PHAR1059 Antimicrobial Drugs 2024-2025 PDF

Antimicrobial Drugs (Antibiotics) NURS1059 2024-2025 Method for Studying  In this section we are going to use the following method for learning Antimicrobials 1. Understand the organism’s structure  Bacteria & Virus 2. Understand the basic way to kill the organis...

Antimicrobial Drugs (Antibiotics) NURS1059 2024-2025 Method for Studying  In this section we are going to use the following method for learning Antimicrobials 1. Understand the organism’s structure  Bacteria & Virus 2. Understand the basic way to kill the organism  General MOA 3. Link the name of the drug to the General MOA 4. Link the purpose to the drug 5. Link the adverse effects to the drug BACTERIA STRUCTURE REVIEW (Cell Walls and Capsules) BACTERIA STRUCTURE IS KEY TO A MOA CELL WALLS  Nearly all prokaryotes (bacteria) have a cell wall. Cell walls provide physical protection and prevent the cell from bursting in a hypotonic environment.  When stained with Gram stain, cell walls of bacteria are either Gram-positive, with simpler cell walls containing peptidoglycan, or Gram-negative, with less peptidoglycan, and more complex and more likely to cause disease. Gram Positive vs Gram negative Like an Onion, Gram Neg- has layers  https://cen.acs.org/articles/93/web/2015/04/New-Spin-Old-Gram-Stain.html BACTERIA STRUCTURE IS KEY TO A MOA  The cell wall of many bacteria is covered by a capsule, a sticky layer of polysaccharides or protein.  The capsule enables bacteria to adhere to their substrate or to other individuals in a colony shields pathogenic bacteria from attacks by a host’s immune system. ANTI-BACTERIAL AGENTS  Through the action of an anti-microbial agent, they produce a “cidal” or “stasis” effect  Cidal = killed, bactericidal, germicides  Stasis = inhibit growth, bacteriostatic means limits or stops growth  Sepsis = bacterial contamination  Asepsis is the absence of significant contamination - Aseptic technique used in surgery helps minimize contamination SOURCES OF ANTIBIOTICS  Natural antibiotics are derived from fungal sources  Natural antibiotics are often more toxic than synthetic antibiotics  Organisms develop resistance faster to natural antimicrobials as they have been pre-exposed to these compounds in nature  Semi-synthetic drugs were developed to decrease toxicity and increase effectiveness, partly natural, partly synthetic  Synthetic drugs have an advantage in that the bacteria are not exposed to these compounds in their natural environment  They are also designed to have greater effectiveness and less toxicity SOURCES OF ANTIBIOTIC AGENTS Sources of Antibacterial Agents  Natural - mainly fungal sources  Semi-synthetic - chemically-altered natural compound  Synthetic - chemically designed in the lab 11 PHAR1059 2024 SOURCES OF ANTIBIOTIC AGENTS 1. The original antibiotics were derived from fungal sources. These can be referred to as “natural” antibiotics Antibiotic resistance develops faster to the natural antimicrobials because they have been pre- exposed to these compounds in nature. Natural antibiotics are often more toxic than synthetic antibiotics. 2. Semi-synthetic drugs were developed to decrease toxicity and increase effectiveness 3. Synthetic drugs have an advantage that the bacteria are not exposed to the compounds in the natural environment. They are also designed to have even greater effectiveness and less toxicity. There is an inverse relationship between toxicity and effectiveness as you move from natural to synthetic antibiotics STRUCTURE & FUNCTION (MOA) Antibiotics are usually classified based on their structure and/or function. Structure - molecular structure. ß-Lactams - Beta-lactam ring Aminoglycosides - vary only by side chains attached to basic structure Function - how the drug works, its mode of action. 5 functional groups These are all components or functions necessary for bacterial growth Indicate the “Target” of action for antibiotics in a bacteria Classification by Chemical “Structure” Classified into broad categories based on their chemical structures and mechanism of action  Penicillins  Sulphonamides  Cephalosporins  Carbapenums  Macrolides  Quinolones  Aminoglycosides  Tetracyclines  Other miscellaneous categories PHAR1059 2024 FUNCTION CLASSIFICATION Five functional groups cover most antibiotics “How do we kill the organism” General MOA ✓ This is how we will proceed in this lecture classify on MOA 1. Inhibitors of cell wall synthesis 2. Inhibitors of protein synthesis 3. Inhibitors of membrane function 4. Anti-metabolites 5. Inhibitors of nucleic acid synthesis FUNCTION CLASSIFICATION (INSIDE VS OUTSIDE ) OUTSIDE: INSIDE: Alteration of membranes and  Damage to proteins or nucleic cell wall acids  Denaturation of proteins Membranes control passage of causes them to change shape nutrients and wastes and lose function Damage causes leakage which  DNA and RNA control the interferes with growth or production of proteins. causes death of the cell  If proteins cannot be made, this is incompatible with life Inhibitors of Cell Wall Synthesis INHIBITORS OF CELL WALL SYNTHESIS 1. Beta-lactams CLASS OF ANTIBIOTIC  Penicillins  Cephalosporins  Monobactams (Aztreonam) SUBCLASS  Carbapenems (Penems)  β-lactamase Inhibitors (Penam) 2. Glycopeptides 3. Fosfomycins BETA LACTAMS β-lactam ring in its molecular structure MOA = inhibit cell wall synthesis by the bacteria The most widely used group of antibiotics (about 50 currently on market) Humans have no cell wall (no peptidoglycan), so this is a good selective medication Typically, they share the following characteristics They are all bactericidal They are non-toxic They are relatively inexpensive They are organic acids, and most are soluble in water BETA LACTAMS Subgroup Names of Penicillin Narrow Pen G, Pen V Spectrum Cloxacillin, Oxacillin Penicillin Extended Amoxicillin, Ampicillin Spectrum Carboxypenicillins, Ureidopenicillins Carbapenems Imipenem, Ertapenem Cephalosporins Cefazolin, Cefaclor, Cefixime, Cefuroxime, Ceftriaxone Monobactams Aztreonam β-lactamase Tazobactam, Clavulanic acid Inhibitors Combinations Amoxicillin/clavulanic acid, Imipenem/cilastatin, Piperacillin/tazobactam PENICILLIN SUBCLASS (ß-Lactams) MOA  Bactericidal  Interfere with the synthesis of bacterial cell wall  Do not hinder growth of human cells Effect  Weakens bacteria cell wall, destroy bacteria by osmotic lysis  Most effective against bacteria that rapidly multiply Indication (Used for)  Treats otitis media, pneumonia, meningitis, UTI’s, syphilis, gonorrhoea, prophylaxis for surgical or dental procedures  PENICILLIN SUBCLASS (ß-Lactams) Contraindications  Drug allergy Adverse Effects  Diarrhea, GI upset  Thrombophlebitis (IV penicillin),  Electrolyte imbalance  Hyperkalemia & hypernatremia due to having larger amounts of it in the formulation  PENICILLIN SUBCLASS (ß-Lactams) Contraindications (Drug Interactions Cautions) NSAIDS Displacement from plasma binding proteins Increases to larger amounts of free active med Methotrexate Decreased kidney elimination = increased amounts of circulating med Warfarin Increases the effect of warfarin by reducing vitamin K in the GIT Oral contraceptive May reduce the efficacy of contraceptive (not sure of mechanism) Pg 701, Table 43.5  CEPHALOSPORIN SUBCLASS (ß-Lactams) MOA Bactericidal Broad- spectrum, interferes with bacterial cell wall synthesis and bind to penicillin-binding proteins (PBP) in bacteria cell wall Four generations producing various actions Are semi-synthetic antibiotic Produced by a fungus but synthetically altered to produce an antibiotic Are structurally and pharmacologically related to penicillin  CEPHALOSPORIN SUBCLASS (ß-Lactams) Indication (Used for)  Penicillin allergies (with caution)  Urinary and Respiratory Tract Infections (UTI, RTI)  Abdominal infections  Septicemia  Meningitis  Ear infections Adverse Effects  Diarrhea  Secondary infection (oral thrush, yeast infections)  CEPHALOSPORIN SUBCLASS (ß-Lactams) Adverse Events  Thrombophlebitis  Electrolyte imbalances (hyperkalemia, hypernatremia)  Renal (potentially nephrotoxic)  Liver Contraindications (Drug Interactions)  Absorption may be inhibited by  Antacids  H2 antagonist  FE supplements  Alcohol (CIDLR - cephalosporin-induced disulfiram-like reaction)  CEPHALOSPORIN SUBCLASS (ß-Lactams) Cephalosporins (Approved for use in Canada) Gen 1 Cefazolin (IV) Good for use against Gram (+) Staphylococcus and Increasing spectrum of Cephalexin (Keflex®, po) Streptococcus efficacy Cefadroxil Gen 2 Cefuroxime Increased activity against Gram (-) Cefaclor Slightly less activity against Gram (+) Cefoxitin Cefprozil Gen 3 Ceftriaxone (Rocephin®, Very good Gram (-) coverage IV) Reasonable against Gram (+) Ceftazidime Ceftazidime has action against pseudomonas Cefotaxime Cefixime Gen 4 Cefepime Very broad spectrum on Gram (-) (+) Gen 5 Ceftobiprole Similar coverage to Gen 3 and 4 Ceftolozane-tazobactam Also has coverage against MRSA and enterococci https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR00291  CARBAPENUM SUBCLASS (ß-Lactams) MOA  Bactericidal  Binds to penicillin-binding proteins, inhibits bacterial cell wall synthesis  Act against gram-positive and gram-negative aerobic and anaerobic organisms  Broadest antibacterial spectra of any antibiotic to date  Used for: Body cavity, connective tissue infections  Examples: Meropenem, Ertapenem and imipenem Adverse Events  May cause drug-induced seizure activity in a small percentage of clients GLYCOPEPTIDES SUBCLASS (ß-Lactams) MOA  Bactericidal  Glycopeptides have a complex chemical structure  Inhibit cell wall synthesis at a site different than the beta-lactams  Resistance is largely restricted to nosocomial enterococcus faecium  Used for: MRSA, endocarditis (gram + infections)  Example: Vancomycin  GLYCOPEPTIDES SUBCLASS (ß-Lactams) VANCOMYCIN  Inhibits bacterial cell wall by binding to a cell wall precursor, causing cell lysis, may also inhibit RNA synthesis  Used primarily to treat serious infections that cannot be treated with less toxic agents such as penicillin or cephalosporins  Particularly useful in treating clostridium difficile, MRSA  Only comes in IV formulations Adverse Effects  Diarrhea (bloody)  Nausea  Tinnitus  Irritation at IV site GLYCOPEPTIDES SUBCLASS (ß-Lactams) Adverse Events  Hearing loss  Kidney damage  Hypokalemia  Red man syndrome  Anaphylaxis Red man syndrome is an infusion-related reaction  It typically consists of pruritus, an erythematous rash that involves the face, neck, and upper torso.  Can lead to shock  Infusion is stopped while Benadryl is given and then restarted slowly https://www.ncbi.nlm.nih.gov/pmc/articles/PMC270616/#:~:text=penicillins%20and%20cephalosporins. - ,Vancomycin%20can%20cause%20two%20types%20of%20hypersensitivity%20reactions%2C%20the%20red,%2C%20neck%2C%20and%20upper%20torso. ß-Lactam RESISTANT BACTERIA There are mechanisms that bacteria will use to adapt to ß-Lactams 1. Reduce the access of the protein receptors on a bacteria 2. Reduce the binding affinity of the protein receptors on a bacteria 3. Production of beta lactamase, an enzyme that destroys the ß-Lactam Natural or acquired resistance Huge problem in medicine, started when penicillin discovered and immediately overprescribed Staphylococcus Aureus (MRSA) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498059/#:~:text=The%203%20mechanisms%20of%20%CE%B2,%2Dlactams)%20(Table). Anti-Metabolites ANTI-METABOLITES Used primarily as a Bacteriostatic Called folate pathway inhibitors or anti-metabolites Folic acid is essential for the synthesis of DNA and chromosomes in bacteria These drugs compete for folate binding sites and block metabolism of DNA Humans do not synthesize folic acid  This is a good selective medication ANTI-METABOLITES - Sulfonamides Bacteriostatic in low doses Bactericidal in higher doses Introduced in 1930’s – first effective systemic antimicrobial agent- Sulfanilamide Single drug and combinations Indication (Used for) Urinary tract infection (UTI) Ear infections Respiratory tract infections (RTI)  Sulfasalazine is another sulfonamide but is used in the treatment of RA and ulcerative colitis-not for infections ANTI-METABOLITES - Sulfonamides Synthetic derivatives of sulfanilamide Commonly prescribed agents in this subclass are  Sulfadiazine  Sulfamethoxazole  Sulfisoxazole  Trimethoprim/sulfamethoxazole (Cotrimoxaxole, Septra®)  This combination is bactericidal Achieve high levels of concentration in the kidneys, through which they are eliminated, can produce bactericidal effects ANTI-METABOLITES - Sulfonamides Adverse Effects  Nausea, vomiting, anorexia, diarrhea  Rash, photosensitivity  Tinnitus, headache, dizziness, drowsiness, confusion Drug Interactions (Cautions)  Oral hypoglycaemic (Type 2) agents to cause hypoglycaemia  Enhances warfarin effect  Enhances Methotrexate toxicity Contraindications  Known cases of sulphonamides allergy  Pregnancy Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis - SUBCLASSES Subclasses:  Aminoglycosides  MLSK (Macrolides, lincosamides, streptogramins, ketolides)  Tetracyclines  Glycylcyclines  Oxazolidinones  Ansamycins (broad spectrum, maybe anti-viral) We will focus on the 3 most common Inhibitors of Protein Synthesis - AMINOGLYCOSIDES MOA  Bactericidal  Act by binding to ribosomes and prevent protein synthesis in bacterial cells  Usually used in combination with other antibiotics Indication (Used for)  Effective primarily against Gram (-) bacteria that cause  UTI  Wound infections  Septicaemia  Mainstay treatment of nosocomial infections  Reserved mainly for use in life-threatening infections  Monitoring of drug levels required Inhibitors of Protein Synthesis - AMINOGLYCOSIDES Natural antibiotics  Gentamicin  Kanamycin  Neomycin  Streptomycin  Tobramycin Semi-synthetic  Amikacin  Netilmicin  Poorly absorbed when administered orally Inhibitors of Protein Synthesis - AMINOGLYCOSIDES Adverse Effects  Dizziness  Headache  Skin rash  Fever Adverse Events  Not favourable for long-term use due to possible renal failure (5-25%)  Nephrotoxicity can be reversable in some instances  Ototoxic (hearing and balance), headaches, vertigo Interactions:  Any drug that can increase risk of nephrotoxicity  Reduce amount of Vit K so will enhance effects of anticoagulants- what should be checked?  Contraindicated in pregnancy Inhibitors of Protein Synthesis - MLSK (MLSK=Macrolides, lincosamides, streptogramins, ketolides)  Bacteriostatic  But in high enough doses bactericidal  Four different classes of antibiotics which are unrelated in terms of structure, but which have a similar mode of action and spectrum of activity Inhibitors of Protein Synthesis - MACROLIDES MOA  Bacteriostatic, may be bactericidal in high doses  Inhibit protein synthesis in susceptible bacteria (RNA)  Can fight bacteria that get into host cells as opposed to just bloodstream Examples:  Erythromycin  Azithromycin  Clarithromycin Inhibitors of Protein Synthesis - MACROLIDES Indication (Used for)  GIT infections  Respiratory infections  If beta lactams are contraindicated or cannot be used in STDs or soft tissue infections Adverse Effects  GI upset  Vertigo  Rash  Headache Inhibitors of Protein Synthesis - MACROLIDES Adverse Events Cardiac (QT prolongation, Palpitations, chest pain) Hepatoxicity Hearing loss / Tinnitus Contraindications  Macrolides and pimozide is contraindicated, death has resulted from combination drug therapy Interactions: Drugs that compete with liver metabolism Inhibitors of Protein Synthesis - LINCOSAMIDES MOA Bacteriostatic, may be bactericidal  Inhibits protein synthesis by binding to bacterial ribosomes and preventing peptide bond formation, do not interfere with human cells Agents  Lincomycin  Clindamycin - semi-synthetic derivative of lincomycin Inhibitors of Protein Synthesis - TETRACYCLINES MOA  Bacteriostatic Inhibits protein synthesis in susceptible bacteria, binds to portion of ribosome to inhibit bacterial growth Natural tetracyclines:  Demeclocycline,  Oxytetracycline (older)  Tetracycline Semisynthetic tetracyclines:  Doxycycline  Minocycline Inhibitors of Protein Synthesis - TETRACYCLINES Indication (Used for)  Effective against a wide range of gram -ve and gram +ve bacteria  Acne in adolescents  Lyme Disease  Syphilis, Chlamydia  Mycoplasma and some protozoa Adverse Effects  Superinfection (esp. Candida)  GI upset  Photosensitivity Inhibitors of Protein Synthesis - TETRACYCLINES Drug Interactions (Cautions)  Warfarin  Enhances warfarin's effects  Methoxyflurane  Can cause kidney damage  Depending on dose they can cause elevation of BUN  Should not be administered with milk, antacids, iron  Reacts with the calcium, magnesium, Aluminum and iron  Creates an insoluble complex Contraindicated  Children under 8 years (inhibits skeletal growth)  Pregnancy Inhibitors of Nucleic Acid Synthesis Inhibitors of Nucleic Acid Synthesis Quinolones Bactericidal antibiotic MOA = interfere with the synthesis of DNA This MOA is a shared process with human cells There are 2 generations of this category of drugs The first Generation of Quinolones had a very narrow spectrum Gen 1 is not used very much and are more susceptible to bacterial resistance Gen 2 of these drugs are widely used  Fluorquinolones  Subclass of Quinolones Inhibitors of Nucleic Acid Synthesis - FLUROQUINOLONES MOA  Bactericidal Inhibit and impair the replication of bacterial DNA Metabolised by liver and excreted by urine (except for Moxifloxacin) Indications for use in Canada  Fluoroquinolones (taken by mouth or by injection)  For the treatment of many types of bacterial infections UTI’s, soft tissue infections, resp tract infections Adverse Effects  GI upset  Headaches, dizziness  Fever  Tinnitus Inhibitors of Nucleic Acid Synthesis - FLUROQUINOLONES Adverse Events  Tendonitis/Tendinopathy (Achilles tendon rupture)  Peripheral Neuropathy  CNS disorders  Cardiac arrythmias Interactions  Decreases absorption when used with antacids  Decreases absorption of calcium, magnesium https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?linkID=SSR00151 Inhibitors of Nucleic Acid Synthesis - FLUROQUINOLONES Contraindications  Previous allergic reaction to the medications  Certain cardiac disorders that predispose to arrhythmias or bradycardia QT-interval prolongation Uncorrected hypokalemia Hypomagnesemia  Use of medications known to prolong the QT interval or to cause bradycardia Special note (not responsible for testing)  Due to the adverse events listed on previous slide there is some prevailing concerns regarding uses in pregnancy and children under 8 yrs. This is under contention by American Academy of Pediatrics https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/fluoroquinolones#Indications_v1003302 Inhibitors of Nucleic Acid Synthesis - FLUROQUINOLONES DRUG NAME SPECTRUM GEN 1 Nalidixic Active against some Gram negative bacteria. Increasing spectrum & Cinoxacin Highly protein bound drugs. efficacy Short half life. GEN 2 *Norfloxacin* Protein binding (50%). *Ciprofloxacin* Longer half life than previous agents. *Ofloxacin* Improved activity against Gram negative bacteria. Enoxacin GEN 3 *Levofloxacin* Active against Gram negative bacteria. Sparfloxacin Also active against Gram positive bacteria Gatifloxacin Gemifloxacin GEN 4 Trovafloxacin Show extended activity against both strains of *Moxifloxacin* bacteria Clinafloxacin Active against anaerobes and atypical bacteria. Sitafloxacin https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-fluoroquinolones-assessing-potential-risk-persistent-disabling-effects.html https://www.researchgate.net/publication/40849381_Fluoroquinolone_antibacterials_A_review_on_chemistry_microbiology_and_thera peutic_prospects Inhibitors of Nucleic Acid Synthesis - FLUROQUINOLONES For the purposes of this course students are only required to know the fluroquinolones that are approved for use in Canada Starred, Red font and bolded on previous slide 1. Ciprofloxacin (Cipro) 2. Norfloxacin Gen 2 3. Ofloxacin 4. Levofloxacin Gen 3 5. Moxifloxacin (Avelox) Gen 4  General Nursing Considerations for Antibiotics  Take microbiology specimens before antibiotics are started  Blood, Urine C/S (culture and sensitivity)  Tissue swabs C/S (throat, wounds)  Ensure MD or NP is alerted to new C&S results  Always check allergies and be aware of cross-allergies  Be aware of factors that contribute to resistance- pt teaching?  Ensure pre-op antibiotics are given as per protocol  Screen for history of resistant infections (MRSA, VRE, CPE)  Follow instructions on mixing IV drugs  Monitor IV site  Food and drug interactions