Antifungal Agents by Robert Goggs PDF

Part 1: Antifungal drugs Part 2: Approach to prescribing Robert Goggs Associate Professor, E/CC [email protected] ANTIFUNGAL DRUGS  Learning Objectives 1. Contrast spectrum of activity for antifungal agents with that of antibacterial agents 2. Explain the mechanisms of acti...

Part 1: Antifungal drugs Part 2: Approach to prescribing Robert Goggs Associate Professor, E/CC [email protected] ANTIFUNGAL DRUGS  Learning Objectives 1. Contrast spectrum of activity for antifungal agents with that of antibacterial agents 2. Explain the mechanisms of action of the commonly used classes of antifungal agents 3. Compare development of antimicrobial drug resistance in fungi with that in bacteria 4. Give examples of drugs used for treatment of common fungal diseases 5. Understand the following facets of antimicrobial prescribing practice: Micro-organism Pharmacokinetics Pharmacodynamics Host considerations Toxicity and adverse effects Cost 6. Give examples of available guides and frameworks to aid AMD prescribing *Note: Learning objectives generally describe the minimum knowledge needed to pass the course. Fungal infections Fungal infections are being recognized with increasingly frequency Fungi are also emerging as important causes of hospital-acquired infections Immunosuppression Malnutrition Indwelling catheters Use of broad-spectrum antibacterial drugs Range of antifungal drugs is limited compared to antibacterial drugs Mammals and their fungal pathogens have more common cellular characteristics Antifungal drugs: Overview ✭ Antifungal drugs 1: Azoles Microbiol. Mol. Biol. Rev. 2011; doi:10.1128/MMBR.00045-10 Imidazole drugs Ketoconazole Miconazole Lipophilic with good oral bioavailability Used for dermatophytosis Limited distribution Malassezia spp. Cheap Microsporum canis Adverse effects are common Microsporum gypseum Broad spectrum Trichophyton mentagrophytes Less effective than triazoles Part of many topical skin products Synergistic with amphotericin Commonly ineffective as sole drug Synergistic with flucytosine Often combined with chlorhexidine, polymyxin B, glucocorticoids Resistance is reported Conferred across whole azole class Ophthalmic and otic preparations also CYP3A12 and Pgp effects ✭ Triazole drugs Fluconazole Water soluble, good oral bioavailability, short half-life Narrow spectrum Adverse effects rare Indicated for candidiasis Itraconazole Lipophilic, short half-life, widely distributed, binds keratin Broad spectrum Adverse effects rare, primarily GI Indicated for blastomycosis Voriconazole Good oral bioavailability, excellent tissue penetration Broad spectrum Adverse effects uncommon, primarily neurologic signs esp. cats Antifungal drugs 2: Flucytosine & Griseofulvin Benzofuran antibiotics: Griseofulvin Orally bioavailable but variable absorption, short half-life Selectively deposited in keratin so prolonged therapy required to effect cure Narrow spectrum Occasional resistance reported Drug is teratogenic in cats Also causes neuro and GI signs Largely replaced by triazoles Pyrimidine synthesis inhibitors: Flucytosine Good oral bioavailability, short half-life, good tissue penetration Synergistic with amphotericin Narrow spectrum Resistance reported in Candida and Cryptococcus Adverse effects uncommon: GI signs, skin lesions Indications: Cryptococcosis but superseded by triazoles Antifungal drugs 3: Polyenes Microbiol. Mol. Biol. Rev. 2011; doi:10.1128/MMBR.00045-10 Natamycin Nystatin Polyenes: Amphotericin B Broad spectrum, long half-life, extensive Vd Resistance reported in Candida, Cryptococcus, Coccidioides Adverse effects are frequent and severe – reduced using lipid formulations Nephrotoxic Thrombophlebitis Hypokalemia Indications: Systemic fungal infections Candida Blastomyces Coccidioides Histoplasma Antifungal drugs 4: Allyl amines Allyl amines: Terbinafine Lipophilic, good oral absorption, urinary excretion Penetrates keratinized tissues → prolonged persistence in hair Synergistic with azoles Broad spectrum Resistance not reported Adverse effects are rare, but GI signs reported Indications: Dermatophytosis Malassezia  Antifungal drugs 5: Echinocandins Microbiol. Mol. Biol. Rev. 2011 doi:10.1128/MMBR.00045-10 Echinocandins: Caspofungin Extensive tissue distribution IV only Potentially synergistic with azoles Narrow spectrum Resistance is presently rare Adverse effects are also rare Very rarely used in vet. med. Pharmacodynamics of antifungal drugs Time dependent effects %T > MIC Flucytosine Short post-antifungal effect Concentration dependent effects Cmax / MIC Polyenes and echinocandins Long post-antifungal effect Concentration (and time) dependent effects AUC / MIC Triazoles  Antifungal drug resistance Fungal Genet Biol 2019;132:103254 Antifungal drug resistance Usually results from prolonged treatment with antifungals Acquired resistance depends on mode of action of antifungal, for example: Reduced drug uptake e.g. azoles Drug export through efflux pumps e.g. azoles Reduced affinity of target enzymes e.g. allylamines Unlike bacteria, fungi do not readily take up exogenous DNA Transferable drug resistance does not occur in fungi Antifungal susceptibility testing Fungi exist in various forms: Yeasts (e.g. Candida, Cryptococcus) Filamentous fungi (e.g. Aspergillus, Fusarium) Yeast forms of dimorphic fungi (e.g. Blastomyces, Coccidioides, Histoplasma) In vitro antifungal susceptibility tests standardized for yeasts, filamentous fungi https://clsi.org/about/about-clsi/about-clsi-antimicrobial-and-antifungal-susceptibility-testing-resources/# Technically challenging and costly to perform Empirical choices: Likely species involved Probable susceptibility of those fungi PRINCIPLES OF ANTIMICROBIAL DRUG SELECTION AND USE  Micro- organism PK Costs considerations Antimicrobial Therapy Adverse PD reactions considerations Host considerations Are antimicrobials indicated? Common non-infectious causes of fever Hemorrhage Metabolic Conditions Pulmonary embolism Gastrointestinal Heat stroke Thrombophlebitis Peritoneal / Retroperitoneal Hyperthyroidism Vascular access associated Pulmonary / Pleural Malignant hyperthermia Pheochromocytoma Tissue damage Inflammatory conditions Seizures Pain Blood product transfusion Surgery GD(V) / Ischemic bowel Neoplasia Trauma IMHA / ITP Carcinoma IM polyarthropathy Leukemia / Lymphoma Toxicities Pancreatitis Malignant histiocytosis SLE Sarcoma Vasculitis: Idiopathic Medications Thromboembolism Immune-mediated Allergic reactions Arterial thromboembolism Idiopathic drug fever Central venous thrombosis Antibacterial spectrum of activity Akinesia, CC BY-SA 4.0. https://commons.wikimedia.org/w/index.php?curid=64751804 Susceptibility patterns of bacterial organisms https://target.naccvp.com/loi/drugPath  Micro- organism PK Costs considerations Antimicrobial Therapy Adverse PD reactions considerations Host considerations Routes of administration Intravenously (IV) Factors influencing administration route: Drug type Drug pharmacokinetics Intramuscularly (IM) Drug physicochemical properties Drug formulation Subcutaneously (SC) Drug bioavailability Route of elimination Orally (PO) Location, nature and severity of infection Topically Regional infusion e.g. intramammary  Physicochemical drug properties Polar (hydrophilic) low lipophilicity Moderate to high lipophilicity Highly lipophilic (Non-polar) Acids Bases Weak acids Weak bases Amphoteric Low ionization β-Lactamase inhibitors Aminoglycosides Sulfonamides Azalides Tetracyclines Chloramphenicol Cephalosporins Polymyxins Lincosamides (Not doxycycline or Fluoroquinolones Penicillins Spectinomycin Macrolides minocycline) Lipophilic tetracyclines Trimethoprim Metronidazole Rifamycins Do not readily penetrate Cross cellular barriers more readily Cross cellular barriers very readily ‘natural body barriers’ Can enter transcellular fluids. Weak bases ion-trapped Penetrate into transcellular fluids e.g. Effective concentrations rarely achieved in (concentrated) in acidic fluids e.g. prostatic fluid, milk prostatic fluid and bronchial secretions CSF, milk, secretions (except chloramphenicol and tetracyclines) Can penetrate into cells if lipophilic enough (e.g. erythromycin) Effective concentrations may be achieved Penetrate CSF in joints, pleural and peritoneal fluids Penetration into CSF and ocular fluids is affected by plasma (except tetracyclines and rifamycins) protein binding as well as lipophilicity Penetration assisted by inflammation Penetrate into intracellular fluids Azalides have prolonged half-lives due to extensive uptake to, and slow release from, tissues. Azalides penetrate phagosomes and phagolysosomes and concentrate in macrophages and neutrophils ✭ vetmed.tamu.edu/antimicrobials/  Micro- organism PK Costs considerations Antimicrobial Therapy Adverse PD reactions considerations Host considerations Pharmacodynamic targets Barker CIS et al. Adv Drug Deliv Rev 2014; 73:127-39. ✭ MICs and Breakpoints MIC: The lowest concentration (µg/mL) of an antibacterial drug required to prevent growth of a single bacterial isolate. For a population of isolates the MIC can be represented by the modal (median) concentration. Breakpoint: Concentration (µg/mL) of an antibacterial drug that defines whether a bacterial isolate is susceptible or resistant. The susceptible breakpoint concentration is at least 1 dilution less than the resistant breakpoint concentration for each drug. Susceptible: Isolate MIC is below the susceptible breakpoint concentration Resistant: Isolate MIC is above the resistant breakpoint concentration Intermediate: Isolate MIC is between the sensitive and the resistant breakpoint concentrations. Occurs when there are 2 or more dilutions between the susceptible and resistant breakpoints. How are breakpoints established? EUCAST (https://www.eucast.org/clinical_breakpoints/) CLSI (https://clsi.org/standards/products/free-resources/access-our-free-resources/) Established population MIC distribution for a large number of isolates (>100) Clinical pharmacology of the drug in the target species for the labeled dose Cmax and Cmin AUC24h t½ Documentation that bacteria defined as susceptible in vitro respond clinically as expected, i.e. susceptible bacteria in vitro are inhibited in vivo Breakpoint interpretation Breakpoint interpretation Breakpoints are tissue specific  Micro- organism PK Costs considerations Antimicrobial Therapy Adverse PD reactions considerations Host considerations Effect of physiologic and pathologic states Drug disposition can be influenced Common physiologic causes by physiologic and pathologic states Neonates / Juveniles Pregnancy Key PK parameters may be altered: Protein-binding Common pathologic causes Bioavailability Cachexia Volume of distribution Fever Clearance Dehydration Half-life Liver failure Kidney injury Limited data on influence of these scenarios on antimicrobial drug ADME in veterinary medicine  Host considerations: Immune response Dranoff G. Nat Rev Cancer 2004;4:11-22. Host considerations: Devices and implants encyclopedie-environnement.org/ Latif A et al. Curr Infect Dis Rep. 2015; 17(7):491. Gieling F et al. Vet J 2019; 250:44-54 Duration of therapy: Clinical trials in humans bradspellberg.com/shorter-is-better  Duration of therapy: Common infections in humans Kozierowski K. John Hunter Hospital. NSW, Australia ✭ Potential reasons for antimicrobial treatment failure There is no infection The infection is not susceptible to antibacterial drugs You are using the wrong antimicrobial drug You are using the wrong route of administration Your antimicrobial drug dosing is inappropriate Source control is inadequate An Eagle effect is occurring Antimicrobial drug penetration to the target site is poor Antimicrobial drug activity is being inhibited Antimicrobial drug antagonism has developed Antimicrobial drug are working, but the patient has deteriorated regardless  Micro- organism PK Costs considerations Antimicrobial Therapy Adverse PD reactions considerations Host considerations ✭ Adverse drug reactions Renal Aminoglycosides (Cephalosporins) Polypeptides BM suppression CNS / PNS Potentiated sulfonamides Cephalosporins Aminoglycosides Penicillins (Carbapenems) Phenicols Skin Potentiated sulfonamides Fluoroquinolones Fluoroquinolones Macrolides Tetracyclines Nitroimidazoles Polypetides Ocular Fluoroquinolones Potentiated sulfonamides Musculoskeletal Fluoroquinolones Tetracyclines Hepatic Nitrofurans Hypersensitivity Phenicols Cephalosporins Potentiated sulfonamides GI Macrolides Rifamycins Penicillins Cardiovascular Tetracyclines Carbapenems Potentiated sulfonamides Aminoglycosides Cephalosporins Tetracyclines Fluoroquinolones Nitrfurans Nitroimidazoles Penicillins decade3d Phenicols Tetracyclines  Micro- organism PK Costs considerations Antimicrobial Therapy Adverse PD reactions considerations Host considerations Cost cddep.org/tool/current_prices_antibiotics_class_age/ Withdrawal periods zoetisus.com/draxxin-25/Withdrawal_Time.aspx PRESCRIBING GUIDES 4 Moments 1. Does my patient have an infection that requires antibiotics? 2. What diagnostic tests do I need to order? 3. If antibiotics are indicated, what is the narrowest, safest, and shortest regimen I can prescribe? 4. Does the client understand what to expect and the follow-up plan? ahrq.gov/antibiotic-use/index.html Texas A&M University College of Veterinary Medicine & Biomedical Sciences Center for Educational Technology, used with permission Stephen Cole PennVet ✭ Firstline (https://firstline.org/ovc-cphaz/)