Anmicrobials

Anmicrobials

Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU

Overview

• Anmicrobials • Anmycobacterials • Anvirals • Disinfectants • Anfungals • Anparasics • Adverse Effects by Systems

Anbiocs

• Cell Wall (β- lactams, Glycopepdes- Vanc) • Cell membrane (Polymyxin B) • Protein synthesis (Aminoglycosides,Tetracycline, Linezolid Macrolides, Chloramphenical) • Nucleic Acids (Fluoroquinolones, Metronidazole, Rifampin) • An-metabolites (Sulfonamides,Trimethoprim)

1 Anmicrobials

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 inhibion, • disulfiram rxn • Cefaclor = serum sickness • Imipenem: Seizures, Picrotoxin binding site • No PNC cross reacvity with Impenem, Aztreonam

Disulfiram reacons

• 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 Anmicrobials

Aminoglycosides

• Inhibits 30s ribosomal subunit • Nephrotoxicity, Ototoxicity, Vebulotoxicity • NMB: inhibit presynapc release of ACH

Chloramphenical

• Inhibits 50s ribosomal subunit • Metabolism: glucuronyl transferase • limited conjugate in children • “Grey baby”-voming,anorexia, ash color, met acidosis • Aplasc anemia, peripheral neuropathy , opc neuris , metabolic acidosis, cardiovascular collapse

Drugs that undergo primary Synthec Phase II Biotransformaon that you may forget

• Glucuronidaon : Valproic acid, lamotrigine, opioids, APAP, irinotecan, 5-FU, chloramphenical

• Acetylaon: INH, hydrazines, Sulfonamide, Dapsone, amonafidine

3 Anmicrobials

Macrolides/Ketolides/Licosamides

• Inhibit 50s ribosomal subunit • Eythromycin,azithromycin,clarithromycin, Clindamycin • Inhibit 3A4 except azithromycin, ↑QT • Inhibit PGP intesnal = Digoxin • Chronic cholestac hepas, 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 discoloraon, hypoplasc enamel, seen aer 4th month • Benign intracranial hypertension • Phototoxicity, pneumonis, drug-induced Lupus • Minocycline: Lupus like syndrome, Diabetes Insipidus ( DI) • Democycline: nephrogenic DI

Linezolid

• Inhibits N-formylmethionyl- tRNA • HA, thrombocytopenia • Brown discoloraon tongue • Weak MAO inhibitor • Serotonin syndrome with SSRIs

4 Anmicrobials

Nitrofurantoin

• Pulmonary: dyspnea/cough, intersal fibrosis • Rash, Lupus like syndrome • Neuropathy peripheral • Disulfiram reacons

Fluoroquinolones

• Inhibit DNA gyrase/topoisomerase • Binds Caons, esp. Mg2+ • Seizures: Binds Mg2+, + NMDA, (-) GABA • QTc= sequestraon Mg2+ • Carlage/Tendon damage • Hepatoxicty • Psychosis, serum sickness

Metronidazole

• Metallic taste • Peripheral neuropathy • Disulfiram reacon

5 Anmicrobials

Sulfonamides

• Inhibit para-amino acid/para-amino acid glutamic acid • Folate synthesis inhibitor • Hypersensivity Rxns • MetHgb, hemolysis • Pneumonis, hepatotoxicity- cholestasis, asepc menigis

Folate Inhibitors- Anmetabolites

• MTX • Sulfasalazine • Proguanil • Aminopterin • Pyrimethane • 5-FU • Dapsone • Atovaquone • Sulfonamides • Trimethoprim • Triamterene

Anmycobacterials- TB Drugs

• INH • Rifampin • Ethambutol • Pyrazinamide – niconamide analog, hepas, gout • Cycloserine • Para-Aminosalicylic acid- hepas, hypersensivity reacon, thrombocytopenia • Capreomycin

6 Anmicrobials

INH

• OD: Seizures, coma, metabolic acidosis • INH Tox : opc neuris, pancreas, hepas • TOX: +/-slow acetylators, 2E1 • TX: Pyridoxone

Goldfrank’s Toxicologic Emergencies. 6th edion. 2006. Figure 55-3 p.863

B6 ( Pyridoxine)

• Tx: hydrazines, ethylene glycol • Dose: INH- gram/gram • OD: sensory neuronal neuropathy, ataxia

Hydrazines

• INH • Non-selecve MAO A/B Inhibitors: -Phenelzine, Isocarboxazid, Procarbazine • Hydrazine ( Diamine) • Monomethyhydrazine • Gyromitra • Ginkgo Biloba seeds ( 4-Methoxypyridoxine)

7 Anmicrobials

Rifampin

• Binds B units DNA dependent RNA polymerase • * 3A4 inducer • Red/orange body fluids • False negave PPD • TOX: hepas, Lupus like syndrome, ARF, thrombocytopenia, hemolyc anemia, eosinophilic colis

Ethambutol

• 1st line in pregnancy • Chelates metal • ** Zn chelaon = opc neuris • ** shi wavelength discriminaon • ** loss red/green discriminaon

Cycloserine

• Analog of alanine • Neuro dysfuncon • Sz, psychosis • Contraindicated in Seizure Paents • Safe in breast feeding

8 Anmicrobials

Capreomycin

• * Hearing loss, nnitus • Preonuria, electrolyte loss • Sterile abscess at injecon sites

Anmalarial

• Quinine • Chloroquine/Hydroxychloroquine/Amodiaquine • Primaquine- MetHgb, Contraindicated Pregnancy • Mefloquine: Neuropysch- Sz, psychosis • Proguanil/Pyimethamine/Suldoxine • Atovaquone • Dapsone • Artemisinin: very safe, sz

Chloroquine Quinine • Cardiac: Class Ia effect, neg • Cinchoa tree ( Rubiacea) ionotropy, VT, VF • Cinchoism: auditory, GI, sweang, HA, vasodilaon • Hypokalemia • Cardiac: Class Ia affect, • Sz, transient blindness myocardial depression, phase 0 • TX: AC, Hypokalemia depression, vasodilaon protecve Do NOT treat • Heme: thrombocytopenia, aggressive, diazepam pupura, hemolysis • CNS: Blindness, Tinnitus/ deafness • Hypoglycemia- sulfonyurea like • TX: MDAC, Bicarb, ?Octreode

9 Anmicrobials

Anmalarials:Folate Inhibitors

• Atovaquone: Rash, erythema mulformae • Proguanil: GI, megaloblasc anemia, rash • Pyrimethamine: N/V, SZ, megaloblasc anemia • Dapsone

Dapsone

• Bacteriostac synthec sulfone, inhibits folic acid synthesis, binds dihydropterate synthase • Oxidizer, MetHgb, Hemolysis, also Sulemoglobin • “Sulfone Syndrome” delayed hypersensivity syndrome = fever, eosinophilic pneumonia, dermas, hepac necrosis • Also: thrombocytopenia, neutropenia, neuropathy • TX: MDAC, Methylene Blue, Exchange transfusion

HIV Drugs

Nucleoside Reverse Non-Nucleoside Reverse Nucleode Analogue Transcriptase Inhibitors (NRTI) Transcriptase Inhibitors tenofovir DF/Viread (TDF) zidovudine/Retrovir (AZT, ZDV) (Non- NRTI ) Adefovir/Hepsera didanosine/Videx, Videx EC (ddI) nevirapine/Viramune Emtricitabine/Emtriva zalcitabine/HIVID (ddC) delavirdine/Rescriptor stavudine/Zerit (d4T) efavirenz/Susva lamivudine/Epivir (3TC) Fusion (entry) inhibitors abacavir/Ziagen (ABC) Protease Inhibitors (PI) Enfuvirde/ Fuzeon indinavir/Crixivan ritonavir/Norvir saquinavir/Invirase,Fortovase nelfinavir/Viracept amprenavir/Agenerase lopinavir/ritonavir, Kaletra Atazanavir/Reyataz

10 Anmicrobials

HIV Drug Toxicies

NRTI • Protease Inhibitors -lacc acidosis, impaired -Dyslipidemias, Hyperglycemia β –oxidaon *ritanovir- hepatotoxicity, PGP TX: L-carnine inhibitor -peripheral neuropathy *Indinavir-nephrolithiasis -Lipodystrophy syndrome

NNRTI - Skin rashes ( Stevens- Johnson, TEN, Eosinophilic systemic) * nevirapine - Hepatotoxicity, pancreas - * Efavirenz- neurotox

Side effects of anretroviral medicaons Side Effect Drugs

Lactic acidosis Nucleoside reverse transcriptase inhibitors, especially didanosine, stavudine

Hypersensitivity reaction Abacavir, nevirapine

Liver toxicity Saquinavir, ritonavir, nelfinavir, tenofovir, nevirapine, efavirenz, atazanavir

Pancreatitis Didanosine, stavudine, zalcitabine, lopinavir/ritonavir

Nephrolithiasis Indinavir

Acute tubular necrosis Tenofovir

Acute interstitial Indinavir, ritonavir nephritis

Myelosuppression Zidovudine

Myopathy Zidovudine

Neuropathy Stavudine, didanosine, zalcitabine

AnVirals

• Fusion Inhibitors- • M2 protein Blockers Guanosine Analogs - Amantadine, Rimantadine -Acyclovir • Neurominidase Inhibtors -Famciclovir -Oseltamivir -Ganciclovir • Other -Valacyclovir - Ribavirin -Valganciclovir - Cidofovir • Pyrofosfate Analog - Palivizumab - Foscarnet

11 Anmicrobials

Anvirals

• Amantadine: pre-synapc DA blockade; TOX: Hyperthermia,↑QT, ? Ancholinergic • Oseltamivir: GI • Acyclovir: Neurotox/Nephrotox- crystal formaon • Ganciclovir: Renal 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

Ansepcs, Disinfectants, Sterilants

• Ansepc: 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 classificaon

• 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 inhibion, occ. asthma

12 Anmicrobials

Ansepcs

• Chlorhexidine: vaporized converts p-chloraniline, MetHgb

• Hydrogen peroxide: Conc. dependent, possible air emboli, local injury

- • Iodophors: (I2 ) elemental iodine, (I ) iodide: ingeson, blue- purple emesis with starch, false posive Hematest (orthotoluidine), causc, 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 aborons,Oligiospermia mutagenic, Possible carcinogenic- leukemia, gastric CA, motor/ sensory neuropathies • Glutaraldehyde: vapor- cp, palpitaons, mucosal irritant

Anfungals

• Amphotericin • Imidazoles -Liposome B complex to reduce ( ketaconazole, clotrimazole, econazole, nephrotox miconazole) -Inhibit fungal cell walls -Nephrotox • 3A4 Inhibitors, ↑QT with -Fever, chills due to PGE2 disrupon terfenadine,cisapride,astemizole -↓ K, Mg, WBC, Plts • Ketoconazole: Alopecia, gynecomasa, adrenal suppression, - Tinnitus androgen suppression, hepas

• Triazole (fluconazole, itraconazole, terconazole, voriconazole) -Inhibits ergosterol synthesis, ↑LFTs - Inhibits * 3A4

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Anhelmincs

• Mebenazole: teratogenic,rash • Thiabendazole: GI, cholestasis,leukopenia,Hypersensivity rxn • Levamisole: ↓Plts, encephalopathy, TEN • Niridazole: Sz • Piperazine: Angioedema, sz • Metrofonate: inhibits ACHE, cholinergic crisis • Hyocanthone:mutagenic, carcinogenic • Ivermecn: Facial edema, bullous skin • Suramin: Renal/adrenal insufficency, TEN • Anmony ( 3+/5+): GI, dermas; 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,colismethate Aminoglycosides, Clindamycin, Vancomycin, Benzalkonium chloride • Myosis: 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 • Opc neuris: Ethambutol, Chloramphenical, Cidofovir, Gancyclovir • Renal 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 • Vasculis: Levamisole • Acute Hypersensivity Syndrome: Sulfas, Bacitracin, Clindamycin, Lincomycin, Nitrofurazone, nevirapine • Alopecia: Selenium Sulfide

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Renal/GU Adverse Effects

• Acute Tubular Necrosis: Aminoglycosides, Acyclovir, Amphotericin,Pentamidine, Polymyxins, Fluroquinolones,Foscarnet, Ritonavir, Tenovir, Phenazopyridine • Acute Intersal Nephris: PNC,Ampicillin,Rifampin,Sulfonamides, Vancomycin • Nephrolithiasis/Obstrucon: Indanavir, Sulfonamides ( crystal deposits), Acyclovir • Tubular dysfuncon: Aminoglycosides, Amphotericin, Tetracycline, Griseofulvin • Decrease Sperm: Ethylene oxide , Nitrofurantoin, Ribavirin • Aborons: 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 8th CN • Streptomycin: Hearing loss • Tetracycline: Teeth discoloraon, hypoplasc enamel, seen aer 4th month • Trimethoprim: NTD, hypospadias • *See Folate inhibitor list*

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Hematologic/Immune

• Type I: IgE: PNC, tetracyclines, Sulfonamides, Nitrofurantoin,Streptomycin • Type II: Anbody IgG/IgM- cytopenias: Amoxicillin, Sulfonamide • Type III: Immune Complex IgG/IGM- Serum Sickness: Cefaclor • Type IV: T- lympocyte- contact dermas: Topical PNC • Oxidave 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

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