Antibacterial Drugs

• The presentation provides an overview of antimicrobial agents, focusing on antibacterial drugs.
• Rajan Radhakrishnan is the presenter.
• The presentation date is March 13, 2025.

Learning Objectives

• Recognizing pathogenic bacteria and their characteristics
• Understanding the targets of antibacterial drugs
• Listing major antibacterial drug classes and their mechanisms
• Listing common drug indications, side effects, contraindications and interactions
• Explaining resistance to antibacterial drugs

Terminology

• Antimicrobials include antibacterials, antifungals, antivirals, and antiparasitics.
• Antibiotics are antibacterial substances from microorganisms, loosely used for all antibacterials.
• Disinfectants are used on external nonliving surfaces.
• Antiseptics are used on external skin or living tissues.
• Bactericides kill bacteria in vitro.
• Bacteriostatics inhibit bacterial growth or replication in vitro.
• Broad spectrum antimicrobials act on a wide range of bacteria.
• Narrow spectrum antimicrobials act on a specific group of bacteria.

Origin and Selective Action of Antimicrobials

• Antimicrobials originate from natural sources and chemical synthesis.
• Semisynthetic antimicrobials include amoxicillin.
• Synthetic antimicrobials include sulfa drugs.
• Antibacterial drugs target eukaryotic vs. prokaryotic cells.
• Antifungal drugs target eukaryotic vs. eukaryotic cells.
• Antiviral drugs target eukaryotic intracellular mechanisms used by viruses.
• Anticancer drugs target normal cells vs. cancer cells within the same organism.
• Antibacterials selectively harm target organisms without affecting host cells

Major Pathogenic Bacteria

• Gram-positive cocci: Staphylococcus, Streptococcus, Enterococcus
• Gram-negative cocci: Neisseria
• Gram-positive rods: Corynebacterium, Listeria, Bacillus, Clostridium, Actinomyces, Nocardia
• Gram-negative rods exist.
• Enteric tract organisms: Escherichia, Salmonella
• Pathogenic bacteria inside and outside the tract: Shigella, Vibrio, Campylobacter, Helicobacter
• Pathogenic bacteria from outside the tract: Klebsiella-Enterobacter-Serratia group, Pseudomonas, Proteus-Providencia-Morganella group, Bacteroides
• Respiratory tract organisms: Haemophilus, Legionella, Bordetella
• Organisms from animal sources: Brucella, Francisella, Pasteurella, Yersinia
• Not readily Gram stained: Mycobacterium, Mycoplasma, Treponema, Leptospira
• Obligate intracellular bacteria: Chlamydia, Rickettsia

Antibacterial Classes and Targets

• Cell Wall Synthesis Inhibitors: Beta-lactams (Penicillins, Cephalosporins, Carbapenems), Glycopeptides (vancomycin)
• Cell Membrane Disruptors: Polymyxins
• Folate Synthesis Inhibitors: Sulfonamides, Trimethoprim
• Protein Synthesis Inhibitors: Aminoglycosides, Tetracyclines, Macrolides, Oxazolidinones, Lincosamides
• DNA Synthesis Inhibitors: Fluoroquinolones
• Antibacterials target cell wall, plasma membrane, folate synthesis, protein synthesis, and nucleic acid synthesis.

Cell Wall Inhibitors - Beta-Lactams

• Penicillins, cephalosporins, and carbapenems are beta-lactam antibiotics.

Penicillins

• Penicillins inhibit cell wall synthesis during active multiplication.
• They are bactericidal and kill bacteria.

Beta-Lactams - Mechanism of Action

• Bacterial cell walls have glycopeptide polymers linked by amino acid bridges.
• Cross-linking is catalyzed by transpeptidases (PBPs).
• Penicillins and cephalosporins inhibit transpeptidases (PBPs).

Preventing Degradation of Beta-Lactamase

• Beta-lactamase degrades beta-lactam antibiotics.
• Clavulanate, sulbactam, and tazobactam inhibit beta-lactamase.
• Amoxicillin + clavulanate potassium = Augmentin.

Allergy to Penicillins

• Penicillin and its metabolites are haptens and IgE-mediated and can cause allergic reactions.
• Desensitization is possible for sensitive patients
• Epinephrine manages anaphylactic shock.

Common Penicillins

• Penicillin G: parenteral administration, effective against Gm +ve
• Penicillin VK: oral administration, effective against Gm +ve
• Ampicillin: broader spectrum, effective against Gm +ve
• Amoxicillin: broader spectrum, effective against Gm +ve

Cephalosporins

• Cephalosporins are beta-lactam antibiotics and are bactericidal.
• They inhibit cell wall synthesis in actively dividing cells like penicillins.
• Cephalosporins are derived from Cephalosporium spp.

Cephalosporins - Different Generations

• First Generation: Non-toxic, excreted via the kidney, mainly active against Gram +ve. Includes cephalexin, cefazolin, cefadroxil
• Second Generation: Heterogeneous group, excreted via the kidney, more resistant to beta-lactamase, less active against Gram +ve and active against Gram -ve. Includes cefaclor, cefoxitin, cefuroxime, cefotetan, and cefprozil.
• Third Generation: Crosses BBB, increased resistance to beta-lactamase, expanded Gram –ve coverage and lesser Gram +ve coverage Includes cefotaxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftazidime, ceftibuten, and ceftriaxone.
• Fourth Generation: More resistant to beta-lactamase, crosses BBB, active against both Gram +ve and -ve. Includes cefepime.
• Fifth Generation: Active against MRSA. Includes ceftaroline.

Cephalosporins - Precautions

• Cephalosporins can cause hypersensitivity reactions similar to penicillins.
• Some individuals may tolerate them due to structural differences.
• Cephalosporins can cause renal toxicity and superinfections.
• Disulfiram-like interaction with alcohol is possible.
• Warnings include cross-allergenicity with penicillins, neurotoxicity, coagulation abnormalities, hemolytic anemia, and arrhythmia with cefotaxime.
• Drug Interactions (DIs) include alcohol, anticoagulants, and antacids.

Carbapenems

• Carbapenems are semisynthetic beta-lactam antibiotics and are bactericidal.
• They have a wide spectrum of activity, are resistant to beta-lactamase, and have high tissue penetration including the CNS.
• They are cleared renally, and usually reserved for resistant strains.
• Common carbapenems include ertapenem, meropenem, and imipenem.
• Imipenem is inactivated by dehydropeptidases, so it is administered with cilastatin.
• Adverse drug reactions (ADR) include GIT disturbances and hypersensitivity.

Glycopeptides - Vancomycin

• Vancomycin is produced by Streptococcus orientalis.
• It binds to cell wall precursor units and inhibits RNA synthesis via a dual mechanism, and resistance is uncommon.
• It is bactericidal and active against Gram +ve bacteria, including MRSA and is reserved for serious infections.
• Warnings include infusion reactions, ototoxicity, nephrotoxicity, and neutropenia.
• Parenteral vancomycin should be used for systemic effect and not orally absorbed.
• Therapeutic drug monitoring (TDM) aims to maintain plasma levels within a therapeutic range to prevent resistance.
• Drug interactions include bacterial vaccines.

Cell Membrane Disruptors - Polymyxins

• Member drugs include Polymyxin B and Polymyxin E (Colistimethate).
• They can sometimes disrupt the human cell membrane and can be very toxic.
• Polymyxin B binds to phospholipids, alters permeability, and damages the bacterial cytoplasmic membrane, permitting leakage of intracellular constituents, and is used topically with other antibacterials.
• Polymyxin B is for both Gram +ve and –ve infections, reserved for serious infections; intrathecal administration only in meningeal infections.
• Black box warnings include nephrotoxicity, neurotoxicity, concomitant use with nephrotoxic agents should be avoided, neuromuscular blockade, caution with use in pregnancy.
• Polymyxin E (Colistimethate) is a surface-active polymyxin antibiotic that penetrates into a bacterial cell membrane.
• Polymyxin E (Colistimethate) is effective in Gram –ve infections via injection for systemic effect.
• Warnings/Precautions/ADRs include neurotoxicity, nephrotoxicity, respiratory arrest, use with caution with NMBs.