Adverse drug reaction

Risk Factors

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

Classification

Type	Description
Type A	Understood pharmacologic effects
Type B	Idiosyncratic
Type C	Chronic effects
Type D	Delayed effects, including carcinogenic or teratogenic

Immunologic Hypersensitivity Reactions

Type	Description
I	IgE-mediated
II	hemolytic anemia from PCN
III	Serum sickness from cephalosporings
IV	DRESS

Non-immunologic Reactions

Predictable

• Pharmacologic side effect, eg serotonin syndrome from linezolid
• secodary pharma side effect, eg. thrush after abx
• drug toxicity
• drug-drug interactions
• ..
• ...
• ..

Non-predictable

...

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 abx
  • 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 factosr 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 withing 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 diruption of normal gut flora, which can also cause impaired fermentation
• Highest risk includes macrolides (promotility), fluroquinolones, amoxicillin/clavulatate

Acute Tubular Necrosis

• Aminoglycosides
• Vancomycin
• Inter

Interstitial Nephritis

• Typically beta lactams
• Oliguria, malaise, anorexisa, 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 msot common penicillin, more commoly 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