Adverse drug reaction

Background

• Any noxious and unintended response to a drug or natural health product that occurs at a normal dose
  • Causality is attributed to the treatment based on clinical judgment as related, not related, or unknown; if at least a possible relationship exists, it is considered an adverse reaction
• A serious adverse drug reaction is one that requires inpatient hospitalization (or prolongation of existing hospitalization), causes congenital malformation, results in persistent or significant disability or incapacity, is life threatening, or results in death
  • Also known as a serious adverse event
• A serious unexpected adverse drug reaction is one that is not identified in the brochure or label of the drug or natural health product
  • Also known as a suspected unexpected serious adverse reaction

Risk Factors

• Extremes of ages (elderly and young)
• Polypharmacy
• Pregnancy
• Breastfeeding
• Genetic factors
  • e.g. specific genes predispose to AG ototoxicity
• Comorbidities, including renal and hepatic dysfunction
• Antimicrobials are one of the largest causes of adverse drug reactions

Immune-Mediated Hypersensitivity Reactions

• See also Hypersensitivity reaction

Type		Description	Examples
I		immediate IgE-mediated reaction	anaphylaxis
II		antibody-mediated cytotoxic reaction	hemolytic anemia from penicillin
III		immune complex-mediated reaction	serum sickness from cephalosporins
IV	IV	delayed cell-mediated reaction	DRESS
	IVa	delayed Th1-mediated reaction
	IVb	delayed Th2-mediated reaction
	IVc	delayed CD8 T-cell-mediated reaction
	IVd	delayed T-cell-mediated neutrophilic reaction

Non-Immune-Mediated Hypersensitivity Reactions

Type	Description	Examples
Type A	Understood pharmacologic effects	serotonin syndrome from linezolid, thrush after antibiotics, drug toxicities, drug-drug interactions
Type B	Idiosyncratic
Type C	Chronic effects
Type D	Delayed effects, including carcinogenic or teratogenic

Major Examples

Fluoroquinolones

• CNS: dizziness, HA, sleep disturbance, hallucinations, seizures, depression, peripheral neuropathy (3%)
  • Seizures, especially with concomitant NSAIDs or theophylline due to GABA binding and NMDA activation
    • Cipro worst culprit
• QT prolongation
• Tendon rupture
  • 90% was Achilles tendon; 50% bilateral
  • Cipro caused 90% of cases
  • Risk persists for up to a year
  • Most cases resolve after discontinuation
  • Risk factors: elderly, concomitant steroids, renal failure, diabetes, history of MSK disorders, male sex
    • Steroids cause chondrocyte apoptosis

Beta Lactams

• Seizures
  • Inhibits GABA release
  • More common with renal failure, elderly, high doses
  • 1 to 10 days after starting the antibiotics
  • Resolves 2 to 7 days after stopping

Metronidazole

• Peripheral neuropathy
  • Usually reversible but takes time
  • Starts after 4 weeks or 42 grams
  • Free radicals causing nerve damage, and metronidazole causes degeneration
  • Resolves in 2 to 24 weeks

Nitrofurantoin

• Pulmonary fibrosis
• May be acute or chronic (9 days vs months or years)
• No fevers, eosinophilia, or pleural effusions
• Risk factors include CKD, high prolonged doses, older age, female sex
• Mechanism is toxic metabolites induce injury of lung microsomes with oxidative stress
• Acute: Type I or III hypersensitivity, resolves with discontinuation
• Chronic: cell-mediated or toxic response, fibrosis is irreversible

Drug Fevers

• Most commonly beta lactams and Septra
• Caused by byproducts of hepatically created metabolites?
• Can be high fevers; relative bradycardia, patient appears well, no rigors, maybe liver enzymes up, normal eosinophils, often left shift of elevated WBC
• Usually takes 5 to 10 days
• Normalizes within 72 hours of discontinuation

QT Prolongation

• Risk factors include electrolyte abnormalities, age, female sex, structural heart disease, bradycardia, hypothyroidism, CNS process, obesity, genetics, alcohol and cocaine use
  • Potassium wasting diuretics
  • Antiarrhythmics
  • Drug-drug interactions
  • Higher dose
  • Route of drug (IV > PO)
• EMA paper QT prolongation
  • Concern if the drug causes 30-60 ms increase
  • Clear concern if QTc >500 ms or increases by >60 ms
• Check repeat ECG at 3 to 5 days

Diarrhea

• Antibiotics are 25% of drug-induced diarrhea
• Appears within days, resolves after discontinuing
• Mechanism includes disruption of normal gut flora, which can also cause impaired fermentation
• Highest risk includes macrolides (promotility), fluoroquinolones, amoxicillin/clavulanic acid

Acute Tubular Necrosis

• Aminoglycosides
• Vancomycin
• Inter

Interstitial Nephritis

• Typically beta lactams
• Oliguria, malaise, anorexia, nausea/vomiting
• Rash, fever, eosinophils, arthralgias
• T-cell mediated hypersensitivity
• Reversible over weeks
• Should probably avoid the whole class of antibiotics

Rash

• Amipicillin is the most common penicillin, more commonly in women, especially with viral infections
• Maculopapular rash
  • Most common
  • Not immediate (>1 hour after dose)
  • Mechanism is T-cell mediated

Neutropenia/Thrombocytopenia

• From beta lactams
  • Can either be from induced antibody formation against wthe bloodline with immune complex formation; can also have a direct marrow effect
  • Anemia is rare, but can get autoimmune hemolytic anemia
  • At least 10 days of penicillin before you see bone marrow suppression
  • Start to recover after 3 to 4 days of discontinuation if it was marrow suppression
  • Longer if immune-mediated reaction
• Linezolid, vancomycin

Aplastic Anemia

• From Septra

Daptomycin

• Asymptomatic CK rise:
  • 8/8 patients in one case series were able to resume with normalized CK by withholding a dose and resuming 24 h later

List of Adverse Drug Reactions

Antibiotics

	Adverse drug reaction
Amikacin
Aminoglycosides
Amoxicillin-clavulanic acid
Ampicillin-sulbactam
Antipseudomonal antibiotics
Aztreonam
Bedaquiline	QTc prolongation Hepatitis Arthralgias Dizziness Headache Hyperuremia Insomnia Myalgia Nausea Prolonged QTc Pruritus Vomiting
Cefazolin
Cefepime
Cefiderocol
Cefipime
Ceftaroline
Ceftobiprole
Ceftolozane-tazobactam
Cefuroxime
Cephalosporins
Ciprofloxacin
Clindamycin
Clofazimine
Cloxacillin
Colistin
Dalbavancin
Dapsone
Daptomycin
Daptomycin lock therapy
Doxycycline
Eagle phenomenon
Eravacycline
Ertapenem
Ethambutol	Optic neuritis Rash
Fluoroquinolones
Fosfomycin
Imipenem-relebactam
Intrinsic antibiotic resistance
Intrinsic vancomycin resistance
Isoniazid	Rash Hepatitis Peripheral neuropathy CNS toxicity Sideroblastic anemia
Linezolid	Serotonin syndrome Thrombocytopenia Anemia Leukopenia
Macrolides
Methenamine
Metronidazole	Disulfiram-like reaction Peripheral Neuropathy
Minocycline
Oritavancin
Penicillin
Piperacillin-tazobactam
Plazomicin
Polymixins
Pretomanid
Pyrazinamide	Hepatitis Rash Arthralgias Gout
Pyrimethamine	Pancytopenia GI intolerance Rash Hepatitis Headache Dizziness Insomnia
Rifampin	Drug-drug interactions Rash Hepatitis Influenza-like illness Neutropenia Thrombocytopenia
... further results

Antifungals

	Adverse drug reaction
Antifungal spectrum of activity
Caspofungin
Ciclopirox
Fluconazole	Hepatitis QTc prolongation Drug-drug interactions
Flucytosine	Neutropenia
Ibrexafungerp
Isavuconazole
Itraconazole	Headache Relative adrenal insufficiency Hepatotoxicity QTc prolongation
Manogepix
Micafungin
Posaconazole
Terbinafine
Voriconazole	Hepatotoxicity QTc prolongation Photosensitivity Floaters Visual hallucinations Colour vision loss Photophobia Blurred vision

Antivirals

	Adverse drug reaction
Acyclovir	Acute kidney injury Phlebitis Neurotoxicity
Antiviral spectrum of activity
Brincidofovir
Cidofovir	Renal tubular necrosis
Foscarnet
Ganciclovir
HIV medications
Lamivudine
Letermovir
Maribavir
Nevirapine
Oseltamivir
Palivizumab
Raltegravir
Remdesivir
Ribavirin
Valacyclovir
Valganciclovir
Zidovudine

Antiparasitics

	Adverse drug reaction
Albendazole	Leukopenia Thrombocytopenia Hepatotoxicity Alopecia
Artesunate
Atovaquone
Atovaquone-proguanil
Chloroquine
Diethylcarbamazine
Ivermectin
Levamisole
Mebendazole
Nitazoxanide
Pentavalent antimony
Praziquantel
Primaquine
Pyrantel pamoate