Lecture 5 - Introduction to Antibiotics (Part 1) Lecture Notes PDF

Lecture 5 — Introduction to Antibiotics (Part 1) Dr. Ed El Sayed NURS 342 Objectives General mechanism of action of: 1. cell wall inhibitors 2. cell membrane inhibitors 3. protein synthesis inhibitors Major indications/spectrum of activity Classification of ß-lactamases Toxicities associated with an...

Lecture 5 — Introduction to Antibiotics (Part 1) Dr. Ed El Sayed NURS 342 Objectives General mechanism of action of: 1. cell wall inhibitors 2. cell membrane inhibitors 3. protein synthesis inhibitors Major indications/spectrum of activity Classification of ß-lactamases Toxicities associated with antibiotic therapy Drug class MOA when/what Toxicity anything unique 1. Cell wall inhibitors A. Clycopeptides Penicillins Loading… i. Penicillin G and V ii. Aminopenicillins iii. Penicillinase resistant penicillins B. Cephalosporins C. Carbapenems D. Monobactam Miscellaneous Bacterial Peptidoglycan Cell Wall Structure A. Penicillins Beta-lactam antibiotic Binds and inactivates the penicillin- binding protein (PBP) on the Loading… transpeptidase, the enzyme needed for cross-linking of peptidoglycan polymer chains Cell wall becomes osmotically unstable — this results in cell lysis i. Penicillin G and V Cover streptococcus infections, anaerobic infections and spirochetes (e.g. syphilis) Will NOT reliably cover staphylococcus infections or Gram negative infections (e.g. E. coli) Many organisms produce penicillinase — an enzyme produced by many bacteria that destroys the penicillin molecule (i.e. resistance) Penicillin V is ORAL Penicillin G is INTRAMUSCULAR (benzathine formulation) or INTRAVENOUS (aqueous formulation) ii. Aminopenicillins Peperacillin tazobactam covers pseudomonas infection Introduction of amine group to the basic structure of beta-lactam Ampicillin, Amoxicillin Better oral absorption compared to penicillin V Same coverage as penicillins IN ADDITION TO Gram negative coverage (but they will still not cover staphylococcus infections) Beta-lactamases are enzymes produced by certain bacteria — these enzymes breakdown beta-lactam antibiotics (resistance) Combining the aminopenicillins with beta-lactamase inhibitors (like ampicillin/sulbactam or amoxicillin/clavulanic acid) expands Gram negative coverage and adds staphylococcus coverage Piperacillin/tazobactam covers pseudomonas infection iii. Penicillinase/ß-lactamase resistant beta-lactams antibiotics Modification in structure to make the drug molecule bulky (resist breakdown by enzymes) Oxacillin, cloxacillin, dicloxacillin and nafcillin Will reliably cover streptococcus and staphylococcus infections Will NOT reliably cover Gram negative, anaerobic or methicillin resistant staphylococcus aureus (MRSA) infections B. Cephalosporins Also contain beta-lactam ring (i.e. will also work by inhibiting PBP) Subdivided into generations (1st to 5th) All generations cover Gram positive agents, and as you go higher in the generation the ability to cover Gram negative agents increases 5th generation is unique because the cover MRSA infections Loading… Unique cephalosporins: Which cephalosporins cover anaerobic infections? Cefotetan, Cefoxitin Which cephalosporins cover pseudomonas? Ceftazidime, Cefepime Which cephalosporin covers MRSA? Ceftaroline C. Carbapenems Also contain beta-lactam ring (i.e. will also work by inhibiting PBP) Imipenem, meropenem and ertapenem These agents resist degradation by beta-lactamases All agents cover pseudomonas except ertapenem Only imipenem is combined with cilastatin — an inhibitor of an enzyme that degrades imipenem into toxic metabolite in the kidney D. Monobactam Only one agent in class — Aztreonam Also contains beta-lactam ring (i.e. will also work by inhibiting PBP) Resists degradation by beta-lactamases Excellent coverage against Gram negative infections including pseudomonas No reliable Gram positive or aerobic coverage It does not cross-react with other beta-lactam antibiotics E. Glycopeptides This class does NOT contain beta-lactam ring (i.e. will NOT work by inhibiting PBP) They inhibit cell wall synthesis by another mechanism (bind the terminal molecule of the peptidoglycan and prevent further elongation of cell wall polymers) Agents include vancomycin, telavancin, dalbavancin and oritavancin Good coverage against Gram positive infections, including MRSA No reliable Gram negative or anaerobic infections Vancomycin is used FIRST LINE to treat C. diff infection and MRSA bacteremia Telavancin, dalbavancin and oritavancin are longer acting vs vancomycin F. Miscellaneous cell wall inhibitors Two agents: bacitracin and fosfomycin Do not contain beta-lactam ring Bacitracin: Inhibits NAM (one of the building blocks of the peptidoglycan polymer) which prevents cell wall growth Bacitracin is active against Gram positive infections and mainly used topically (for wounds and burn injuries) Fsofomycin: inhibits pyruvyl-transferase — an enzyme required for cell wall synthesis Fosfomycin is mainly active against Gram negative organisms (some minor Gram positive organisms but has no anaerobic coverage); primarily used to treat urinary tact infections Toxicities associated with cell wall inhibitors All antibiotics in general are associated with gastrointestinal upset and rash (may or may not by pruritic) All antibiotics are associated with infection (thrush in mouth and vagina) due to disruption of normal microbiota is often seen Unique toxicities: - Cefepime: Encephalitis - Ceftriaxone: Kernicterus in neonates (increases bilirubin level in blood) - Vancomycin: Renal toxicity, “Red-man” syndrome (I HATE this terminology!) - Carbapenems (mainly imipenem): Seizures (lowers the threshold) Classification of ß-lactamases Serine ß-lactamses (Do not require zinc) Class C Hydrolyze cephalosporins Cannot be inhibited by clavulanic acid or tazobactam e.g. Enterococcus Metallo ß-lactamses (Require zinc) Class A & D Hydrolyze penicillins & carbapenems Can be inhibited by clavulanic acid or tazobactam e.g. Klebsiella, E. coli Class B Hydrolyze all ß-lactam antibiotics except aztreonam Cannot be inhibited by clavulanic acid or tazobactam e.g. Pseudomonas Note: these examples can also be non-resistant, and some bacteria can produce more than one type of ß-lactamases 2. Cell membrane inhibitors A. Daptomycin Penetrates cell membrane (with the help of Ca2+ ions) resulting in efflux of K+ from bacterial cell (hyperpolarizes the cell) Only active against Gram positive agents including MRSA (no anaerobic coverage) Can not be used for lung infections (destroyed by alveolar surfactant) Toxicity: Muscle injury (rhabdomyolysis) A. Polymyxins (aka colistin) Detergent-like activity, destroys cell membrane by direct chemical interaction with LPS Only active against Gram negative agents (no anaerobic coverage) Used as LAST LINE agent for kidney infections Toxicity: Nephrotoxicity, neurotoxicity 3. Protein Synthesis Inhibitors Ribosomes are cellular organelles that translate mRNA into protein (amino acids) There are two main ribosomal subunits in bacteria (30S and 50S) This class of antibiotics stop important protein synthesis by inhibiting either the 30S or 50S subunit. A. 30S Inhibitors Tetracyclines: Tetracycline Doxycycline Minocycline Tigecycline Demeclocycline Aminoglycosides: Gentamicin tobramicin streptomycin amikacin neomycin I. Tetracyclines This class is active against both Gram positive and Gram negative organisms Treats rickettsial infections (e.g. Lyme disease) Doxycycline treats and prevents sexually transmitted infections Only doxycycline and tigecycline are active against MRSA Tetracycline is primarily used to treat H. pylori infection Minocycline is primarily used to treat acne Demeclocycline is not used to kill bacteria, but to treat a hormonal disease (syndrome of inappropriate ADH release “SIADH”) I. Tetracyclines Toxicity: - GI disturbances - Photosensitivity - Teeth discoloration in children (primarily tetracycline) Drug interaction: - This class can form insoluble complexes with divalent ions (Ca2+, Mg2+) - Avoid with dairy products or supplements Tetracycline associated cutaneous drug eruption II. Aminoglycosides This class is primarily active against Gram negative infections Has narrow therapeutic index (i.e. higher risk of toxicity with slight change in dose or concentration) Can be combined with ß-lactam antibiotics for synergy Intravenous gentamicin is used to treat Pseudomonas and Klebsiella Amikacin primarily reserved for infections not responding to gentamicin Neomycin is often combined with bacitracin for topical skin infections or burns Tobramycin is used topically for eye infections II. Aminoglycosides Toxicity: - GI disturbances - Nephrotoxicity - Ototoxicity - Neuromuscular toxicity - Dermatitis Loading…. B. 50S Inhibitors Macrolides: Erythromycin Azithromycin Clarithromycin Fidaxomicn I. Linezolid II. Clindamycin I. Macrolides This class is active mainly against Gram positive organisms (plus very few Gram negative infections) Also covers spirochetes, mycobacteria avian complex (MAC) and chlamydia Azithromycin is used first line for traveler’s diarrhea and Bortadella pertussis (whooping cough) Fidaxomicin is primarily used to treat C. diff infection Owing to better pharmacokinetics and less risk for drug interactions, azithromycin is the primary agent used in this class Erythromycin is rarely used as antibiotic — mainly used to stimulate peristalsis (GI movement) in Parkinson disease Macrolide toxicity: - GI disturbances - Ototoxicity - QT prolongation - Erythromycin and clarithromycin inhibit CYP450 III. Linezolid Only active against Gram positive organisms Mainly reserved for MRSA and vancomycin-resistant enterococcus infections Toxicity: - Thrombocytopenia - Lactic acidosis Drug interaction: Linezolid increases risk of “serotonin syndrome” if taken with other serotonergic drugs IV. Clindamycin Active against anaerobic infections (mainly those above the diaphragm) Also active against MRSA infection In toxic shock syndrome (caused by staphylococcus and streptococcus), clindamycin is added to vancomycin to prevent the release of toxins Topical formulations sometimes used to treat skin conditions like acne Toxicity: - Pseudomembranous colitis (high risk for C. diff infection) - Metallic taste D-Test for clindamycin: - Clindamycin resistance closely follows macrolide resistance - Bacteria known to be resistant to macrolides is grown on a plate with two discs (one containing erythromycin (e) and the other containing clindamycin (c)) - If there is inhibition of bacterial growth around the clindamycin disc, the bacteria is susceptible to clindamycin (D-test negative) and clindamycin can be used - If there is no inhibition of bacterial growth around the clindamycin disc, the bacteria is resistant to clindamycin (D-test positive) and clindamycin can not be used, this is because erythromycin was able to induce the resistance genes against clindamycin in the bacteria V. Chloramphenicol Active against Gram negative organisms and anaerobic infections Limited used in contemporary clinical practice due to toxicity - Bone marrow suppression - Hemolytic anemia - “Gray baby syndrome” due to inability of hepatic enzymes in neonates to metabolize the drug Question Which one of these antibiotics is MOST toxic to human cells? A. Ceftaroline B. Doxycycline C. Daptomycin D. Azithromycin E. Ampicillin/Sulbactam “If you can't yet do great things, do small things in a great way.”