AnTmicrobials Overview AnTbioTcs

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AnTmicrobials Overview AnTbioTcs

An#microbials An#microbials Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU • An#microbials • An#mycobacterials • An#virals Overview • Disinfectants • An#fungals • An#parasi#cs • Adverse Effects by Systems An#bio#cs • Cell Wall (β-­‐ lactams, Glycopep#des-­‐ Vanc) • Cell membrane (Polymyxin B) • Protein synthesis (Aminoglycosides,Tetracycline, Linezolid Macrolides, Chloramphenical) • Nucleic Acids (Fluoroquinolones, Metronidazole, Rifampin) • An7-­‐metabolites (Sulfonamides,Trimethoprim) 1


An#microbials Β-­‐lactam • Penicillins: -­‐ Anaphylaxsis, SZ ( Picrotoxin binding site GABA), ↑K – Hoigne Syndrome: males, fear/illusion, apprehension – Jarisch-­‐Herxheimer: fever, chills, rash; lysed bacteria • Cephalosporins: nMTT side chain • ( moxalactam, cefazolin, cefoperazone, cefmetazole, cefmandole, cefotetan) • hypothrombinemia, Vit. K epoxide reductase inhibi7on, • disulfiram rxn • Cefaclor = serum sickness • Imipenem: Seizures, Picrotoxin binding site • No PNC cross reac#vity with Impenem, Aztreonam Disulfiram reac#ons • Metronidazole • Cephalosporins with NMTT side chain: -­‐ cefoperazone, cefamandole, moxalactam, cefotetan, cefmetazole • Chloramphenical • Nitrofurantoin • Trimethoprim-­‐sulfamethoxazole • Griseofulvin • OSHA: chlorpropamide, tolbutamide • Mushrooms: Coprinus,Clitocybe,Tricholoma Clinical Environmental Health and Toxic Exposures .Sullivan and Kreiger.2001 . Table 18-­‐4. P.238 Vancomycin • Inhibits cell wall synthesis binding D-­‐alanyl-­‐D-­alanine cell wall precursors • Tox: Red Man syndrome, ototoxicity, nephrotoxicity 2


An#microbials Aminoglycosides • Inhibits 30s ribosomal subunit • Nephrotoxicity, Ototoxicity, Ve#bulotoxicity • NMB: inhibit presynap7c release of ACH Chloramphenical • Inhibits 50s ribosomal subunit • Metabolism: glucuronyl transferase • limited conjugate in children • “Grey baby”-­‐vomi#ng,anorexia, ash color, met acidosis • Aplas#c anemia, peripheral neuropathy , op#c neuri#s , metabolic acidosis, cardiovascular collapse Drugs that undergo primary Synthe#c Phase II Biotransforma#on that you may forget • Glucuronida#on : Valproic acid, lamotrigine, opioids, APAP, irinotecan, 5-­‐FU, chloramphenical • Acetyla#on: INH, hydrazines, Sulfonamide, Dapsone, amonafidine 3


An#microbials Macrolides/Ketolides/Licosamides • Inhibit 50s ribosomal subunit • Eythromycin,azithromycin,clarithromycin, Clindamycin • Inhibit 3A4 except azithromycin, ↑QT • Inhibit PGP intes7nal = Digoxin • Chronic cholesta7c hepa77s, sensory neural hearing loss • Telithromycin: carbamate side chain; cholinergic crisis in Myasthenia pts • Clindamycin: C.diff, Stevens-­‐Johnson, NMB, dysrhythmias Tetracycline • Inhibits 30s/50s ribosomal subunit • Teratogen-­‐ Teeth discolora#on, hypoplas#c enamel, seen amer 4 th month • Benign intracranial hypertension • Phototoxicity, pneumoni#s, drug-­‐induced Lupus • Minocycline: Lupus like syndrome, Diabetes Insipidus ( DI) • Democycline: nephrogenic DI Linezolid • Inhibits N-­‐formylmethionyl-­‐ tRNA • HA, thrombocytopenia • Brown discolora#on tongue • Weak MAO inhibitor • Serotonin syndrome with SSRIs 4


An#microbials Nitrofurantoin • Pulmonary: dyspnea/cough, inters##al fibrosis • Rash, Lupus like syndrome • Neuropathy peripheral • Disulfiram reac#ons Fluoroquinolones • Inhibit DNA gyrase/topoisomerase • Binds Ca#ons, esp. Mg 2+ • Seizures: Binds Mg 2+ , + NMDA, (-­‐) GABA • QTc= sequestra#on Mg 2+ • Car7lage/Tendon damage • Hepatoxicty • Psychosis, serum sickness Metronidazole • Metallic taste • Peripheral neuropathy • Disulfiram reac#on 5


An#microbials Sulfonamides • Inhibit para-­‐amino acid/para-­‐amino acid glutamic acid • Folate synthesis inhibitor • Hypersensi#vity Rxns • MetHgb, hemolysis • Pneumoni#s, hepatotoxicity-­‐ cholestasis, asep#c menigi#s Folate Inhibitors-­‐ An7metabolites • MTX • Proguanil • Pyrimethane • Dapsone • Atovaquone • Sulfonamides • Trimethoprim • Triamterene • Sulfasalazine • Aminopterin • 5-­‐FU An#mycobacterials-­‐ TB Drugs • INH • Rifampin • Ethambutol • Pyrazinamide – nico#namide analog, hepa##s, gout • Cycloserine • Para-­‐Aminosalicylic acid-­‐ hepa##s, hypersensi#vity reac#on, thrombocytopenia • Capreomycin 6


An#microbials INH • OD: Seizures, coma, metabolic acidosis • INH Tox : op#c neuri#s, pancrea##s, hepa##s • TOX: +/-­‐slow acetylators, 2E1 • TX: Pyridoxone Goldfrank’s Toxicologic Emergencies. 6 th edi#on. 2006. Figure 55-­‐3 p.863 B6 ( Pyridoxine) • Tx: hydrazines, ethylene glycol • Dose: INH-­‐ gram/gram • OD: sensory neuronal neuropathy, ataxia Hydrazines • INH • Non-­‐selec#ve MAO A/B Inhibitors: -­‐Phenelzine, Isocarboxazid, Procarbazine • Hydrazine ( Diamine) • Monomethyhydrazine • Gyromitra • Ginkgo Biloba seeds ( 4-­‐Methoxypyridoxine) 7


An#microbials Rifampin • Binds B units DNA dependent RNA polymerase • * 3A4 inducer • Red/orange body fluids • False nega#ve PPD • TOX: hepa##s, Lupus like syndrome, ARF, thrombocytopenia, hemoly#c anemia, eosinophilic coli#s Ethambutol • 1 st line in pregnancy • Chelates metal • ** Zn chela#on = op#c neuri#s • ** shim wavelength discrimina#on • ** loss red/green discrimina7on • Analog of alanine • Neuro dysfunc7on • Sz, psychosis Cycloserine • Contraindicated in Seizure Pa7ents • Safe in breast feeding 8


An#microbials Capreomycin • * Hearing loss, 7nnitus • Preo#nuria, electrolyte loss • Sterile abscess at injec#on sites An#malarial • Quinine • Chloroquine/Hydroxychloroquine/Amodiaquine • Primaquine-­‐ MetHgb, Contraindicated Pregnancy • Mefloquine: Neuropysch-­‐ Sz, psychosis • Proguanil/Pyimethamine/Suldoxine • Atovaquone • Dapsone • Artemisinin: very safe, sz Chloroquine • Cardiac: Class Ia effect, neg ionotropy, VT, VF • Hypokalemia • Sz, transient blindness • TX: AC, Hypokalemia protec#ve Do NOT treat aggressive, diazepam Quinine • Cinchoa tree ( Rubiacea) • Cinchoism: auditory, GI, swea7ng, HA, vasodila7on • Cardiac: Class Ia affect, myocardial depression, phase 0 depression, vasodila#on • Heme: thrombocytopenia, pupura, hemolysis • CNS: Blindness, Tinnitus/deafness • Hypoglycemia-­‐ sulfonyurea like • TX: MDAC, Bicarb, ?Octreo7de 9


An#microbials An#malarials:Folate Inhibitors • Atovaquone: Rash, erythema mul#formae • Proguanil: GI, megaloblas#c anemia, rash • Pyrimethamine: N/V, SZ, megaloblas#c anemia • Dapsone Dapsone • Bacteriosta#c synthe#c sulfone, inhibits folic acid synthesis, binds dihydropterate synthase • Oxidizer, MetHgb, Hemolysis, also Sulvemoglobin • “Sulfone Syndrome” delayed hypersensi7vity syndrome = fever, eosinophilic pneumonia, derma##s, hepa#c necrosis • Also: thrombocytopenia, neutropenia, neuropathy • TX: MDAC, Methylene Blue, Exchange transfusion HIV Drugs Nucleoside Reverse Transcriptase Inhibitors (NRTI) zidovudine/Retrovir (AZT, ZDV) didanosine/Videx, Videx EC (ddI) zalcitabine/HIVID (ddC) stavudine/Zerit (d4T) lamivudine/Epivir (3TC) abacavir/Ziagen (ABC) Non-­‐Nucleoside Reverse Transcriptase Inhibitors (Non-­‐ NRTI ) nevirapine/Viramune delavirdine/Rescriptor efavirenz/Sus=va Protease Inhibitors (PI) indinavir/Crixivan ritonavir/Norvir saquinavir/Invirase,Fortovase nelfinavir/Viracept amprenavir/Agenerase lopinavir/ritonavir, Kaletra Atazanavir/Reyataz Nucleo7de Analogue tenofovir DF/Viread (TDF) Adefovir/Hepsera Emtricitabine/Emtriva Fusion (entry) inhibitors Enfuvir#de/ Fuzeon 10


An#microbials HIV Drug Toxici#es NRTI -­‐lac7c acidosis, impaired β –oxida#on TX: L-­‐carni7ne -­‐peripheral neuropathy -­‐Lipodystrophy syndrome • Protease Inhibitors -­‐Dyslipidemias, Hyperglycemia *ritanovir-­‐ hepatotoxicity, PGP inhibitor *Indinavir-­‐nephrolithiasis NNRTI -­‐ Skin rashes ( Stevens-­‐ Johnson, TEN, Eosinophilic systemic) * nevirapine -­‐ Hepatotoxicity, pancrea##s -­‐ * Efavirenz-­‐ neurotox Side effects of an7retroviral medica7ons Side EffectDrugsLactic acidosisNucleoside reverse transcriptase inhibitors, especially didanosine, stavudineHypersensitivity reactionAbacavir, nevirapineLiver toxicitySaquinavir, ritonavir, nelfinavir, tenofovir, nevirapine, efavirenz, atazanavirPancreatitisNephrolithiasisAcute tubular necrosisDidanosine, stavudine, zalcitabine, lopinavir/ritonavirIndinavirTenofovirAcute interstitialnephritisMyelosuppressionIndinavir, ritonavirZidovudineMyopathyNeuropathyZidovudineStavudine, didanosine, zalcitabineAn#Virals • Fusion Inhibitors-­‐ Guanosine Analogs -­‐Acyclovir -­‐Famciclovir -­‐Ganciclovir -­‐Valacyclovir -­‐Valganciclovir • Pyrofosfate Analog -­‐ Foscarnet • M2 protein Blockers -­‐ Amantadine, Rimantadine • Neurominidase Inhibtors -­‐Oseltamivir • Other -­‐ Ribavirin -­‐ Cidofovir -­‐ Palivizumab 11


An#microbials An#virals • Amantadine: pre-­‐synap7c DA blockade; TOX: Hyperthermia,↑QT, ? An#cholinergic • Oseltamivir: GI • Acyclovir: Neurotox/Nephrotox-­‐ crystal forma7on • Ganciclovir: Re7nal tox • Valacyclovir: TTP • Foscarnet: *chelates divalet metals: Ca, Mg, Fe, Zn, Nephrotox • Cidofovir: Nephrotox, OD TX: * Probenicid decreases renal clearance/renal failure • Ribavirin: teratogen,sperm morphology An#sep#cs, Disinfectants, Sterilants • An7sep7c: Agent applied to living #ssue to kill/inhibit microorganism • Disinfectant: Agent applied to inanimate objects to kill microorganisms. • Sterilant : Agent applied to inanimate objects to kill all microorganisms and spores Disinfectants • Formalin: 37 % Formaldehyde + 15 % methanol, Formaldehyde IARC 1 classifica7on • Phenol ( carbolic acid ) : severe burns skin /oral white ulcers, sz, met acidosis, rabbit syndrome (↓DA) -­‐TX: PEG ,Isoproponal – skin burns • Benzalkonium chloride: quarternary ammonium-­‐ occasional paralysis, NMJ-­‐ ACHE inhibi#on, occ. asthma 12


An#microbials An#sep#cs • Chlorhexidine: vaporized converts p-­‐chloraniline, MetHgb • Hydrogen peroxide: Conc. dependent, possible air emboli, local injury • Iodophors: (I 2 ) elemental iodine, (I -­‐ ) iodide: inges#on, blue-­‐ purple emesis with starch, false posi#ve Hematest (orthotoluidine), caus#c, GI bleed psuedohyperchloremia. TX: Covert Iodine to Iodide with milk/starches, thiosulfate • Potassium Permanganate: oxidizer, reacts with H20 to form manganese dioxide ( stains areas brown-­‐black), potassium hydroxide and molecular oxygen. -­‐Acute : local injury, MetHGB. -­‐ Chronic: possible Manganese poisoning-­‐ ams, parkinsonism, behavior d/o. -­‐TX: Skin stains-­‐ dilute oxalic acids, NAC Sterilants • Ethylene Oxide: spontaneous abor7ons,Oligiospermia mutagenic, Possible carcinogenic-­‐ leukemia, gastric CA, motor/sensory neuropathies • Glutaraldehyde: vapor-­‐ cp, palpita#ons, mucosal irritant An#fungals • Amphotericin -­‐Liposome B complex to reduce nephrotox -­‐Nephrotox -­‐Fever, chills due to PGE2 disrup7on -­‐↓ K, Mg, WBC, Plts -­‐ Tinnitus • Imidazoles ( ketaconazole, clotrimazole, econazole, miconazole) -­‐Inhibit fungal cell walls • 3A4 Inhibitors, ↑QT with terfenadine,cisapride,astemizole • Ketoconazole: Alopecia, gynecomas7a, adrenal suppression, androgen suppression, hepa77s • Triazole (fluconazole, itraconazole, terconazole, voriconazole) -­‐Inhibits ergosterol synthesis, ↑LFTs -­‐ Inhibits * 3A4 13


An#microbials An#helmin#cs • Mebenazole: teratogenic,rash • Thiabendazole: GI, cholestasis,leukopenia,Hypersensi#vity rxn • Levamisole: ↓Plts, encephalopathy, TEN • Niridazole: Sz • Piperazine: Angioedema, sz • Metrofonate: inhibits ACHE, cholinergic crisis • Hyocanthone:mutagenic, carcinogenic • Ivermec#n: Facial edema, bullous skin • Suramin: Renal/adrenal insufficency, TEN • An7mony ( 3+/5+): GI, derma77s; TX:BAL Neurologic Adverse effects • AMS: Ethambutol, PNC, Chloramphenical, Mefloquine, Efavirenz • Intracranial Hypertension: Tetracyclines, Albendazole • Seizures: PNC, Cephalosporins, Rifampin, Sulfonamides, Fluoroquinolones, INH, Ethylene oxide, Imipenim • Neuromuscular blockade: Polymyxin B, Fluoroquinolones,colis#methate Aminoglycosides, Clindamycin, Vancomycin, Benzalkonium chloride • Myosi7s: Chloroquine, PNC, Rifampin, Sulfonamides, Zidovudine • Peripheral Neuropathy: Chloramphenical, Flagyl, Ritanovir, Didanosine, Zalcitabine,Stavuidine, amprenavir • Movement Disorder: Potassium Permanganate, Phenol • Ototoxicity: Vancomycin, Chloroquine/Quinine, Aminoglycosides, erythromycin • Op7c neuri7s: Ethambutol, Chloramphenical, Cidofovir, Gancyclovir • Re7nal Blindness: Quinine, Hydroxychloroquine Skin Rash Adverse Effects • “Red Man”-­‐ Vancomycin • “Grey baby”-­‐ Chloramphenical • Blue ( MetHgb): Sulfonamides,Dapsone, Primaquine, chloroquine, nitrofurans, • Stevens-­‐Johnson: PNC, Cephalosporins, Sulfa, nevirapine • TEN: PNC, Sulfas, nevirapine • Vesiculobullous: PNC, Rifampin, Sulfonamides, Griseofulvin • Vasculi7s: Levamisole • Acute Hypersensi7vity Syndrome: Sulfas, Bacitracin, Clindamycin, Lincomycin, Nitrofurazone, nevirapine • Alopecia: Selenium Sulfide 14


An#microbials Renal/GU Adverse Effects • Acute Tubular Necrosis: Aminoglycosides, Acyclovir, Amphotericin,Pentamidine, Polymyxins, Fluroquinolones,Foscarnet, Ritonavir, Tenovir, Phenazopyridine • Acute Inters77al Nephri7s: PNC,Ampicillin,Rifampin,Sulfonamides, Vancomycin • Nephrolithiasis/Obstruc7on: Indanavir, Sulfonamides ( crystal deposits), Acyclovir • Tubular dysfunc7on: Aminoglycosides, Amphotericin, Tetracycline, Griseofulvin • Decrease Sperm: Ethylene oxide , Nitrofurantoin, Ribavirin • Abor7ons: Ethylene Oxide Electrolyte Adverse Effects • Diabetes Insipidus: Amphotericin, Foscarnet, Minocycline, Rifampin, Streptozotocin • Hypokalemia ( ↑ QT): Aminoglycosides, Amphotericin, Chloroquine • Hyperkalemia: PNC, Triamterene, Trimethoprim • Hypocalcemia (↑QT): Aminoglycosides, Neomycin • Hypomagnesium ( ↑QT): Aminoglycosides, Foscarnet, Fluroquinolones Teratogens • Fluconazole: Abnormal facies, cardiac, femoral bowing • Quinine: Hypoplasia 8 th CN • Streptomycin: Hearing loss • Tetracycline: Teeth discolora#on, hypoplas#c enamel, seen amer 4 th month • Trimethoprim: NTD, hypospadias • *See Folate inhibitor list* 15


An#microbials Hematologic/Immune • Type I: IgE: PNC, tetracyclines, Sulfonamides, Nitrofurantoin,Streptomycin • Type II: An#body IgG/IgM-­‐ cytopenias: Amoxicillin, Sulfonamide • Type III: Immune Complex IgG/IGM-­‐ Serum Sickness: Cefaclor • Type IV: T-­‐ lympocyte-­‐ contact derma##s: Topical PNC • Oxida7ve Hemolysis/MetHgb: Dapsone, Nitrofurantoin, Phenol, Sulfonamides, Novobiocin • Agranulocytosis: B-­‐lactams, Cephalosporins, Chloramphenical, Dapsone, Ganicyclovir, Rifampicin, Sulfonamides, Vancomycin • Thrombocytopenia: Amphotericin, Indinavir, Levamisole, Quinine, Rifampin, Trimethoprim-­‐sulfamethoxazole, Vancomycin • TTP: Valacyclovir 16

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