mutations in PBPs & MRSA and also active against pseudomonas and anaerobes
• Crosses the blood brain barrier

Uses of Cephalosporins

• ENT, RTI, skin infections
• UTI, soft tissue infections (cefuroxine, cefotaxime, ceftriaxone)
• Penicillinase-producing staphylococcal infections
• Septicemia
• Surgical prophylaxis (cefazolin)
• Meningitis
• Gonorrhea

General Adverse Effects of Cephalosporins

• Pain at IM injection site
• Phlebitis - inflammation of vein
• Diarrhea
• Neutropenia
• Nephrotoxicity
• Hypersensitivity
• Bleeding due to hypoprothrombinaemia uses the same mechanism as Warfarin, and is common in cancer, intraabdominal infections & renal failure
• Disulfiram-interactions with alcohol (esp. cefoperazone & cefobitan)
• Cephalosporins are sensitizing & this elicit hypersensitivity because it originates from fungi and it contains sulfur

Beta-Lactamase Inhibitors

• Β-lactamases are a family of enzymes produced by many gram-positive and gram-negative bacteria that inactivate Β-lactam antibiotics by opening the Β-lactam ring
• They include Clavulinic acid, Sulbactam, Tazobactam, and Avibactam
• Clavulinic acid / Amoxicillin = Augmentin
• clavulinic acid/ Ticarcillin = Timentin
• Sulbactam/ Ampicillin = Sulbacin
• Sulbactam/ Ceftriazone
• Sulbactam/Ceftoperazone
• Tazobactam/Piperacillin = Tazobid
• Tazobactam/Ceftriaxone

Mechanisms of Resistance to Penicillin & Cephalosporins

• Alteration or acquisition of novel PBPs
• Microorganisms are intrinsically resistant due to structural differences in the PBPs that are the target for the drugs
• A sensitive strain may acquire resistance of this type by developing high molecular weight PBPs that have decreased affinity for the antibiotic
• Altered PBPs with decreased affinity for Β-lactam antibiotics are acquired by homologous recombination btw PBPs genes of different bacteria species
• Decreased entry into the bacteria:
• Bacterial resistance to the Β-lactam antibiotics are caused by the inability of the agent to penetrate to its site of action
• In gram-positive bacteria, the peptidoglycan polymer is very near the cell surface
• Some gram-positive bacteria have polysaccharide capsules
• Small Β-lactam antibiotic molecules penetrate the bacteria to the outer layer of the cytoplasmic membrane, where the final stages of peptidoglycan synthesis take place
• Gram-negative surfaces are more complex and the inner membrane of bacteria and mycobacteria are covered with lipopolysaccharides and a capsule
• The outer membrane functions as an impenetrable barrier to some antibiotics
• Some small hydrophilic antibiotics diffuse through aqueous channels by proteins called Porins
• Broader spectrum penicillins like ampicillin and amoxicillin and most of the cephalosporins diffuse through these pores in E-coli outer membrane
• Number/size of pores in the outer membrane vary among different gram-negative bacteria
• An example is P. aeruginosa, which lacks the classical high-permeability porins
• Efflux Pumps serve as another mechanism of resistance, removing the antibiotics from the site of action before it can affect the bacteria
• An important mechanism of Β-lactam resistance in E-coli, P. aeruginosa, and N. gonorrhea
• Production of Β-lactamases
• Bacteria can destroy Β-lactam antibiotics enzymatically
• Β-lactamases destroy the Β-lactam ring and render it incapable of binding to the PBPs and thus the bacteria becomes resistant
• In gram-positive bacteria, the Β-lactamases are generally inducible, resulting in a large amount of the enzymes being produced in the presence of the drug
• In gram-negative bacteria, the Β-lactamase enzymes are produced constitutively, even when the antibiotic is not present

Carbapenems

• Broadest antibacterial spectrum of any antibiotic and used in the treatment of multi-drug resistant infections
• Administration via IM or IV
• Excretion via Kidneys, hence dosage adjustment is required in kidney failure
• Examples: Doripenem, Imipenem , Meropenem and Ertapenem
• Imipenem is inactivated by dihydropeptidases in a renal tubule, so it is given together with an inhibitor of renal dihydropeptidases called cilastatin

Monobactam (Monocyclic Β-lactam ring)

• Has a monocyclic Beta-lactam ring
• They are active against only gram-negative bacteria including P. aeruginosa
• They have no activity against gram-positive bacteria
• Excretion via the kidneys
• Examples: Azactam and Aztreonam

Other Cell Wall Inhibitor Antibiotics

• Vancomycin
• Bacitracin
• Fosfomycin
• Cycloserine
• They inhibit different steps in the process of the peptidoglycan synthesis in the bacteria cell wall

Test your knowledge of beta-lactam antibiotics, including penicillins and cephalosporins. Explore their mechanisms of action, spectrum of activity, excretion pathways, and clinical uses. Learn about specific drugs like Ceftriaxone and Ceftazidime, and their roles in treating bacterial infections.