Drugs 16 November 2023 12:51 -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Bacterial Cell wall inhibitors How do they work? ➢Parenteral (IV) antibiotics if patient shows signs of systemic infection (i.e., fever, hypotension); immunocompromise; rapid progression of infection; progression despite oral antibiotics; infection near prosthetic material; or inability to take PO. Vancomycin provides excellent empiric coverage. ➢Otherwise oral therapy is indicated. ➢Non-purulent cellulitis: should cover MSSA and Group A streptococcus, the most common organisms involved in cellulitis ➢Purulent cellulitis (this patient): include MRSA coverage. Treat with oral trimethoprim-sulfamethoxazole (TMP-SMX), clindamycin, or doxycycline Tetracyclines Aminoglycosides 30S subunit Macrolides Clindamycin Oxalodinones Chloramphenicol 50S subunit Protein synthesis DNA Gyrase BYE BYE BACTERIA PLEASE DON’T COME BACK Cell membrane Glycopeptide Beta-lactams Fosfomycin Penicillins Cephalosporins Penicilin G Penicilin V AminoPenicilins (Ampicillin, Amoxicllin) Generation 1 More gram + Lipopeptide (Daptomycin) Generation 2 Penicilinase sensitivity Carbapenems Generation 3 Anti-stapholococcal (Oxacilin, nafcillin, methicillin) Generation 4 Monobactams More gram Antipseudomonal (Piperacillin +tazobactam) Generation 5 Novel (2023) Penicillin + Beta lactam inhibitors (Ampicillin+sulbactam) (Amoxicillin + clavulanic acid) Side effects: Hypersensitivty GI disturbances Neurotoxicity Jarisch-Herxheimer reaction Acute interstitial nephritis/ hem. toxicity Infectious diseases Page 1 MRSA specific Dorpinem Ertapenem Imipenem-cilistatin Meropenem Etc. Aztreonam Folate synthesis Trimethoprim/ sulfonamide DNA integrity Metronidazole Nucleic acid synthesis Cell wall synthesis Peptidoglycan Quinolones Glycolipopeptide (telavancin) Polymyxin Antibacterial Drugs 16 November 2023 17:54 Cell wall synthesis agents: Do not attack human cells because they don’t have cell walls, are often the first line drug and are often beta-alactam antibiotics which inihbit peptidoglycan cross-linking - which prevents formation of the cell wall. Vocabulary and translations Therefore, bacteria have evolved antiobiotic resistance through: 1) an enzyme that produces beta lactamae or penicillinase that hydrolyze and destroy drug activity 2) Structural changes to penicillin binding receptors to have lower affinity to beta lactam drugs 3) Decreasing the permeability of the drug through efflux pumps or porins They come in 4 types: Jarisch-Herxheimer Group Mechanism of action Penicillin G and V Beta-lactam rings binds to and Penicillinase, alteration of binding competitively inhibits transpeptide enzyme proteins and decreased membrane which prevents peptidoglycan cross-linking. permeability Variation in the R group allows stability of the enzyme or acidic hydrolysis Questions? Which antibiotic is used empirically for gram negative bacteria? Cefepime, ceftaroline, piperacillin-tazobactam, meropenem, aminogylcosides have broad gram-negative coverage and often empirically used for severe infections. Which ones cover Pseudomonas? Antibiotics with Pseudomonas coverage include: some cephalosporins (ceftazidime and cefepime), piperacillintazobactam, carbapenems, monobactams, fluoroquinolones Which ones cover MRSA? Antibiotics with methicillin-resistant S. aureus (MRSA) coverage include: vancomycin, daptomycin, linezolid, ceftaroline, doxycycline, trimethoprim-sulfonamide, clindamycin How about VRE? Antibiotics with Vancomycin-resistant Enterococcus (VRE) coverage include: daptomycin and linezolid How about anaerobic ones? Antibiotics with anaerobic coverage include: metronidazole, clindamycin, amoxicillin-clavulanate, piperacillin-tazobactam, meropenem Which are broad spectrum antibiotics used before the agent is identified? Cephalosporins, Fluoroquinolones, Penicillin, Glycopeptides, Nitroimidazoles, Oxazolidinone, and Carbapenems. Which drug is the first choice for otitis media? Amoxicillin Antistaphylococcal Penicillin (IV) (Diclxacillin, nafcillin, oxacillin) Resistance Acquiring genes that negance for penicillin binding protein 2a or expression of PC1 beta lactamase Adverse effect Indication Pharmacokinetics • Hypersensitivity from rash to angioedema Pencillin G (4) or Penicillin PO (5) are given fro syphyllis, (10% of population) streptococcal infections of skin, endocarditis and • Cross allergy with cephalosporins meningococcal meningtis and less so with carbapenems but not with monobactam • Avoid similar side chains • GI • Neurotoxicity • Jarisch-Herxheimer reaction if in conjuction with syphilis treatment • Acute interstitial nephritis, hemotologic toxicities although rare Liver function test abnormalies and toxicitis Very narrow spectrum: Staphyloccous subspecies, and streptococcus but not enterococcus Iv onlyh, through urine unchanged except [nafcillin and oxacillin] they are metabolized through the liver. MSSA infections: endocarditis, skin and soft tisuse infection, osteomyeletis and meningitis Aminopencillins (amoxicillin, ampicillin) Has an extra amino group to penicillin which enhaces its gram negative coverage and is worse against penicillinase so can be used with beta-lactamase inhibitors to increase coverage. Antipseudomonals (e.g, Piperaccillintazobactam) Are the most powerful penicillin with expanded activties against gram positive, negative and Pseudomonas aeruginosa (which employs permeability decreasers and have MDR). Usually added with betalactamase inhibitors to increase coverage or gram negative negatiove anaerobic coverage (taxobactam) Can cause pancytopenia with prolonged use. Increase risk of Acute Kidney injury when combine with vancomycin Empiric and definitive anti-pseudomonal coverage/treatment: HAP, VAP, cIAI, Febrile neutropenia, sepsis, SSTIs, UTI (including pyelonephritis) Cephalosporins Also inhibits transpeptidase enzyme • Usually well tolerated • Hypersensitivity ranging from rash to angioedema, cross allergy with PCN • Diarrhea (mostly C.difficile) • Neurotoxicity (cafepime > renal failure) • Ceftatroline > (+) positive direct coombs without hemolysis • Ceftriaxone causing billiary toxicity • Hemotoxicity • Do not use ceftriaxone and IV calciumcontaining solutions ni neonates usae cefotaxime instead. Variety of issues, easier to list when you can use them eg. Well distributed into most tissues and elimated by glomerular filtration with • Listeria monocytogenes half life of 1-2 hours [WITH EXCEPTION to • Atypicals ceftriaxone] • MRSA and Enterococci • Anaerobes (except cephamycins, cefoperazone and sulbactam) Gen 1 (cefazolin, cephalexin, cefadroxil) Side Effects: • Gastrointestinal: diarrhea • Hypersensitivity reaction Clinical Use: • Endocarditis • Skin and soft tissue infection • Osteomyelitis • Septic arthritis • Urinary tract infection • Prostatitis • Surgical prophylaxis Gen 2 (cefaclor, cefuroxime, cefoxitin) Side Effects: • Gastrointestinal: nausea, vomiting, diarrhea • Rash • Vaginitis • Elevated liver enzymes • Hypersensitivity reaction Clinical Use: • Community-acquired pneumonia • Pelvic inflammatory disease • Lyme disease • Surgical prophylaxis Side Effects: • Gastrointestinal: diarrhea • Rash • Vaginitis • Elevated liver enzymes • Hypersensitivity reaction Clinical Use: • Bloodstream infection • Meningitis • Community-acquired pneumonia • Intra-abdominal infection • Skin and soft tissue infection • Osteomyelitis • Urinary tract infection • Lyme disease • Sexually transmitted diseases Side Effects: • Gastrointestinal: nausea, vomiting, diarrhea • Positive direct Coombs test • Elevated liver enzymes • Hypersensitivity reaction Clinical Use: • Blood stream infection or neutropenic fever (empiric therapy) • Pneumonia (including, community-acquired, hospitalacquired, or ventilator-associated) • Intra-abdominal infection • Urinary tract infection What about pneumonia? Axithrrmycin, clarithromycin or tetracycline • Specific enterococcal subspecies like (E. faecalis) and Listeria monocytogenes • H.pylori • Amoxicillin for patients with otitis, sinusitis and pharyngitis • Skin and soft tissue infection • Endocarditis prophylaxis • Bite wounds, URTI and CAP As generations; gram negative coverage and reduce gram positive coverage, more stability against beta-lactamases Shhh…. And what about UTI? Trimethroprim and sulfamethoxazole, fosfomycin MDR p.aeruginosa need ceftazidime, cefoperzone, 4th gen cephalosporins and novel ones And strep throat? Penicillin Gen 3 They cover Pseudomonas, ceftraxione has (ceftriaxone, cefotaxime, good CNS and blood barrier penetration if cefpodoxime, ceftazidime) you have meningitis Gen 4 Cover pseudomonas (Cefepime) Well distributed and excreted through urine Ceftriaxone is 50% hepatically metabolized Novel Against MDR bacteria Carbapenemes (Classics: Doripenem, ertapenem, imipenemcilastatin, meropenem) (Newer: Meropenem/vaborbactam; imipenem/cilastatin/relebat am are treatment of choice for CRE, MDR Pseudomonas aeruginosa) Broad spectrum with great coverage even for MDR but no activity against MRSA, E.faecium and atypical pathogens Ertapenem has a narrower spectrum "APE" lacking - acinetobacter, pseudomonas, enterococcus subspecies. Side Effects: • Lowers seizure threshold (imipenem) • Gastrointestinal: nausea, vomiting, diarrhea, constipation • Rash, cross-reactivity with penicillin allergy <1% Clinical Use: • Important in-hospital agents for empiric use in severe life-threatening infections • Blood stream infection or neutropenic fever (empiric therapy) • Meningitis • Intra-abdominal infection • Skin and soft tissue infection Only IV Excreted from urine Imipenem always combined with cilastin (for prevention o renal degrdation by dehydropeptidase) Ertapenem has a half life of 4 hours Monobactams (axtreonam) Covers only gram negative coverage including Pseudomonas Is monocylic and doesn’t attach the betalactam to another ring . Inhibits transpeptidase enzyme and is resistant to beta-lactamase Adverse Effects: Neutropenia, elevated liver enzymes, creatinine, rash Clinical use: bloodstream infection, pneumoniae, UTI. Typically reserved for those patients with a documented PCN allergy Excreted through urine Glycopeptides (Vancomycin, Teicoplanin) Inhibits peptidoglycan synthesis by binding Resistance Mechanism: D-Ala-D-Ala terminal of peptide chain (late alteration in terminal peptide stages of cell wall synthesis) chain to D-Ala-D-Lac results in reduced glycopeptide covers methicillin-resistant Staphylococcus binding (used in VRE) aureus (MRSA), streptococci, enterococci and positive Gram anaerobes (Peptostreptococcus, Actinomyces, Propionibacterium, Clostridioides Adverse Effects: • Nephrotoxicity • Ototoxicity • Diffuse flushing (red man syndrome) GLYCOPEPTIDES (VANCOM CIN, TEICOPLANIN) Clinical Use: • Bloodstream infection • Endocarditis • Pneumonia • Skin and soft tissue infection • Septic arthritis, osteomyelitis • Clostridioides difficile infection Excreted through urine and exists in both oral and IV forms but the oral version is porly absorbed through the GI tract Fosfomycin inhibiting the enzyme UDP-Nacetylglucosamine enolpyruvyl transferase, which catalyzes the first step in peptidoglycan synthesis Adverse effect: • Diarrhea, vaginitis, nausea, and headache • IV: hyperkalemia, hypernatremia Clinicals use • UTI infection, • systemic infections due to drug -resistant organisms IV and oral available. Maintains high concentrations in the urine over several days Broad spectrum: Enterobacteriace, E. faecalis, Enterococcus faecium, Staphylococcus aureus. Cell membrane Inhibitors Group Mechanism of action Adverse effect Indication Pharmacokinetics Lipopeptide (Daptomycin) covers vancomycin-resistant Enterococcus (VRE) and methicillinresistant Staphylococcus aureus (MRSA) Inactivated by pulmonary surfactant and should never be used for pulmonary Infections Clinical Use: • Bloodstream infection • Endocarditis • Skin and soft tissue infection Excreted unchange through urine Mechanism of Action: insertion of antibiotic molecules within the cell wall depolarizes the cell membrane which results in potassium leakage, increased permeability, and cell death Side Effects: • Myopathy, rhabdomyolysis (increased serum CPK) • • Elevated liver enzymes • Eosinophilic pneumonia • Gastrointestinal: diarrhea • Rash Lipophilic side chain anchors drug to the cell wall to increase drug half-life and potency against gram-positive bacteria. Works by depolarizing cell and causing cell death Adverse effect: • Infusion-related reactions (Red man syndrome) • Nephrotoxicity • Telavancin: taste disturbances (metallic), foamy urine, potential fetal harm Clinical use: • SSTI • HAP/VAP Unchanged through glomerular filtration (also urine) Adverse effect Glycolipeptide (telavancin. Dalbavancin, oritavancin) Resistance Polymyxin Bacterial ribosome inhibitors Group Mechanism of action Resistance Indication Pharmacokinetics Tetracyclines [30S] (Tetracyucline, doxycycline, minocycline, Tigecycline, Omadacycline, Eravacycline) broad spectrum of activity, including MRSA, good activity versus chlamydial and mycoplasmal species, H. pylori (GI ulcers), Rickettsia > bacteriostatic Mechanism of Resistance: efflux by • Avoid Pregnancy • Avoid Young children under 8 tetracycline-specific pumps, ribosomal protection protein • Blood stream infection avoid • Gastrointestinal intolerance (dislodges tetracycline) • Nausea/vomiting is significant with tigecycline and loading dose of oral omadacycline • Tooth discoloration • Photosensitivity Combination therapy for H.pylori. Doxycycline • Tick borne infections (Lyme, Rocky Mountain spotted fever, etc.) • Part of therapy in treatment of community acquired pneumonia in hospitalized patients (alternative to azithromycin) • Malaria treatment and prophylaxis • Skin and soft tissue infections • Sexually transmitted infections • Minocycline • Acinetobacter baumanii • Stenotrophomonas matolphilia • Tigecycline, Omadacycline, and Eravacycline • Multi resistant Gram-negative: Enterobacterales, Acinetobacter baumanii • Non-tuberculous mycobacterial infections excreted through urine, except doxycycline • Tetracyclines bound and inactivated by divalent cations (e.g.,calcium or magnesium) Mechanism of Action: inhibits protein synthesis by binding 30S and prevents attachment of aminoacyl-tRNA Pill esophagitis (oral tetracyclines; counsel patient to take with glass of water and sit upright for 30 minutes after administration) Aminoglycosides [50S] (gentamicin, neomycin, amikacin, tobramycin, streptomycin Used for severe gram negative bacteria including pseudomonas and is bacterial cidal. Mechanism of Action: binds aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit to prevent protein synthesis inactivation by aminoglycoside modifying enzymes (e.g., acetylation, phosphorylation, adenylation) Side Effects: narrow therapeutic range, therapeutic drug monitoring is required • Nephrotoxicity • Ototoxicity • Neuromuscular blockade • Contraindicated in pregnancy (teratogenic) Clinical Use: • Synergy in patients with infective endocarditis, in combination with a cell wall active agent (primarily gentamicin, sometimes streptomycin) • Treatment of multi-drug resistant Gram-negative organisms: bloodstream infections, pneumonia, intra-abdominal infection • Cystic fibrosis flares (primarily tobramycin, sometimes amikacin) • Mycobacterial infections • Paromomycin for intestinal amebiasis • IV or topical • Poor Gi absorption • Excreted through urine Macrolides [50S] (azithromycin, clarithromycin, erythromycin, telithromycin) wide-spectrum, including atypical organisms (Chlamydia, Mycoplasma, Ureaplasma), Legionella pneumophila. Low side effect profile with good oral absorption Bacteriostatic, binds 50S subunit to prevent chain elongation during protein synthesis methylation of 23S rRNA-binding site, which prevents drug binding Side Effects: • QT prolongation • Gastrointestinal: nausea, vomiting, diarrhea • Elevated liver enzymes • Ototoxicity (high dose erythromycin) Clinical Use: • Community-acquired pneumonia (covers atypical organisms: Mycoplasma, Chlamydia, Legionella) • COPD exacerbation (immunomodulator) • Sexually transmitted infection • Nontuberculosis mycobacterial infection • Lyme • Helicobacter pylori (clarithromycin) • Infectious diarrhea (azithromycin) excreted through biliary system > urine • Erythromycin and clarithromycin significant CYP450 enzyme inhibitors (Azithromycin is not) which means they have trouble being metabolised by the liver) Erythromicin/ Clindamycin/ E and Clin. Inhibit the translacation of the chloramphenical/ linezolid 50S subunit so tRNA cant move. Chloram. Inhibits peptidyle transferase so amino accids cannot be added. Line. Prevents 50S binding to 30S so 70S cant be formed. Clindamycin Same as erythromycin covering anaerobic bacteria and MRSA Side Effects: • Clostridioides difficile infection, • nausea, • diarrhea Clinical Use: • Skin and soft tissue infection • Osteomyelitis • Toxic shock syndrome (toxin production suppression) Metabolised by liver Oxazolidinones (linezolid, tedizolid) MRSA and VRE coverage. bacteriostatic, binds to the 23S of the 50S subunit, inhibiting the formation of the 70S complex Side Effects: • GI upset, thrombocytopenia, latic acidosis, peripheral and optic neuropathy, Serotonin syndrome Clinical Use: • Community acquired pneumonia • Skin and soft tissue infection • Bloodstream infection (VRE), Mycobacterial infections, Nocardiosis completely orally absorbed, widely distributed, is metabolized via oxidation, excreted through urine Chloramphenicol binds 50S to prevent peptide bond formation • Active against many types of microorganisms including chlamydia, Side Effects: • Aplastic anemia, bone marrow suppression • Optic neuritis • Gray baby syndrome Clinical Use: limited use due to side effects, occasionally used for severe infection Good penetration into CSF, metabolized in the liver and excreted through urine Infectious diseases Page 2 • Gray baby syndrome • Hypersensitivity reaction microorganisms including chlamydia, rickettsia,spirochetes, and anaerobes Nucleic acid synthesis inhibitors Group Mechanism of action Resistance Adverse effect Indication Pharmacokinetics (Fluoro-)Quinolones ("floxacins") (ciproflaxins, moxifloxacin,delafloxacin) Newer versions improves against gram positive and aerobic bacteria. Is bactericidal and inhibitrs DNA gyrase (topoisomerase 2 and 4) Mechanism of Resistance: production of proteins that protect binding to DNA gyrase, mutations to DNA gyrase binging site, efflux pumps Side Effects: • Gastrointestinal: nausea • CNS effect: hallucination • QT prolongation • Tendonitis/tendon rupture • Contraindicated during pregnancy (teratogenic) Clinical Use: • Urinary Tract Infections, Prostatitis, STD • Gastrointestinal (Salmonella) infections • Intra abdominal Infections • Respiratory Tract Infections • Bone and Joint Infections • Skin and Soft Tissue Infections • Mycobacteria infections Excellent oral absorption, excreted in urine (except moxifloxacin, hepatically metabolized) Side Effects: • Hypersensitivity reactions (e.g., StevensJohnson syndrome) • Bone marrow suppression • Hemolysis (for patients with G6PD deficiency) • Nephrotoxicity • Contraindicated during pregnancy (teratogenic) Clinical Use: • Pneumonia • Pneumocystis pneumonia • Skin and soft tissue infection • Urinary tract infection • Sexually transmitted infection • Toxoplasma gondii prophylaxis well absorbed, CNS penetration, metabolized by liver, excreted in urine Side Effects: • Gastrointestinal: nausea, diarrhea • Disulfiram-like reaction with alcohol (severe flushing, tachycardia, hypotension) Clinical Use: Anaerobic Infections and Parasitic Infections • Intra-abdominal infection (including liver abscess from amebiasis) • Pelvic inflammatory disease • Bacterial vaginosis • Trichomoniasis completely orally absorption, metabolized by liver Has a broad spectrum and good penetration to prostrate, lng and bone Trimethoprimsulffmethoxazole Broad spectrum that includes MRSA, Mechanism of Resistance: nocardia subspecies, pneumocystic jiroveci increased PABA synthesis, altered enzymes and s. maltophilia Mechanism of Action: inhibits folate synthesis through blocking dihydrofolate reductase (trimethoprim) and dihydropteroate synthase (sulfamethoxazole). Folic acid to make DNA Metronidazole covers anaerobic bacteria and many protozoa Mechanism of Action: bactericidal, forms toxic free radical metabolites that damage DNA and inhibit nucleic acid synthesis Infectious diseases Page 3 Antifungals 14 December 2023 10:36 Antifungal therapy: studies have shown better outcomes with high intensity (amphotericin B + flucytosine) induction followed by high dose, then low-dose fluconazole to prevent disease recurrence If with HIV Antiretroviral therapy should be delayed, as immune reconstitution can lead to IRIS, which can lead to worsening CNS symptoms, increased ICP, and death as the immune system reacts to fungal pathogen class Drug name Mechanism of Action Pharmacology/pharmacokinetics Uses Advantages Disadvantages Terbinafine (superficial) Blocks squalene epoxidase, which prevents formation of rings needed to make ergosterol • Topical and oral forms available • Distributes overwhelmingly to skin and sebaceous glands with relatively small amounts in systemic circulation • Topical: Tinea skin infections • Oral: Tinea skin infections, onychomycosis • Safe, well tolerated (particularly topical form) • Oral form has infrequent side effects including headache, rash, GI upset, and increased AST/ALT • Safe and well-tolerated • Occasional GI upse • Advantages of using azoles include their broad-spectrum activity against a wide range of fungal species, their oral and topical formulations, and their relatively low toxicity. •Most Azoles are also effective against both yeasts and molds, making them a versatile treatment option •However, there are also some disadvantages to using azoles. One of the main drawbacks is the potential for drug interactions, particularly with other medications that are metabolized by the liver. • Azoles can also cause side effects such as nausea, vomiting, and liver damage (hepatoxicityt is a class effect), although these are generally mild and reversible Squaline -x-> Squalene epoxide Nystatin • Binds to ergosterol, preventing formation of fungal cell membrane leading to cell death • No absorption through the skin or GI tract • Cutaneous candidiasis (powder or cream) • Oral thrush (swish-and-swallow) Nystatin is a topical antifungal that binds to ergosterol and prevents fungal cell membrane formation; used for superficial candida infections (intertrigo and thrush) Inserts ion depleting channels Azoles Terbinafine is an antifungal that concentrates in the skin and blocks synthesis of ergosterol; used for treatment of dermatophyte infections • Block conversion of lanosterol to • Contain 2 or 3 nitrogen per azole ergosterol by interfering with ring structure (imidazole vs triazole, cytochrome P-450 dependent respectively) • Imidazoles (topical, 2 nitrogen): fungal enzyme, lanosterol 14⍺demethylase. ketoconazole, miconazole, • lack of ergosterol leads to clotrimazole • Triazoles (systemic, 3 nitrogen): disruption of cell membrane and fluconazole, itraconazole, cell death. Lanosterol -x-> ergosterol voriconazole, posaconazole, isovuconazole Class effect: hepatotoxicity, GI disturbance (oral solution), QTc prolongation, Drug interaction due to affecting metabolic enzymes > monitor LFTs, bilirubin in first 2 weeks of therapy and then ever 2-4 weeks. • Voriconazole and itraconazole have higher rates of AE (CNS) • Cardiac toxicity: prolong the QT interval, except isavuconazole may shorten QT. Itraconazole has the additional risk of CHF(negative inotropic effects) Spectrum of activity: • Fluconazole has a narrower spectrum of activity • Posaconazole and Isavuconazole have the broadest spectrum Azoles are nitrogen containing antifungals and the primary treatment for non-severe fungal infections; inhibit cytochrome P-450 enzymes which prevents ergosterol synthesis but also leads to interactions with many other drugs Fluconazole Same (tablet, oral, iV) • Available as tablet, oral solution, and IV solution • Limited spectrum of activity: pathogenic yeasts, including Cryptococcus spp. Notable resistance : ‒ Candida glabrata (if susceptible, higher doses required) ‒ Candida krusei ‒ NO intrinsic mold activity Itraconazole same (capsule, oral, IV) • Available as capsules, oral solution, and IV solution • Capsule requires low pH for absorption, oral solution absorption improved, active metabolite • Spectrum of activity ‒ Many pathogenic yeasts, including Cryptococcus spp; ‒ Aspergillus spp. • Notable resistance ‒ Zygomycetes/Mucorales ‒ Variable activity against C. glabrata, C. krusei, and Fusarium spp. Voriconazole same (tablet, oral, IV) • Available as tablets, oral solution, and IV solution • Broad spectrum of activity ‒ Nearly all pathogenic yeasts, including fluconazole-resistant Candida and Cryptococcus spp. ‒ Most pathogenic molds, including Fusarium spp. and Scedosporium spp. • Notable resistance: Zygomycetes/Mucorales • Advantages: Excellent oral absorption and well distributed (include CNS) • Visual disturbance: transient photopsia, photophobia, color changes • Neurotoxicity: concentration-dependent visual and auditory hallucinations, confusion, delirium, agitation, myoclonus, or seizure (trough > 5.5 mcg/ml) • Other: photosensitivity rash, alopecia, and periostitis (long-term use) • Drug Interactions: strong inhibitor of CYP3A4, moderate inhibitor of CYP2C19 Posaconazole same (oral suspension, tablet, IV) Poorly absorbed but less side effects • Available as oral suspension, delayedrelease tablets (different dosing), and IV • Broader spectrum of activity ‒ Nearly all pathogenic yeasts, including fluconazole-resistant Candida and Cryptococcus ‒ Nearly all pathogenic molds, including Zygomycetes/Mucorales • Pharmacology: Suspension is poorly absorbed; requires high-fat meal and acidic pH. Suboptimal CNS/ocular penetration Adverse effects: more favorable than other triazoles • Class effect (less significant) • Pseudohyperaldosteronism: hypertension, hypokalemia, and alkalosis (Concentration-dependent) • Drug Interactions: inhibitor of CYP3A4 and P-glycoprotein (P-gp), not metabolized via the P450 enzyme Isavuconazole same (capsule, IV) Prodrug and loading dose • Available as capsules and IV solution. Administered as the pro-drug which is converted to isavuconazole in human plasma • Broader spectrum of activity – similar posaconazole, especially aspergillosis and mucormycosis • Pharmacology: Excellent oral absorption, very long elimination half-life (~130 hours); requires 2-day loading dose. The IV formulation does not contain the cyclodextrin vehicle, SBECD, which can accumulate in the setting of renal dysfunction Adverse effects: • Class effect: hepatotoxicity, GI (less significant than other azoles) • QTc shortening: Unclear clinical significance. Avoid in patients with familial short QT syndrome • Drug Interactions: Moderate inhibitor of CYP3A4 Echinocandins (IV) • Inhibit Beta-1,3-glucan synthase, • All in IV form - minimal oral bioavailability • Limited spectrum of activity Infectious diseases Page 4 • Advantages: Excellent oral absorption and well distributed (include CNS), • well tolerated Adverse effects: ‒ Hepatotoxicity (class effect): reversible transaminase elevation (2-12%) ‒ Gastrointestinal symptoms (class effect): usually mild; nausea/diarrhea ‒ QTc prolongation (class effect : less significant compared to other azoles ‒ Reversible alopecia: typically observed with longer courses ‒ Drug-Drug Interactions (class effect): Strong inhibitor of CYP2C19, Moderate inhibitor of CYP3A4 and CYP2C9 • “Triad” (hypertension, hypokalemia, peripheral Edema): elderly patients • Heart failure: negative inotrope avoid in patients with a history of cardiac ventricular dysfunction • Drug Interactions: strong inhibitor of CYP3A4, inhibitor of pglycoprotein Advantages: Echinocandins (IV) (caspofungin, adnidulafungin, micafungin) • Inhibit Beta-1,3-glucan synthase, • All in IV form - minimal oral bioavailability which prevents fungi from making • Excreted via hepatic metabolism • Very large molecules that do not essential components of cell wall distribute well into CSF, eyes, urine, prostate • Limited spectrum of activity ‒ Candida spp. (including azole-resistant) ‒ Aspergillus spp. • Notable resistance ‒ Cryptococcus spp. ‒ Molds other than Aspergillus ‒ Dimorphic fungi (endemic) Advantages: • Safe and well tolerated, less toxic compared to other antifungals • LOWEST drug interaction potential Side effects: • Mild asymptomatic elevation in AST/ALT • Rare hypersensitivity reactions Uses: • Candidemia (Candida bloodstream infection): 1st line • Aspergillus: salvage treatment option for invasive pulmonary aspergillosis in patients unable to tolerate azole therapy Echinocandins (caspofungin, anidulafungin, micafungin) prevent fungal cell wall synthesis; well tolerated drugs and first line for Candidemia Amphotericin B (IV) Requirings monitoring and premedication New evidence: Amphotericin B forms aggregates that sequester ergosterolfrom lipid bilayers much like a sponge, resulting in fungal cell death rather than inserting a channel into the membrane • Poorly absorbed (<5%); requires IV administration • Several formulations: non interchangeable: ‒ Conventional Amphotericin B (deoxycholate) - DAmB ‒ Lipid-based Amphotericin B: liposomal, lipid complex, and colloidal dispersion. Generally higher doses and lower nephrotoxicity compared to conventional but more costly • Large molecule, difficult penetrating protected sites (e.g., CSF), but at high doses can achieve therapeutic levels in these areas • Drug broken down to inactive metabolites in serum with excretion in urine or biliary tree (minimal) • Broad spectrum of activity ‒ Nearly all pathogenic yeasts ‒ Nearly all pathogenic molds ‒ Dimorphic fungi (endemic) • Miscellaneous activity ‒ Leishmania spp. (protozoa) • Notable resistance ‒ Candida lusitaniae ‒ Aspergillus terreus ‒ Scedosporium spp Uses: • Cryptococcal meningitis: 1st line, in combination with flucytosine (for 4-6 weeks, then narrowed to fluconazole) • Mucormycosis (invasive fungal sinusitis): 1st line • Severe endemic infection (histoplasma, coccidioides, blastomyces): 1st line • Good against/can be used for most other severe fungal infections (Aspergillus, Candida) but other agents preferred due to toxicity profile Amphotericin B is a broad-spectrum antifungal agent and treatment of choice for most severe fungal infections; binds ergosterol and disrupts fungal cell membranes; it has many side effects including nephrotoxicity and electrolyte wasting Flucytosine Flucytosine taken up by fungal cells and deaminated by fungal enzyme into 5-fluorouracil, then modified into nucleoside analogues and incorporated into DNA/RNA which inhibits DNA/RNA synthesis • Oral medication Uses: • Relies on fungal enzymes to be converted • Cryptococcal meningitis: in combination with Amphotericin B to active metabolites • Always used in combination: resistance develops quickly to monotherapy Flucytosine is a nucleoside analogue that blocks fungal DNA/RNA synthesis; used in combination with Amphotericin B for treatment of Cryptococcal meningiti Infectious diseases Page 5 Advantages: • Broad spectrum activity against almost all fungal infections Disadvantages: Nephrotoxicity • Due to non-specific binding to cholesterol in renal tubules, and renal arteriole constriction. • Often accompanied by electrolyte wasting (Mg++, K+). • To minimize effects: pre-hydrate with normal saline, use lipid-based amphotericin, avoid other nephrotoxins, and aggressively replace electrolytes. Infusion Related Reactions • May pre-medicate with antipyretic, antihistamine • Stop infusion immediately if reaction is severe (e.g. hypotension) Other • Hematologic effects (e.g. cytopenias) and hepatobiliary effects Advantages: • Flucytosine itself generally well tolerated, however typically combined with amphotericin which potentiates side effect profile Side effects: • GI upset: diarrhea and nausea common when combined with amphotericin • Myelosuppression: -cytopenias • Hepatotoxicity: typically asymptomatic AST/ALT elevations Antiviral 10 December 2023 10:34 Against Influenza Ribavarin • Influenza is SSRna (-) replicating in the nucleus • Hemagglutin binds sialic acid receptor that permits entry • Neuramindase degrades protective mucus and cleaves sialic acid to release the viruse • Membrane proteins (m-proteins) involved in uncoating • The virus binds to respiratory epithelial cells and is phagocytosed by endosomes • Endosomes acidify viral protein channels? Group Mechanism of action Adverse effect Indication Pharmacokinetics Neuramindase inhibitors (Zanamir, oseltamivir, peramivir) • Influenza virions use neuraminidase to cleave from infected host cells, thereby releasing viral particles to infect other host cells • Neuraminidase inhibitors prevent viral release by interfering with neuraminidase function, limiting ability to infect new cells Resistance • Occasional nausea or GI upset → typically resolve in 1 to 2 days and are preventable by administration oseltamivir with food • In some countries, drugs may be expensive (particularly peramivir) • Some strains of influenza resistant to neuraminidase inhibitors • Used to treat infections caused by Influenza A and Influenza B (1st-line) • Shortens duration of infection, but most effective if used within 48 hours • Recommended for all patients ill enough to be hospitalized with influenza • May be used prophylactically to prevent influenza in high-risk patients • Drugs very well tolerated • Equally effective for both influenza A and B • Oseltamivir is oral and readily absorbed, typically taken as 5 day course • Oral bioavailability of zanamivir is less than 5% → oral inhalation • Peramivir is IV, single dose (rarely used) M2 ion channel inhibitors (amantadine, rimantadine) • Inhibits M2 proton channel - an early High resistance so not commonly step in viral replication which prevents viral used uncoating and release of viral RNA into the cytoplasm • Rimantadine is 4- to 10-fold more active than amantadine Mainly associated with CNS, particularly in elderly patients or for longer courses, significantly less frequent with rimantadine • CNS side effects: difficulty focusing, confusion, lightheadedness, and less commonly delirium, hallucinations, tremor, myoclonus, seizures • GI effects: loss of appetite, and nausea • Only against influenza A • Not usually recommended • Also used to reat parkinsons and movement disorders • Cost effective • Well tolerated in young healthhy people • Both taken orally with high bioavailability (90%) • Little effect of meals on AUC • Elimination of Rimantadine is higher and is metabolised more • Amantadine is mostly renally excreted Ribavirin A prodrug that is a guanisine analog used to stop viral RNA synthesis and viral mRNA capping so that the virus cannot replicate • feeling tired, headache, nausea, fever, muscle • RSV infection, hepatisis C and viral hemorrhagic fevers pains, and an irritable mood. • RBC breakdown, liver problems and allergy • Do not use during pregnancy Metabolised by liver and passed through urine and faeces. . 44hr single dose halflife. Baloxavir marboxil Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease (part of virus polymerase complex) that blocks influenza proliferation by inhibiting the initiation of viral mRNA synthesis. A prodrug that assumes acid form. • Diarrhea • Bronchitis • Nausea • Sinusistis • headache orally administered prodrug It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual. • It is active against both type A and type B influenza • Activity against oseltamivir-resistant viruses, and may act synergistically with other agents - For patients above 12yrs old About viral mRNA capping • The presence of the cap ensures stability of the transcript against a variety of cellular 5′–3′ exonucleases and recognition of the mRNA by the ribosomal protein eIF4E for efficient translation. The capping was also shown to be involved in other cellular processes such as RNA splicing and export • RNA capping is mainly a nuclear process, although some RNA re-capping events are suspected to occur in the cytoplasm Against Herpes, VCV, EBV, CMV • Can develop latent stage • DSDna, enveloped • Viral thymidine kinase (non-human) gbenerals nucleotides for viral DNA polymerase; which are 2 therapeutic targets Group Mechanism of action Resistance Adverse effect Indication Pharmacokinetics Acyclovir/ Valacyclovir • Acyclovir is a guanosine analogue • Acyclovir brought into cells, where viral thymidine If resistant use foscarnet Side Effects: • Nausea, diarrhea, and headache. While rare, may have serious side effects (IV): • HSV-1, HSV-2, VZV • Minimal activity against EBV and CMV • Drug of choice for essentially all infections caused by • Valacyclovir is oral prodrug of acyclovir • Acyclovir available in topical, oral, or IV • Oral acyclovir has very low Infectious diseases Page 6 thymidine kinase converts it into triphosphate compound that inhibits viral DNA polymerase and causes termination of DNA strand If resistant use foscarnet may have serious side effects (IV): • CNS toxicity: lethargy, confusion, tremor, delirium, seizures (usually only with very high serum concentrations) • Renal toxicity: may cause crystalline nephropathy or interstitial nephritis • Drug of choice for essentially all infections caused by HSV and VZV (including severe infections like encephalitis) - Generally well tolerated • Oral acyclovir has very low bioavailability, improved with valacyclovir • Myelosuppression is the principal doselimiting toxicity: neutropenia, thrombocytopenia common (particularly in setting of HIV) • CNS toxicity reported (similar to acyclovir): headaches, confusion, psychosis, seizures (relatively rare) • Deoxyguanosine analogue (similar to acyclovir) • Activated by virus-specified protein kinase phosphotransferase into triphosphate that inhibit viral DNA polymerase and prevents viral DNA synthesis • Severe CMV infection • Ganciclovir typically given IV due to very low oral bioavailability (6-9% with food) • Valganciclovir is an oral prodrug with much higher bioavailability Ganciclovir/ valganciclover • Deoxyguanosine analogue (similar to acyclovir) • Activated by virus-specified protein kinase phosphotransferase into triphosphate that inhibit viral DNA polymerase and prevents viral DNA synthesis Cidofovir First antiviral nucleoside analogue discovered – largely now replaced by newer drugs • Converted to active nucleoside analogue by human enzymes (not viral enzymes), active form inhibits viral DNA polymerase (by slowing and eventually terminating chain elongation) • 8-600x higher affinity for viral DNA polymerase than human DNA polymerase • Nephrotoxicity: is principal dose-limiting side • Only used for CMV retinitis (particularly if ganciclovireffect. Proximal tubular dysfunction resistant) including proteinuria, azotemia, metabolic • Alternative option to treat ganciclovir-resistant CMV acidosis, and occasionally Fanconi syndrome retinitis • Administration of IV fluids and probenicid required prior to and during cidofovir dosing • Neutropenia relatively common • GI upset common with concomitant probenecid (given to prevent nephrotoxicity) • Only given IV (very low oral bioavailability) • Almost entirely excreted unchanged by kidneys Foscarnet • does not undergo activation by cellular enzymes • Interacting directly at HSV DNA polymerase or HIV reverse transcriptase. Blocks pyrophosphate binding site of viral DNA polymerase, inhibiting cleavage of pyrophosphate from nucleotides and blocking DNA synthesis • 100x more affinity for viral DNA polymerase than human DNA polymerases Side Effects: Major dose-limiting toxicities are nephrotoxicity and hypocalcemia • Nephrotoxicity: can cause significant acute kidney injury, proteinuria, and acute tubular necrosis (severe AKI in ~1/3 of recipients) • Electrolyte derangements common: hypocalcemia, hypomagnesemia, hypokalemia • CNS toxicity: ranges from headaches to tremors, hallucinations, delirium • Anemia • GI side effects common • Rashes common • Ganciclovir-resistant, severe CMV infections • Acyclovir-resistant, severe HSV and VZV infections • Effective in nucleoside analogue resistant HSV, VZV, and CMV • Given IV (poor oral bioavailability and gastrointestinal intolerance) • Over 80% unchanged renally cleared Letermovir Mechanism of Action: novel inhibitor of the CMV viral enzyme DNA terminase → preventing cleavage of newly synthesized CMV DNA into individual viral genomes Does not have cross-resistance with other anti-CMV drugs Side effects: tachycardia, atrial fibrillation, nausea, and diarrhea • CMV prophylaxis in HSCT (hematopeoic stem cell transplant) and SOT (solid organ transplant) • Currently the most active molecule against CMV. • Available oral and injectable • Multiple potential drug-drug interactions due to moderate CYP3A4 inhibition Resistance Adverse effect Indication Pharmacokinetics • Rare lactic acidosis • HBV may flare at discontinuation • Chronic HBV: first-line agent for HBV • Oral, highly bioavailable, well tolerated • Resistance rare and slow to emerge • Dose-related nephrotoxicity and tubular dysfunction: azotemia and hypophosphatemia, acidosis, glycosuria, and proteinuria. • Headache, abdominal discomfort, diarrhea, and asthenia. • Chronic HBV Against Hepatitis B • Host DNA polymerase convers genome to covalently closed circular cccDNA which is the transcribed to mRNAs • This mRNA makes proteins, one of which is viral RNA-dependent NA polymerase (reverse transcriptase) that converts the mRNA back to DNA • Drugs only used for patients with high level of HBV DNA, LFT, cirrhosis and for prevention of disease during immunosuppressive therapies Broadly: Peg interferon (IFN-a) Nucleoside/tide analoges Group Mechanism of action Entecavir (guanosine analogue) • Guanosine nucleoside analog • Enters cells, phosphorylated by cellular enzymes, then interferes with viral reverse transcriptase to prevent DNA synthesis Adefovir (adenosine analogue) • Adefovir dipivoxil is diester prodrug of adefovir, a nucleotide analogue of adenosine monophosphate • Converted by cellular enzymes to the diphosphate, then competitively inhibits HBV DNA polymerase to cause chain termination after incorporation into viral DNA Telbivudine (Thymidine analogue) • ↑ LFTs, headache, nausea, diarrhea, dizziness, myalgia (rare) • HBV may flare at discontinuation • High rate of viral resistance (71% after 5 years of treatment) • increased creatine kinase, myalgia, and myopathy • Nausea, diarrhea, fatigue, lactic acidosis • Chronic HBV (not preferred) • Bioavailability 68%, widely distributed into tissues • Well tolerated Lamivudine (deoxycytidine analogue) • Deoxycytidine analogue • Convert to the triphosphate, inhibits HIV reverse transcriptase and HBV DNA polymerase • ↑ LFTs, headache, nausea, diarrhea, dizziness, myalgia (rare) • HBV may flare at discontinuation • High rate of viral resistance (71% after 5 years of treatment) • Chronic HBV (not preferred), HIV-1 infection • Oral, highly bioavailable, well tolerated Tenofovir (Tenofovir disoproxil (TDF); Tenofovir alafenamide (TAFphosphate ester) • Adenosine analogue, reverse transcriptase inhibitor • Resistance exceedingly rare outside of HIV infection • TDF: Renal dysfunction, osteopenia • TAF: newer, less renal insufficiency and bone toxicity but more expensive • HBV flare at discontinuation (important to screen for HBV if using to treat HIV) • Chronic HBV, HIV-1 infection Peg interferon alfa • Interferon: potent cytokines with complex antiviral and immunomodulatory effects • Enhance natural antiviral responses of host cells, though signaling pathways not fully clear • Once weekly SC, finite duration, absence of selection of resistant variants • Flu-like illness: fevers, chills, myalgias, GI upset (within 6 hours, most patients develop tolerance over weeks) • Chronic use: bone marrow suppression, severe fatigue and weight loss, neurotoxicity, thyroiditis and, rarely heart failure • HBV: First-line agent • Interferon alfa historical used for HCV not a preferred agent because development of viral resistance and nephrotoxicity Infectious diseases Page 7 HCV attaches to cells and enters via endocytosis Positive-sense RNA released into hepatocyte cytoplasm Against Hepatitis C • Viral DNA translated for viral protease by host (human) enzymes which cleaves to make essential proteins RNA polymerase (NS5B and NS5A) which regulate RNA polymerase function • Viral protease, viral RNA polymerase, and viral NS5A new therapeutic targets for treatment of HCV infection • Goal is to cure • Combination therapy due to monotherapy having resistance • Therapy linked to HBV reactivation so needs to be screened 4 classes of directing antiviral agents: 1) NS 5A inhibitors 2) NS 5B nucleoside polymerase inhibitors 3) NS 5B non-nucleoside polymerase inhibitors 4) NS3/4A protease inhibitors Combination therapy HCV genotype Adverse effect Ledipasvir/Sofosbuvir (Harvoni) Mechanism of action 1,4,5,6 headache and fatigue, bradycardia Daclatasvir + Sofosbuvir (Sovodak) 1&3 headache and fatigue, bradycardia (Velpatasvir + Sofosbuvir (Epclusa) Pangenotypic headache, fatigue, nausea, asthenia, and insomnia Elbasvir/Grazoprevir (Zepatier) 1&4 Fatigue, headache, and nausea, ↑ Transaminase > CKD Glecaprevir/Pibrentasvir (Mavyret) Pangenotopic headache, fatigue, and nausea Velpatasvir + Sofosbuvir + voxilaprevir (Vosevi) Pangenotopic headache, nausea and diarrhoea Ombitasvir + Paritaprevir + ritonavir (Technivie) 4 nausea, pruritus, and insomnia, ↑ transaminase Ombitasvir + Dasabuvir + paritaprevir + ritonavir (Vikiera) 1 nausea, pruritus, and insomnia Ritonaivor inhibits CYP3A4 so has drug-drug interactions Infectious diseases Page 8 Indication Pharmacokinetics