Antimicrobials Pharmacology Notes PDF

ANTIMICROBIALS Reference: Lehne, Pharmacology for Nursing Care  https://byjus.com/biology/difference-between-gram-positive-and-gram-negative-bacteria/ Hans Christian Gram (Danish scientist who developed the staining method in 1884 in Berlin)/Carl Friedländer, German pathologist who determin...

ANTIMICROBIALS Reference: Lehne, Pharmacology for Nursing Care  https://byjus.com/biology/difference-between-gram-positive-and-gram-negative-bacteria/ Hans Christian Gram (Danish scientist who developed the staining method in 1884 in Berlin)/Carl Friedländer, German pathologist who determined the bacterial cause of pneumonia in 1882). The technique made bacteria more visible in stained lung tissue sections. Streptococcus pneumoniae (pneumonia) Escherishia Coli (UTI) Group A Streptococcus (tonsillitis, Neisseria Gonorrhea (STD) pharyngitis) Haemophilus influenza (tonsillitis, otitis) Staphylococcus Aureus (skin infection) Pseudomonas Aeroginosa (hospital) UTI: Urinary tract infection; STD: Sexually transmitted diseases  Mycoplasma pneumonia (pneumonia) Size < Chlamydia trachoma (STD) Typical Bacteria Legionella pneumophila (pneumonia) Complicated reproduction Obligate (enriched parasites media/host) Atypical Bacteria Do not Colorless contain cell with gram wall staining STD: Sexually transmitted diseases Antimicrobials’ Classifications 1. Chemical structure 2. Source: Natural {Fungy/bateria} vs. synthetic vs. semisynthetic 3. Spectrum of activity (narrow vs. broad) 4. Antimicrobial activity{Bacteriostatic* (tetracyclines) vs. bactericidal (penicillins)} 5. Kinetic (oral/systemic) 6. Mechanism of action Mechanism Selective inhibition of similar targets of action https://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism Hydrophilic vs. hydrophobic  Hydrophilic Antibiotics Lipophilic Antibiotics ß-lactams Macrolides Penicilins Fluoroquinolones Cephalosporins Tetracyclins Carbapenems Chloramphenicol Glycopeptides Rifampicin Aminoglycosides Linezolid Limited VD Unable to passively diffuse through Large VD PM of eukaryotic cells Free diffuse through PM of eukaryotic Inactive against intracellular cells pathogens Active against intracellular pathogens Eliminated renally as unchanged Eliminated by hepatic metabolization drugs VD: volume of distribution; PM: Plasma membrane Choice of antimicrobials & determinants of successful therapy Factors influencing the choice of an antimicrobial agent or its dosage: - age, renal & hepatic function, pregnancy, host genetic factors - site of infection (abscesses: poor vascularity & anaerobic conditions, prosthetic material: promotes the formation of a bacterial biofilm that impairs phagocytosis + slowly growing bacteria) Pharmacokinetics: i.e., formulation Treatment of UTI by renally excreted drugs. Crossing of the blood-brain barrier UTI: Urinary Tract Infection Combinations of Antimicrobials Additive (indifferent) effect: the activity of two drugs in combination is equal to the sum (or a partial sum) of their activity when separately used. Synergistic effect: the activity of two drugs in combination is greater than the sum of their activity when separately used. Antagonistic effect: the activity of two drugs in combination is less than the sum (or a partial sum) of their activity when used separately. Generally: Bactericidal + bactericidal =? Bactericidal + bacteriostatic =? Combinations of Antimicrobials Empiric therapy: neutropenic patients, unknown cause of infection., i.e., critically ill patients Treatment of polymicrobial infections (abdominal infection, aerobic/anaerobic organisms, etc.) Enhance antimicrobial activity (add/syn) Pseudomonas infections: B-lactam agent & Aminoglycosides  BUT: Problems with combination Antimicrobials ◦ Increased toxicity/adverse events ◦ Increased cost ◦ Superinfection ◦ Candida vaginalis ◦ Clostridium Difficile diarrhea →pseudomembranous Colitis: Unabsorbed drug alters gut flora; 2º overgrowth of C. difficile Some C. difficile elaborates exotoxin-producing diarrhea and pseudomembranous colitis  Acquired microbial resistance Mutation types: ◦ The drug does not reach its target (efflux and reduced permeability) ◦ Drug inactivation (enzymatic degradation) ◦ Target modification/overproduction of the target How: ◦ Vertically (acquired resistance is transferred from parent to offspring during division) ◦ Horizontally: rapid and can be disseminated to other strains +MDR ◦ Transduction: Viral DNA ◦ Transformation; free DNA incorporation ◦ Conjugation: Passage of DNA through a sex pilus. Relationship between antibiotic use and the emergence of drug- resistant microbes “creating selection pressure favoring the growth of resistant strain” 1. Microbes compete with one another for available nutrients. 2. Antimicrobial kills the sensitive organisms. 3. Resistant organisms flourish.  Different classes of antimicrobials Learning objectives Mechanisms of action Mechanisms of drug resistance Adverse Reactions SULFONAMIDES AND ANTIMICROBIAL ANTIFOLATES https://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism  Hypersensitivity https://madhavuniversity.edu.in/sulfonamide-derivatives.html Sulfonamides Activity 1. Bacteriostatic effect against a wide range of Gram-positive and Gram-negative microorganisms and also are active against toxoplasma, Nocardia species, and chlamydia. 2. Sulfonamides alone are usually reserved for the treatment of nocardiosis and toxоplasmosis. Mechanism of action The structural resemblance between Sulfanilamide and PABA is essential for sulfanilamide activity Sulfanilamide p-aminobenzoic acid (PABA) → Competitive inhibitor of dihydropteroate synthase Mechanism of action Pteridine +PABA Dihydropteroate Sulfanilamides synthetase Sulfanilamide p-aminobenzoic acid Dihydropteroic acid (PABA) Glutamate Selectivity 1. Microbes can synthesize the Dihydrofolic acid precursors to dihydrofolic acid; we Dihydrofolate reductase cannot. 2. Microbes have dihydropteroate Tetrahydrofolic acid synthetase; we do not. 3. Microbes are impermeable to folic DNA Proteins RNA acid; we actively transport it. Co-trimoxazole = Trimethoprim (TMP) + sulfamethoxazole (SMZ) Bactrim, Septra (TMP, Diaminopyrimidines, Bacteriostatic) + (SMZ, Sulfonamides, Bacteriostatic) Mechanism of action: synergistic effect Pteridine +PABA Dihydropteroate Sulfanilamides synthetase Selectivity Dihydropteroic acid Both microbes and humans can reduce Glutamate dihydrofolic acid using dihydrofolate reductases Dihydrofolic acid BUT: The microbe dihydrofolate reductase differs from ours Trimethoprim Dihydrofolate reductase →Trimethoprim inhibits theirs; not ours Tetrahydrofolic acid →{MTX (2nM) vs. TMP (30.000nM)} DNA Proteins RNA  ADVANTAGES OF THE COMBINATION Both compounds have a similar half-life (~10 hours) Synergistic effect: two bacteriostatic drugs produce bactericidal action when combined Trimethoprim enters many tissues and has a larger volume of distribution The combination has a wider antibacterial spectrum The combination delays the development of bacterial resistance The MIC of each component can be reduced 3-6 times CLINICAL USE OF SULFONAMIDES More than 70 years after their discovery, sulfonamides continue to be used, though rarely as single agents. They are cheap, easy to administer orally, narrow spectrum, and well tolerated. Treatment and prophylaxis of simple urinary tract infections due to gram- negative bacteria. Sulfonamide Toxicity Photosensitivity Hemolytic anemia Competition for bilirubin binding sites on albumin can cause kernicterus in neonates, especially in premature infants, since their blood-brain barrier is not fully developed Renal damage due to sulfonamide crystals deposition → hydration and urine alkalinization. Idiosyncratic Reactions: - Hemolysis in glucose-6-phosphate-dehydrogenase (G6PD) deficiency - Drug fever, skin rashes, joint pain, and lymphadenopathy. - Long-acting sulfonamides → Stevens-Johnson syndrome Risk in slow acetylators  Trimethoprim Toxicity Rare Rash, nausea and/or vomiting in 3-5% Folate deficiency in nutritionally “deprived” (folate deficient, pregnant, malnourished, alcoholic) patients --> megaloblastic anemia, thrombocytopenia, and neutropenia.  Quinolones https://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism  Highly protein-bound Mostly used in UTI Nalidixic acid Cinoxacin Ofloxacin Norfloxacin Ciprofloxacin Pneumoniae Fluoroquinolones (2nd, 3rd, 4th generation) Enoxacin Lomefloxacin Levofloxacin Modified 1st generation quinolones Not highly protein bound Wide distribution to urine and other Sparfloxacin Gatifloxacin tissues Limited CSF penetration Trovafloxacin Moxifloxacin  FQs Inhibit 2 types of DNA topoisomerases (IV and II Mechanism of action (DNA gyrase)) 1. Topoisomerase IV -Decatenates DNA for separation into daughter cells during DNA replication -Main target in gram-negative pathogens 2. DNA gyrase -Introduces negative superhelical twists and removes positive twists ahead of replication fork during DNA replication It also functions as Topoisomerase IV in organisms lacking this enzyme (i.e., tuberculosis and H. pylori) http://www.factive.com/factive/healthcare/healthcare_mechanism-of actions.jsp The main target of DNA gyrase is gram-positive pathogens. Quinolones are selective, targeting the Type II prokaryotic Topoisomerase II and IV but not the eukaryotic ones*  Quinolones therapeutic uses Broad spectrum of activities Urinary tract infections Sexually Transmitted diseases Infectious diarrhea Diabetic foot infection Mycobacterial diseases (M. Tuberculosis, M. avium) Respiratory tract infections Ciprofloxacin: 500 mg single dose for meningococcal prophylaxis Excellent distribution in lungs, kidneys, stool, bile, joints & soft tissues macrophages, neutrophils. Not good in CNS.  Adverse Reactions Body System Adverse Event Nausea Cardiovascular Hypotension, tachycardia, prolonged QT interval. Vomiting Central Nervous System Headache, dizziness, sleep disturbances, mood change, confusion, psychosis, tremor, seizures Diarrhea Integumentary Rash, pruritis, photosensitivity, leg pigmentation, urticaria Headache Dizziness Hepatic Transient increase in aminotransferases, cholestatic, jaundice, hepatitis, hepatic failure Insomnia Mucoskeletal Arthropathy, tendinitis, tendon rupture: CONTRAINDICATED IN CHILDREN Renal Azotemia, crystalluria, hematuria, interstitial nephritis, nephropathy, renal failure Other Drug fever, chills, serum sickness-like reaction, anaphylaxis, angioedema, bronchospasm, vasculitis, hypo/hyperglycemia Antimicrobials that weaken the bacterial cell wall: Beta-lactams Structure and composition of gram-positive and gram-negative cell walls Penicillin-binding proteins (PBP) activity and inhibition β- Lactam i.e., Penicillin PBPs have two enzymatic activities crucial to synthesizing the peptidoglycan layers of bacterial cell walls: TP: cross-links amino acid side chains GT: links subunits of the glycopeptide polymer A linker region separates the TP and GT domains The glycosyltransferase is thought to be partially embedded in the membrane Penicillin The first true antibiotic antibacterial produced by microorganisms Yellow fluid exuding from the surface of Penicillium chrysogenum fungus  Sir Alexander Fleming: Discovery 1929 Staphylococcal colony undergoing lysis Scottish biologist and pharmacologist After World War I -> elected Professor of Bacteriology at the University of London in1928 Penicillium Accidentally discovered Penicillin while studying the mold properties of Staphylococci Described the mold as being from the genus Penicillium Normal Staphylococcal Named the substance released as Penicillin colony PENICILLIN WAS BORN 7TH MARCH, 1929  Bacterial Resistance Alteration in the PBP site Reduced permeability Beta-lactamase b-Lactamase Mechanism of Action b-Lactamase hydrolyzes (opens) b-Lactam ring Penicilloic acid lacks sterically constrained D- ala-D-ala homology  b-lactamase inhibitors Clavulanate competes with Penicillin for access to b-Lactamase Active Site b-Lactamase hydrolyzes (opens) b-Lactam ring of Clavulanate instead of Penicillin PENICILLIN FAMILY Penicillin G Pharmacokinetics Half life: short Absorption: not well absorbed ◦ acid unstable, erratically absorbed when given PO Distribution CSF penetration ◦ increased penetration with inflammation Elimination ◦ only 10% metabolized, but some products allergenic ◦ renal excretion (glomerular filtration and secretion via organic anion pump [probenecid inhibits]) Penicillins: PK Enhancement Orally available ◦ Penicillin V - acid stable Longer acting ◦ Procaine penicillin ◦ Benzathine penicillin ◦ Very, very slowly absorbed IM. (activity for 26 days) ◦ Syphilis treatment (STD)  Extended Spectrum Aminopenicillins Ampicillin ◦ Spectrum includes some gram negatives incl. H.influenza ◦ Orally bioavailable - 50% ◦ Toxicity ◦ Diarrhea ◦ Skin rash - macular and evanescent. Not allergy. Amoxicillin ◦ 100% bioavailability  Penicillinase-Resistant Penicillins Not hydrolyzed by beta-lactamase Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin Methicillin (historic interest) ◦ "Methicillin Resistant” Staph. aureus (MRSA) or S. epidermidis (MRSE) Anti-pseudomonal Carboxypenicillins Carbenicillin (prototype, no longer used) ◦ Similar to ampicillin but less effective against strep. Ticarcillin ◦ Twice as potent as carbenicillin Ticarcillin with clavulanate Broad spectrum, including pseudomonas Anti-pseudomonal Aminoacylpenicillins Class Drugs ◦ Azlocillin ◦ Mezlocillin ◦ Piperacillin ◦ Piperacillin/tazobactam Extended Spectrum including Pseudomonas A bit broader coverage than ticarcillin b-lactamase inhibitor combinations ◦Amoxicillin and clavulanate oral (Augmentin) ◦Ampicillin and sulbactam intravenous (Unasyn) ◦Piperacillin and tazobactam (Tazocin) Penicillin’s Adverse Effects Allergy due to beta-lactam ring Non-Allergic ◦ Common ◦ Gastrointestinal symptoms (oral drugs) ◦ Sodium Overload (Ticarcillin) ◦ Much Less Common ◦ Bone Marrow Depression ◦ Hepatitis ◦ Impairment of platelet Aggregation (PCN, Ticarcillin) ◦ Seizures  CEPHALOSPORINS https://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism Cephalosporins Adverse Effects ❑Diarrhea, nausea, vomiting ❑Pain and inflammation at the injection site ❑Nephrotoxicity ❑Allergic reactions ❑Liver toxicity if taken with alcohol (cefamandole, cefoperazone) because these block alcohol oxidation. ❑Bleeding (cefamandole, cefoperazone, ceftriaxone) ❑Miscarriage or stillbirth ❑Defects of newborn babies Imipenem (carbapenem) ◦ Disrupts bacterial cell wall synthesis ◦ Spectrum very broad ◦ Gram positive, including enterococcus ◦ Gram negative, including pseudomonas ◦ Anaerobes, including Bacteroides ◦ Empiric treatment for serious hospital infections ◦ Resistant to most “classic” ß-lactamases ◦ Resistance is emerging (Carbapenemase) ◦ Post-antibiotic effect, even for gram-negative. Excessively metabolized in the kidney Inactivated by dehydropeptidases I in renal tubules, resulting in low urinary concentrations (Imipenem + Cilastatin) Imipenem Adverse Events Nausea and vomiting – common Seizure risk Cross allergy with other ß-lactams Increased bleeding tendency  Meropenem Has a reduced potential for causing seizures in comparison with imipenem Aztreonam Gram-negative coverage (NO activity against Gram-positive bacteria or anaerobes) Relatively Resistant to beta-lactamase Well tolerated No cross-allergenicity with penicillin (except ceftazidime) The half-life is 1–2 hours and is greatly prolonged in renal failure  VANCOMYCON USE Bactericidal Vancomycin is used for treating MRSA and MRSE as well as an empiric therapy for gram-positive bacteria (When not possible to treat with pen/ceph) Drug of last resort MRSA: Methicillin-resistant Staphylococcus aureus; MRSE: Methicillin-resistant Staphylococcus epidermidis  Vancomycin Absorption - none; Used in its PO form: ◦ to treat C. difficile colitis Used in its IV form: – When unable to use pen/ceph for G+ cocci, especially staph – Trt. Of MRSA & MRSE PO: per os = oral administration  Vancomycin Pharmacokinetic Absorption: Poorly absorbed orally in GIT but used to treat Clostridium difficile (colitis) When given parenterally, it distributes widely into tissues Excretion by renal filtration GIT: gastro intestinal tract Vancomycin: Toxicity Hypersensitivity ◦ skin rash ◦ eosinophilia ◦ drug fever Phlebitis (Inflammation of a vein) “Redman” - flushing with rapid IV dosing Ototoxicity – increased serum concentration and prolonged administration (potentiated by other ototoxic drugs) Nephrotoxicity Inhibitors of translation Ribosomal inhibitors are site-specific Ribosomal Class Drug examples subunit 30S Aminoglycosides Genta/Tobra-mycin Amikacin Tetracyclines Doxycycline, etc… Glycylines Tigecycline 50S Streptogramins Daflopristine Quinuprustine VRE Oxazolidinediones Linezolid Phenicols Chloramphenicol Lincosamides Clindamycin Macrolides Ery-, Azi-, Clari- thromycin, VRE: Vancomycin resistant enterococci Inhibitors of translation Aminoglycosides Bactericidal  Clinical Use Severe infection with Aerobic Gram-Negative organisms Rarely used alone because of toxicity In combination with b-lactams (synergism) Used in combination to treat serious hospital infections. Cannot be mixed in the same saline bag (for example Penicillin will inactivate aminoglycoside)  Aminoglycosides: Adverse Effects Nephrotoxicity: ◦ Disruption of cytoplasmic membrane ◦ Rarely severe, reversible ◦ Cumulative ◦ Careful with other drugs such as vancomycin, cephalosporins Ototoxicity ◦ Uncommon Neuromuscular paralysis ◦ May be: Exceedingly rare ◦ Cochlear: hearing loss risks: Similarities between bacterial and eukaryotic mitochondrial ribosome (LUCKILY REVERSIBLE) ◦ Long-term (e.g., >8 weeks) treatment: o peripheral neuropathy o optic neuritis o lactic acidosis Clindamycin (bacteriostatic) – Gram-positive cocci: but now have less toxic drugs –Most anaerobes (Bacteroides fragilis) Clindamycin: Toxicity Pseudomembranous Colitis: high association ◦ Treatment ◦ Metronidazole (Oral or IV) (First Line of therapy) ◦ Oral vancomycin in failures (Second Line option) Macrolides (bacteriostatic) Mostly reserved for Atypical Organisms (although they can be active against gram-positive and gram-negative) Penicillin Allergy Strep. Pneumoniae Group A Streptococcus Macrolides: Intra-Group Differences Erythromycin (prototype) ◦ Cheap ◦ GI Side Effects Azithromycin ◦ Once Daily ◦ Expensive Clarithromycin ◦ Expensive ◦ Twice Daily  Macrolides: toxicity –Safest of all antimicrobials –Nausea and vomiting –Erythromycin and Clarithromycin inhibit CYP3A CYP (Cytochromp450) Metronidazole (Flagyl) (Bactericidal) IV therapy for serious anaerobic infections such as clostridium Oral therapy for infections caused by parasites {i.e., intestinal infections (amebiasis, giardiasis) and genital infections (trichomoniasis)} Oral (and IV) therapy for colitis due to C. Difficile Metronidazole: Mechanism of action A reduced form interacts with DNA, causing DNA strand breakage. →(DNA integrity) Resistance: ◦ Decreased activity of reductases needed to reduce it to its active form ◦ Less common with anaerobes Metronidazole: Adverse effects GI disturbance and metallic taste Neurotoxicity (dizziness & vertigo) Blood dyscrasias and neutropenia Metronidazole, such as Disulfiram, inhibits acetaldehyde dehydrogenase necessary for alcohol metabolism (increased levels of acetaldehyde due to decreased acetaldehyde dehydrogenase) CYP (Cytochrome P450) interactions EXAMPLES EXAMPLES Sulfonamides Aminoglycosides Trimethoprim Beta-lactams Linezolid Vancomycin Clindamycin Quinolones Macrolide The Antifungal Amphotericin B for serious systemic mycosis Binds to ergosterol → more permeable membrane → leakage of ions->Death Amphotericin toxicity Infusion related ◦ Chills, fever, rigors, nausea, headache ◦ Pretreatment with diphenhydramine, acetaminophen, glucocorticoid (to decrease the toxicity) Nephrotoxicity Anemia Azole antifungal agents Itraconazole (Sporanox) Fluconazole (Diflucan) Clotrimazole ◦ (Beta micoter and lotriderm cream mix ◦ canesten vaginal suppository) Miconazole (Daktarin cream) Ketoconazole (Nizoral cream) Oil based creams may weaken latex condoms and diaphragms Mechanism of action is to inhibit a type of CYP enzyme involved in ergosterol synthesis Itraconazole Therapeutic uses: ◦ Systemic and superficial fungal infections Pharmacokinetics: ◦ IV and PO ◦ Variable absorption ◦ Inhibits CYP3A4 Toxicity ◦ Cardiac suppression ◦ Liver injury ◦ Drug-drug interactions