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Antimicrobials Lapoint.Key

Antimicrobials Lapoint.Key

Antimicrobials Jeff Lapoint, DO ! Michelle Burns & Michael Policastro Antimicrobials

• • Antifungals

• Anti-mycobacterials • Antihelminthics

• Antimalarials • Sterilants

• Antivirals

!

! Antibiotics

• Beta lactams •

• PCN and • Tetracyclines • • Sulfonamides • • Aminoglycosides • Quinolones • Ketolides/Macrolides • Misc Beta-lactams PCN Toxicity

• Jarish-Herxheimer: IM/IV Pen G

• Hoigne Syndrome: IM/IV Pen G

• : - Toxicity

• MTT side chain (N-methylthiotetrazole)

•

•

• Cefmetazole Moxalactam

MTT side chain Cephalosporin Toxicity

• :

• Pseudolithiasis: Gall-bladder sludging

• Kernicterus 2º bilirubin displacement

• (ceclor):

• Type III Hypersensitivity (immune complexes) Sulfonamides

• Hypersensitivity: Most common adverse effect

• /Hemolysis: Rare

• Suppression: Rare Aminoglycosides

• Gentamicin, Tobramicin, Amikacin

• Neuromuscular blockade

• Chronic:

• Ototoxicity and nephrotoxicity Ketolides/Macrolides

• Telithromycin: Hepatotoxicity; exacerbation of Myasthenia Gravis

• Erythromycin, Clarithromycin, Azithromycin

• QTc: Torsades de Pointes

• Drug-drug interactions

• Erythromycin: GI side effects (pro-motility) Vancomycin

• Ototoxicity:

• May be permanent

• Excessively high levels (60-100 mcg/mL)

• Nephrotoxicity:

• Caution when used in combination with aminoglycosides Tetracyclines

• Tetracyline

• Doxycycline

• Minocycline

• Demeclocycline

• Tigecycline Chloramphenicol

• Grey Baby Syndrome:

• Bone Marrow Toxicity:

• Supression: , , ↓ plt

• Idiosyncratic: aplastic anemia, often fatal Dapsone

• Toxicity: Primary from P-450 metabolites

• RBC oxidant stress

• Methemoglobinemia

• Quinolones

• Orthopedic

• ↑ QTc

• Drug-drug

• Hepatoxicity

• Neurotoxicity Miscellaneous Abx

• Linezolid

• Metronidazole

• Nitrofurantoin Pentamidine

• Toxicity:

• Hypotension

• Hypoglycemia

• IDDM

• ↑ QTc: Torsades de Pointes

• Pancreatitis Antituberculosis Meds

• (INH) • Para-Aminosalicylic Acid • Rifampin • Capreomycin • Ethambutol

• Pyrazinamide

• INH

• Structurally related to nicotinic acid (niacin or Vit B3 shown on right side)

• Pyridine ring essential for antituberculous activity

• Rapidly absorbed with peak [plasma] within 2 hrs Glutamate PLP Pyridoxine Pyridoxine GAD Kinase

GABA INH Toxicity

• Acute: Triad of seizures, coma, lactic acidosis

• Chronic: Hepatitis (hepatocellular necrosis) INH Toxicity

• Chronic:

• Peripheral neuropathy: stocking glove distribution, progress proximally

• Primarily sensory, although may see myalgias/ weakness

• Optic neuritis (red-green discrimination intact)

• Increased incidence in malnourished, alcoholics, slow acetylators INH Toxicity cont’d

• Drug-drug:

• inhibits 3A4 (cbz), 1A2 (theophylline), 2C9 (/ warfarin)

• Induce 2E1 (APAP)

• Food-drug:

• weak MAOI activity → tyramine reaction

• serotonin syndrome reported in pts taking meperidine + INH INH Seizure Treatment

• Pyridoxine B6: Give with GABA agonists

• Rapidly terminates seizures, reverses coma, corrects metabolic acidosis

• Give gram per gram ingested if known

• Empiric dosing is 5 grams (70 mg/kg pedi) Rifampin

• Semisynthetic derived from Steptomyces mediterranei

• Inhibits initial steps in RNA chain polymerization

• Greatest teratogenic effect of all TB meds

• Malformation rate 4.4%

• Anencephaly, hydrocephalus, congenital limb Δ Rifampin

• N/V, diarrhea (only TB med to do so)

• Flushing, angioedema, periorbital/facial edema

• Reddish discoloration of body fluids Rifampin

• CSF also affected, leading to confusion of xanthochromia

• Skin discoloration may be washed off

• Hepatitis

• Drug-drug: Induces 3A4 Ethambutol

• 1st line in pregnancy

• Chelates metal

• Zn chelation = optic neuritis

• Shift wavelength discrimination

• Loss red/green discrimination Ethambutol Toxicity

• Acute: N/V, abdominal pain

• Could see optic neuropathy acute > 10 grams Ethambutol Toxicity

• Chronic:

• Optic neuritis: unilateral or bilateral

• Loss of red-green discrimination: distinguish from INH optic neuropathy

• Contraindicated in children too young to comply with formal ophtho exam

• Peripheral neuropathy, asymptomatic ↑ uric acid Cycloserine

• Neuro dysfunction is very common

• Sz, psychosis , contraindicated in

• CHF Capreomycin

• Hearing loss, tinnitus

• Proteinuria, electrolyte loss

• Sterile abscess at injection sites Pyrazinamide

• Structural analog of nicotinamide

• Prodrug

• Toxicity

• Hepatitis

• Hyperuricemia Antimalarials

• Quechuas 1st antimalaria: bark of cinchona tree

• Europe 350 years ago- Antimalarials

• Types: • Proguanil/ Pyimethamine/ • Quinine Suldoxine

• / • Atovaquone hydroxychloroquine • Artemisinin: very • Primaquine safe, sz

• Mefloquine Quinine

• Optical isomer quinidine

• Once widely used for malaria

• Occasionally used for chloroquine-resistant cases

• Nocturnal muscle cramps

• Sources: Tonic water, street heroin

• Abortifacient: Oxytocic activity, Preterm labor Quinine Toxicity

• Cardiac: Na & K channel inhibition

• Metabolic: Pancreatic ATP-sensitive K+ channel blocked

• Otic: 8th nerve dysfunction → tinnitus & deafness

• Retinal toxicity Chloroquine/ Hydroxychloroquine

• Uses:

• Chloroquine: antimalarial

• Hydroxychloroquine: anti-inflammatory

• Toxicity: Hypotension more prominent

• Treatment: Early, aggressive management Fatality ↓ 91% to 9% Antimalarials

• Primaquine: RBC oxidant stress

• Methemoglobinema

• Hemolysis (G6PD)

• Mefloquine: Neuropsych changes 1:200 pts

• Insomnia with odd dreams

• “Clouded consciousness” Antimalarials: Inhibitors • Atovaquone: Rash, erythema multiformae

• Proguanil: GI, , rash

• Pyrimethamine: N/V, SZ, megaloblastic anemia

• Dapsone Antivirals NRTI’s

• Mainly undergo renal excretion EXCEPT

• Zidovudine (AZT) undergoes glucuronidation

• Abacavir metabolized by alcohol dehydrogenase

• Do not have P-450 drug interactions NRTI’s

• Class adverse effects

• Lactic acidosis with hepatic steatosis

• body fat redistribution (lipodystrophy) Lipodystrophy

Dorsocervical fat pad Central Obesity Aka “Buffalo Hump” NRTI Adverse Effects

Zidovudine Abacavir Lamivudine Emtricitabine

Bone marrow Hypersensitivity suppression reaction: fever, (anemia/ rash, fatigue, Generally well- )! , nausea, tolerated, Hyperpigmentation Nausea! vomiting, headache, dry of palms and soles Nail diarrhea, loss of mouth discoloration! appetite, Myopathy! pharyngitis NRTI Adverse Effects

Stavudine Didanosine Tenofovir

Peripheral Pancreatitis GI upset neuropathy Peripheral Flatulence Pancreatitis neuropathy Nephrotoxicity Dyslipidemia Diarrhea NRTI Lactic Acidosis

• Treatment ?

• L-carnitine (50 mg/kg/d 3 times a day over 2 hrs)

• Riboflavin 50 mg/day NNRTI’s - General

• Hepatic metabolism-no renal dosage adjustments required

• Many P-450 drug interactions

• Class adverse effects:

• increased transaminase levels

• rash (nevirapine > delavirdine > efavirenz) Non-nucleoside Reverse Transcriptase Inhibitors Efavirenz Etravirine Nevira Rilpivirine Abnormal pine Insomnia dreams, Depression drowsiness, Elevation Liver Elevations in dizziness, s in liver failure liver function confusion function Rash tests Mood changes tests (7%) Elevations in Elevations in serum liver function creatinine tests Hyperlipidemia Protease Inhibitors

• Hepatic metabolism - no renal dosage adjustments

• Many drug interactions PI - Class Adverse Effect

• Hyperglycemia

• Lipodystrophy

• Hyperlipidemia (less with atazanavir)

• Increased transaminases PI Adverse Effects

Amprenavir/fos-amprenavir GI intolerance, rash, oral paresthesias

Atazanavir Hyperbilirubinemia Indinavir Nephrolithiasis, hyperbilirubinemia Lopinavir/ritonavir Nausea, diarrhea, pancreatitis Nelfinavir Diarrhea

Ritonavir GI intolerance, paresthesias, asthenia, taste perversion, hepatitis Saquinavir GI intolerance

Tipranavir GI intolerance, hepatitis, rash, intracranial hemorrhage Darunavir GI intolerance, rash Fusion Inhibitors

• Enfuvirtide

• Injection site reactions; erythema, cysts, and nodules at injection sites

• Neutropenia

• Possible increased frequency of pneumonia Chemokine Co-receptor Antagonists • Maraviroc

• Hepatoxicity: may be preceded by a systemic reaction (pruritic rash, eosinophilia)

• Dizziness/postural hypotension

• Increased risk of CV events (ischemia, MI)

• Diarrhea, nausea Integrase Inhibitors

• Raltegravir

• Nausea, diarrhea, flatulence

• Elevations in amylase and

• Headache

• Dizziness, abnormal dreams

• Pruritus, rash

• Fatigue, muscle pain Integrase Inhibitors

• Elvitegravir/cobicistat

• Insomnia, abnormal dreams

• Rash Antivirals

• Fusion Inhibitors- Guanosine Analogs

• Pyrofosfate Analog

• M2 protein Blockers

• Neurominidase Inhibtors

• Misc Antivirals

• Amantadine: Dopamine agonist

• TOX: Hyperthermia,↑QT & QRS, Anticholinergic

• Oseltamivir: GI

• Acyclovir: Neurotox/Nephrotox- crystal formation

• Ganciclovir: Retinal tox Antivirals

• Valacyclovir: TTP & HUS

• Foscarnet: *chelates divalet metals: Ca, Mg, Fe, Zn, Nephrotox

• Cidofovir: Nephrotox

• OD Rx: IV fluids & Probenicid decreases renal tubular uptake

• Ribavirin: Teratogen, sperm morphology Sterilants

Agent applied to inanimate objects to kill all microorganisms and spores

• Ethylene Oxide:

• Acute: chemical burns, necrosis, pulmonary edema, arrhythmias, seizures Sterilants

• IARC Group 1: , non Hodgkins lymphoma spontaneous abortions, oligiospermia

• Motor/sensory neuropathies

• Glutaraldehyde: vapor- skin and respiratory irritant, cough, lacrimation, asthma, chest pain, palpitations Antifungals

• Triazole: Fluconazole, itraconazole & voriconazole

• Imidazoles: Ketoconazole/clotrimazole, miconazole: Amphotericin B Toxicity

• Fever, chills, rigors 1-3 hours post infusion

• Hypokalemia - ⅓ pts require supplemental K+ Amphotericin B

• Nephrotoxicity: 80% patients azotemia 2º distal tubule damage & vasoconstriction

• Cardiac arrest with overdose (5-15 mg/kg)

• Liposomal preparations less toxic (chest pain) Antihelmintics

• Mebenazole: GI, hematuria, ↑LFTs

• Thiabendazole: GI, cholestasis,leukopenia,Hypersensitivity rxn

• Levamisole: , leukoencephalopathy

• Niridazole: ∆ MS, Sz

• Piperazine: N/V, ∆ MS, Sz Antihelmintics

• Metrifonate: inhibits ACHE, cholinergic crisis

• Hycanthone: Hepatotoxicity, mutagenic

• Ivermectin: CNS depression, ataxia, pontentiates GABA

• Suramin: Proteinuria/adrenal insufficency, ↑LFTs, coagulopathy

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