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== Risk Factors ==
==Background==

* Extremes of ages (elderly and young)
* Any noxious and unintended response to a drug or natural health product that occurs at a normal dose
* Polypharmacy
** 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
* Pregnancy
* 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
* Breastfeeding
** Also known as a serious adverse event
* Genetic factors
* A '''serious unexpected adverse drug reaction''' is one that is not identified in the brochure or label of the drug or natural health product
** Specific genes predispose to AG ototoxicity
** Also known as a suspected unexpected serious adverse reaction
* Comorbidities, including renal and hepatic dysfunction

* Antimicrobials are one of the largest causes of adverse drug reactions
===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]]


== Classification ==
{| class="wikitable"
{| class="wikitable"
! Type
! colspan="2" |Type
! Description
!Description
!Examples
|-
|-
| colspan="2" |I
| Type A
|immediate IgE-mediated reaction
| Understood pharmacologic effects
|[[anaphylaxis]]
|-
|-
| colspan="2" |II
| Type B
|antibody-mediated cytotoxic reaction
| Idiosyncratic
|[[hemolytic anemia]] from [[penicillin]]
|-
|-
| colspan="2" |III
| Type C
|immune complex-mediated reaction
| Chronic effects
|[[serum sickness]] from cephalosporins
|-
|-
| rowspan="5" |IV
| Type D
|IV
| Delayed effects, including carcinogenic or teratogenic
|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
|
|}
|}


== Immunologic Hypersensitivity Reactions ==
===Non-Immune-Mediated Hypersensitivity Reactions===
{| class="wikitable"
{| class="wikitable"
! Type
!Type
! Description
!Description
!Examples
|-
|-
| I
|Type A
|Understood pharmacologic effects
| IgE-mediated
|[[serotonin syndrome]] from [[linezolid]], [[thrush]] after antibiotics, drug toxicities, drug-drug interactions
|-
|-
| II
|Type B
|Idiosyncratic
| hemolytic anemia from PCN
|
|-
|-
| III
|Type C
|Chronic effects
| Serum sickness from cephalosporings
|
|-
|-
| IV
|Type D
|Delayed effects, including carcinogenic or teratogenic
| DRESS
|
|}
|}


==Major Examples==
== Non-immunologic Reactions ==

=== Predictable ===
===Fluoroquinolones===
* Pharmacologic side effect, eg serotonin syndrome from linezolid

* secodary pharma side effect, eg. thrush after abx
*CNS: dizziness, HA, sleep disturbance, hallucinations, seizures, depression, peripheral neuropathy (3%)
* drug toxicity
**Seizures, especially with concomitant NSAIDs or theophylline due to GABA binding and NMDA activation
* drug-drug interactions
***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


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


*Antibiotics are 25% of drug-induced diarrhea
== Major Examples ==
*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|amoxicillin/clavulanic acid]]


=== Fluoroquinolones ===
===Acute Tubular Necrosis===
* 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
**


*Aminoglycosides
=== Beta Lactams ===
*Vancomycin
* Seizures
*Inter
** 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 ===
===Interstitial Nephritis===
* 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


*Typically beta lactams
=== Nitrofurantoin ===
*Oliguria, malaise, anorexia, nausea/vomiting
* Pulmonary fibrosis
*Rash, fever, eosinophils, arthralgias
* May be acute or chronic (9 days vs months or years)
*T-cell mediated hypersensitivity
* No fevers, eosinophilia, or pleural effusions
*Reversible over weeks
* Risk factosr include CKD, high prolonged doses, older age, female sex
*Should probably avoid the whole class of antibiotics
* 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 ===
===Rash===
* 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


*Amipicillin is the most common penicillin, more commonly in women, especially with viral infections
=== QT Prolongation ===
*Maculopapular rash
* Risk factors include electrolyte abnormalities, age, female sex, structural heart disease, bradycardia, hypothyroidism, CNS process, obesity, genetics, alcohol and cocaine use
**Most common
** Potassium wasting diuretics
**Not immediate (>1 hour after dose)
** Antiarrhythmics
**Mechanism is T-cell mediated
** 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


===Neutropenia/Thrombocytopenia===
=== 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


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


===Aplastic Anemia===
=== 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


*From [[Septra]]
=== 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


===Daptomycin===
=== 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,


*Asymptomatic CK rise:
== Aplastic anemia ==
**8/8 patients in one case series were able to resume with normalized CK by withholding a dose and resuming 24 h later
* From Septra


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


[[Category:Antimicrobials]]
[[Category:Medications]]
[[Category:Research]]

Latest revision as of 14:27, 27 March 2024

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

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

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

Antiparasitics

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