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Home , Megaloblastic anemia

8/20/14

Antimicrobials Jeff Lapoint, DO Michelle Burns & Michael Policastro

Antimicrobials

• Antibiotics • Antifungals

• Anti-mycobacterials • Antihelminthics

• Antimalarials • Sterilants

• Antivirals

Antibiotics

• Beta lactams • Vancomycin

• PCN and • Tetracyclines cephalosporins • Chloramphenicol • Sulfonamides • Dapsone • Aminoglycosides • Quinolones • Ketolides/Macrolides • Misc

1 8/20/14

Beta-lactams

PCN Toxicity

• Jarish-Herxheimer: IM/IV Pen G

• Hoigne Syndrome: IM/IV Pen G

• Hepatitis: Amoxicillin-clavulanic acid

Cephalosporin Toxicity

• MTT side chain (N-methylthiotetrazole)

• Cefazolin Cefamandole

• Cefotetan Cefoperazone

• Cefmetazole Moxalactam

2 8/20/14

MTT side chain

Cephalosporin Toxicity

• Ceftriaxone:

• Pseudolithiasis: Gall-bladder sludging

• Kernicterus 2º bilirubin displacement

• Cefaclor (ceclor): Serum sickness

• Type III Hypersensitivity (immune complexes)

3 8/20/14

Sulfonamides

• Hypersensitivity: Most common adverse effect

• /: 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)

4 8/20/14

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: , leukopenia, ↓ plt

• Idiosyncratic: , often fatal

5 8/20/14

Dapsone

• Toxicity: Primary from P-450 metabolites

• RBC oxidant stress

• Methemoglobinemia

•

Quinolones

• Orthopedic

• ↑ QTc

• Drug-drug

• Hepatoxicity

• Neurotoxicity

Miscellaneous Abx

• Linezolid

• Metronidazole

• Nitrofurantoin

6 8/20/14

Pentamidine

• Toxicity:

• Hypotension

• Hypoglycemia

• IDDM

• ↑ QTc: Torsades de Pointes

• Pancreatitis

Antituberculosis Meds

• Isoniazid (INH) Acid

• Rifampin • Capreomycin

• Ethambutol

• Pyrazinamide

• Cycloserine

• Para-Aminosalicylic

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

7 8/20/14

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

8 8/20/14

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 antibiotic 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

9 8/20/14

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

• Chelates metal

• Zn chelation = optic neuritis

• Shift wavelength discrimination

• Loss red/green discrimination

10 8/20/14

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 epilepsy

• CHF

11 8/20/14

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-quinine

12 8/20/14

Antimalarials

• Types: • Proguanil/ Pyimethamine/ • Quinine Suldoxine

• Chloroquine/ • 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

13 8/20/14

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, megaloblastic anemia, rash

• Pyrimethamine: N/V, SZ, megaloblastic anemia

• Dapsone

14 8/20/14

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)

15 8/20/14

Lipodystrophy

Dorsocervical fat pad Central Obesity Aka “Buffalo Hump”

NRTI Adverse Effects

Zidovudine Abacavir Lamivudine Emtricitabine

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

NRTI Adverse Effects

Stavudine Didanosine Tenofovir

Peripheral Pancreatitis GI upset neuropathy Peripheral Flatulence Pancreatitis neuropathy Nephrotoxicity Dyslipidemia Diarrhea

16 8/20/14

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 Nevira Efavirenz Etravirine Rilpivirine pine Abnormal dreams, Insomnia drowsiness, Depression dizziness, Elevation Liver Elevations in confusion s in liver failure liver function Mood changes function Rash tests Elevations in tests (7%) Elevations in liver function serum tests creatinine Hyperlipidemia • Abnormal dreams, drowsiness, dizziness, confusion Efavirenz! • Mood changes • Elevations in liver function tests • Hyperlipidemia Etravirine! • Elevations in liver function tests • Liver failure 17 Nevirapine! • Rash (7%) • Insomnia • Depression Rilpivirine! • Elevations in liver function tests • Elevations in serum creatinine 8/20/14

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 GI intolerance, paresthesias, asthenia, Ritonavir taste perversion, hepatitis Saquinavir GI intolerance GI intolerance, hepatitis, rash, Tipranavir intracranial hemorrhage Darunavir GI intolerance, rash

18 8/20/14

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 liver function tests

• Headache

• Dizziness, abnormal dreams

• Pruritus, rash

• Fatigue, muscle pain

19 8/20/14

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

20 8/20/14

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: leukemia, non Hodgkins lymphoma spontaneous abortions, oligiospermia

• Motor/sensory neuropathies

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

21 8/20/14

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)

22 8/20/14

Antihelmintics

• Mebenazole: GI, hematuria, ↑LFTs

• Thiabendazole: GI, cholestasis,leukopenia,Hypersensitivity rxn

• Levamisole: agranulocytosis, 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

23