Penicillins and Cephalosporins Antibiotics

• The text provides a detailed overview of antibacterial antibiotics, specifically focusing on penicillins and cephalosporins, including their history, mechanisms of action, resistance, and structure-activity relationships

History of Antibiotics

• Alexander Fleming discovered penicillin serendipitously in 1929, which was later initiated into therapy by Howard Florey and Ernst Chain
• Louis Pasteur and Jules Joubert observed in 1877 that certain bacteria could inhibit the growth of others
• Selman Waksman discovered Streptomycin, the first effective agent against TB, cholera, and typhoid fever in 1943 and also isolated Neomycin

Antibiotics

• Antibiotics are products of metabolism or synthetic analogs that antagonize the growth of microorganisms, effective in low concentrations

Other Terminologies

• Empiric Therapy involves administering treatment before a definitive diagnosis is made
• Definitive Therapy involves treatment after diagnosis
• Selective Toxicity refers to drugs selectively targeting bacterial cells while disregarding human cells
• Chemotherapeutic Spectra are classified as narrow, extended, or broad-spectrum, depending on their range of activity against different microorganisms

Bacterial Resistance

• Some bacteria, especially Gram-negative bacteria, exhibit natural resistance to antibiotics
• Biochemical mechanisms of penicillin resistance include bacterial elaboration of enzymes (β-lactamases), decreased permeability of penicillins, changes in the number and nature of porins, and altered affinity of penicillin-binding proteins (PBPs)
• Gram-negative bacteria include Bacilli like Escherichia coli, Helicobacter pylori, Legionella pneumophila, and Cocci like Neisseria gonorrheae and Neisseria meningitidis

Beta-Lactam Antibiotics: Penicillins

• Penicillins inhibit bacterial cell wall synthesis by binding to and inhibiting penicillin-binding proteins (PBPs) and obstruct the cross-linking of peptidoglycan strands, compromising the cell wall, leading to bacterial cell lysis and death

General Structure of Penicillins and SAR

• Beta-Lactam Ring is crucial for antibacterial activity and modification leads to loss of activity
• Thiazolidine Ring is important for stability and binding to PBPs, contributing to the correct positioning of the β-lactam ring
• Acyl Side Chain/R-Group determines the spectrum of activity, β-lactamase resistance, and pharmacokinetics, located at position 6 on the β-lactam ring
• Carboxyl (-COOH) Group is hydrophilic and enhances water solubility, affecting drug absorption, distribution, and excretion

Natural Penicillins

• Penicillin G (Benzylpenicillin) is the DOC for Syphilis but is given IV/IM due to acid-labile nature
• Penicillin V (Phenoxymethylpenicillin) is acid-stable and given PO, with uniform concentration in the blood

Penicillinase Resistant/Anti-Staphylococcal Penicillins

• Methicillin is the prototype PDR penicillin, not inactivated by penicillinase, but has adverse effects like severe interstitial nephritis and nephrotoxicity
• Nafcillin has substituents in positions ortho to the point of attachment of the aromatic ring and can be used in patients with renal failure
• Oxacillin is restricted to the treatment of infections caused by staphylococci resistant to Pen G and is highly resistant to inactivation by penicillinase
• Cloxacillin has a Cl- atom ortho to the position of attachment of the phenyl ring, enhancing its oral absorption
• Dicloxacillin has chlorine atoms on both carbons ortho to the position of attachment of the phenyl ring, to enhance its stability and produce high plasma concentrations

Aminopenicillins

• Ampicillin has a broader antibacterial spectrum than Pen G and is used to treat infections caused by gram (-) bacilli
• Amoxicillin has an antibacterial spectrum similar to ampicillin, resistant to acid, and absorption is not impaired by food

Carboxypenicillins

• Carbenicillin is the prototype in carboxypenicillins and is effective in the treatment of systemic & UTI caused by P. aeruginosa, Proteus spp and Providencia spp
• Ticarcillin is an isostere of carbenicillin and has an antibacterial spectrum similar to carbenicillin

Ureidopenicillins

• Mezlocillin has a similar antibacterial spectrum to carbenicillin & ticarcillin and more active against most Klebsiella spp, P. aeruginosa and anaerobes
• Piperacillin is the most potent ureidopenicillin

Carbapenems

• Imipenem is the first-ever carbapenem, has potent antibacterial activity and is inactivated by dehydropeptidase-1 (DHP)
• Cilastin is a DHP inhibitor, used with Imipenem
• Thienamycin is derived from Streptomyces cattleya

Monobactams

• Aztreonam is active against aerobic gram (-) bacilli and used to treat urinary, lower RTI, intra-abdominal & gynecological infections, & septicemias

Beta-Lactamase Inhibitors

• Class I Inhibitors possess an atom leaving group at position 1, prolong inactivation by enzymes and prevent degradation of β- lactams
• Clavulanic Acid has a broad spectrum activity when combined, covering Gram-positive, Gram-negative and anaerobic bacteria
• Sulbactam is a synthetic penicillin derivative, and is used in tx of skin, tissue, intra-abdominal, & gynecological infections
• Tazobactam is more potent than sulbactam

Cephalosporins

• Cephalosporins inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs) involved in peptidoglycan synthesis
• They are categorized into generations, with later generations generally having increased resistance to β-lactamases and broader Gram-negative activity
• ADRs can include cross-sensitivity with penicillins, hypersensitivity reactions, and severe reactions

Cephalosporin SAR

• Beta-Lactam Ring binds to Penicillin-Binding Proteins (PBPs), inhibiting peptidoglycan synthesis
• Dihydrothiazine Ring increases β-lactamase resistance & greater stability in acidic conditions
• Acyl-Side Chain/R-Group affects affinity to PBPs

Cephalosporin Generations

• Cefazolin, Cephalexin, and Cefadroxil are 1st Generation Cephalosporins with the best Gram-positive coverage
• Cefotetan, Cefoxitin, and Cefuroxime are 2nd Generation with better Gram-negative coverage
• Cefotaxime, Ceftazidime, and Ceftriaxone are 3rd Generation Cephalosporins with strong Gram-negative coverage
• Cefepime is a 4th Generation Cephalosporin, covers pseudomonas and is highly beta-lactamase resistant
• Ceftaroline fosamil and Ceftobiprole are 5th Generation Cephalosporins and have Anti-MRSA activity