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== Risk Factors ==
==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


*Extremes of ages (elderly and young)
== Classification ==
*[[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

==Classification==
{| class="wikitable"
{| class="wikitable"
! Type
!Type
! Description
!Description
|-
|-
| Type A
|Type A
| Understood pharmacologic effects
|Understood pharmacologic effects
|-
|-
| Type B
|Type B
| Idiosyncratic
|Idiosyncratic
|-
|-
| Type C
|Type C
| Chronic effects
|Chronic effects
|-
|-
| Type D
|Type D
| Delayed effects, including carcinogenic or teratogenic
|Delayed effects, including carcinogenic or teratogenic
|}
|}


== Immunologic Hypersensitivity Reactions ==
==Immunologic Hypersensitivity Reactions==
{| class="wikitable"
{| class="wikitable"
! Type
!Type
! Description
!Description
!Example
|-
|-
| I
|I
| IgE-mediated
|immediate IgE-mediated reaction
|[[anaphylaxis]]
|-
|-
| II
|II
|antibody-mediated cytotoxic reaction
| hemolytic anemia from PCN
|[[hemolytic anemia]] from [[penicillin]]
|-
|-
| III
|III
|immune complex-mediated reaction
| Serum sickness from cephalosporings
|[[serum sickness]] from cephalosporins
|-
|-
| IV
|IV
|delayed cell-mediated reaction
| DRESS
|[[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-immunologic Reactions ==
==Non-immunologic Reactions==
=== Predictable ===
===Predictable===
* Pharmacologic side effect, eg serotonin syndrome from linezolid
* secodary pharma side effect, eg. thrush after abx
* drug toxicity
* drug-drug interactions
* ..
* ...
* ..


*Pharmacologic side effect, eg serotonin syndrome from linezolid
=== Non-predictable ===
*secodary pharma side effect, eg. thrush after abx
*drug toxicity
*drug-drug interactions
*..
*...
*..

===Non-predictable===
...
...


== Major Examples ==
==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
=== Fluoroquinolones ===
*Appears within days, resolves after discontinuing
* CNS: dizziness, HA, sleep disturbance, hallucinations, seizures, depression, peripheral neuropathy (3%)
*Mechanism includes diruption of normal gut flora, which can also cause impaired fermentation
** Seizures, especially with concomitant NSAIDs or theophylline due to GABA binding and NMDA activation
*Highest risk includes macrolides (promotility), fluroquinolones, amoxicillin/clavulatate
*** 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 ===
===Acute Tubular Necrosis===
* 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


*Aminoglycosides
=== Metronidazole ===
*Vancomycin
* Peripheral neuropathy
*Inter
** 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 ===
===Interstitial Nephritis===
* 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


*Typically beta lactams
=== Drug Fevers ===
*Oliguria, malaise, anorexisa, nausea/vomiting
* Most commonly beta lactams and Septra
*Rash, fever, eosinophils, arthralgias
* Caused by byproducts of hepatically created metabolites?
*T-cell mediated hypersensitivity
* Can be high fevers; relative bradycardia, patient appears well, no rigors, maybe liver enzymes up, normal eosinophils, often left shift of elevated WBC
*Reversible over weeks
* Usually takes 5 to 10 days
*Should probably avoid the whole class of antibiotics
* Normalizes withing 72 hours of discontinuation


=== QT Prolongation ===
===Rash===
* 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


*Amipicillin is the msot common penicillin, more commoly in women, especially with viral infections
=== Diarrhea ===
*Maculopapular rash
* Antibiotics are 25% of drug-induced diarrhea
**Most common
* Appears within days, resolves after discontinuing
**Not immediate (>1 hour after dose)
* Mechanism includes diruption of normal gut flora, which can also cause impaired fermentation
**Mechanism is T-cell mediated
* Highest risk includes macrolides (promotility), fluroquinolones, amoxicillin/clavulatate


===Neutropenia/Thrombocytopenia===
=== Acute Tubular Necrosis ===
* Aminoglycosides
* Vancomycin
* Inter


*From beta lactams
=== Interstitial Nephritis ===
**Can either be from induced antibody formation against wthe bloodline with immune complex formation; can also have a direct marrow effect
* Typically beta lactams
**Anemia is rare, but can get autoimmune hemolytic anemia
* Oliguria, malaise, anorexisa, nausea/vomiting
**At least 10 days of penicillin before you see bone marrow suppression
* Rash, fever, eosinophils, arthralgias
**Start to recover after 3 to 4 days of discontinuation if it was marrow suppression
* T-cell mediated hypersensitivity
**Longer if immune-mediated reaction
* Reversible over weeks
*Linezolid, vancomycin,
* Should probably avoid the whole class of antibiotics


=== Rash ===
===Aplastic anemia===
* 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


*From Septra
=== 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 ===
===Daptomycin===
* From Septra


*Asymptomatic CK rise:
=== Daptomycin ===
**8/8 patients in one case series were able to resume with normalized CK by withholding a dose and resuming 24 h later
* 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 ==
==List of Adverse Drug Reactions==
=== Antibiotics ===
===Antibiotics===
{{#ask:
{{#ask:
[[Category:Antibiotics]]
[[Category:Antibiotics]]
|?Adverse drug reaction
|?Adverse drug reaction
}}
}}
=== Antifungals ===
===Antifungals===
{{#ask:
{{#ask:
[[Category:Antifungals]]
[[Category:Antifungals]]
|?Adverse drug reaction
|?Adverse drug reaction
}}
}}
=== Antivirals ===
===Antivirals===
{{#ask:
{{#ask:
[[Category:Antivirals]]
[[Category:Antivirals]]

Revision as of 23:45, 29 July 2020

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

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 Example
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 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-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

List of Adverse Drug Reactions

Antibiotics

 Adverse drug reaction
Amikacin
Aminoglycosides
Amoxicillin-clavulanic acid
Ampicillin-sulbactam
Antipseudomonal antibiotics
Aztreonam
BedaquilineQTc 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
EthambutolOptic neuritis
Rash
Fluoroquinolones
Fosfomycin
Imipenem-relebactam
Intrinsic antibiotic resistance
Intrinsic vancomycin resistance
IsoniazidRash
Hepatitis
Peripheral neuropathy
CNS toxicity
Sideroblastic anemia
LinezolidSerotonin syndrome
Thrombocytopenia
Anemia
Leukopenia
Macrolides
Methenamine
MetronidazoleDisulfiram-like reaction
Peripheral Neuropathy
Minocycline
Oritavancin
Penicillin
Piperacillin-tazobactam
Plazomicin
Polymixins
Pretomanid
PyrazinamideHepatitis
Rash
Arthralgias
Gout
PyrimethaminePancytopenia
GI intolerance
Rash
Hepatitis
Headache
Dizziness
Insomnia
RifampinDrug-drug interactions
Rash
Hepatitis
Influenza-like illness
Neutropenia
Thrombocytopenia
... further results

Antifungals

 Adverse drug reaction
Antifungal spectrum of activity
Caspofungin
Ciclopirox
FluconazoleHepatitis
QTc prolongation
Drug-drug interactions
FlucytosineNeutropenia
Ibrexafungerp
Isavuconazole
ItraconazoleHeadache
Relative adrenal insufficiency
Hepatotoxicity
QTc prolongation
Manogepix
Micafungin
Posaconazole
Terbinafine
VoriconazoleHepatotoxicity
QTc prolongation
Photosensitivity
Floaters
Visual hallucinations
Colour vision loss
Photophobia
Blurred vision

Antivirals

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