Download Trimethoprim-Sulfamethoxazole Induced Rash & Fetal Hematologic

Noura Al-Osaimi
Fatima Al-Nefaei
Questions
Our System in a Balance
Immunosuppression
Immunostimulation
Normal
Altered resistance to
Infectious Disease
and Neoplasia
Hypersensitivity
Autoimmunity
Hypersensitivity
reactions:



Immune-mediated that
cause tissue damage
Unexpected
Different types.
Pseudoallergic
(anaphylactoid)
reactions
 Non-immune mediated.
 Direct release of mediators
without prior sensitization
period.
 Vancomycin


Red man syndrome
pseudoallergic
True IgE-mediated
anaphylaxis.
Drug idiosyncrasy/intolerance
responses
Mimic immune-mediated drug
reactions
 Major drugs induce idiosyncrasy:

 ASA
 NSAIDs
 ACEIs
Classification of hypersensitivity
reactions

Different types of hypersensitivity reactions are
distinguished by:
 The time required for symptoms or skin test
reactions to appear after exposure to an antigen
 On type of Ags
 Or on the nature of organ involvement.

Type I: immediate or anaphylactic hypersensitivity

Type II: antibody-dependent cytotoxic hypersensitivity

Type III: complex-mediated hypersensitivity

Type IV: cell-mediated hypersensitivity
Type I: immediate
(anaphylactic hypersensitivity)

Most common (20% of population)

IgE is made in response to allergen (drug).

In allergic individuals, IgE >> those without
allergies.

Th2 cells >> Th1 cells
Most (but not all) Allergies
How can type I
hypersensitivity reactions
occur?
Type I: immediate
(anaphylactic hypersensitivity)
Type I: immediate
(anaphylactic hypersensitivity)
Type I: immediate (anaphylactic hypersensitivity) -cont’d
Inflammatory Mediators:
Histamine, PAF,
eicosanoides, &
cytokines
Localized effect
Nose  hay fever
Bronchial tree asthma
Skin  urticaria
GI  food allergy
Generalised
effect
Anaphylactic
shock
Diagnostic test for type I
Hypersensitivity:



skin (prick and intradermal) tests
RAST (radioallergosorbent test)
Serum tryptase
Therapeutic consideration of type I
hypersensitivity

Discontinue drug.
Consider epinephrine, antihistamines, systemic
corticosteroids, bronchodilators.

patient monitoring, if severe

Type II: antibody-dependent
cytotoxic hypersensitivity



IgG or IgM is made against normal self Ags
foreign Ag looks like cell-surface molecule stimulate Abs
(IgG, IgM) response Abs bind to foreign Ag  attack cell
surface.
The results:
1.
2.
3.
opsonization of the host cells
activation of the classical complement pathway causing
MAC lysis of the cells
ADCC destruction of the host cells by NK cells.
How can opsonization
of the host cells
occurs?
Opsonization During Type-II Hypersensitivity
How can MAC lysis of the
cells occurs?
MAC Lysis During Type-II Hypersensitivity
ADCC destruction of the
host cells by NK cells.
ADCC Destruction During Type-II Hypersensitivity
ADCC Apoptosis by NK Cells During Type II Hypersensitivity
Diseases and problems caused
by type II hypersensitivity


Autoimmune diseases

Rheumatic fever (Abs damage to joints and heart valves)

Idiopathic thrombocytopenia purpura (Abs destroy platelets)

Myasthenia gravis (Abs destroy NM connections).

Grave’s disease (Abs stimulate the overproduction of THS)

multiple sclerosis (Abs ≠ oligodendroglial cells that make myelin)
Reactions to drugs (penicillin)
Diagnosis of type II hypersensitivity
The direct antiglobulin test (DAT) and indirect antiglobulin test (IAT)
Type III hypersensitivity
Soluble Ag-Ab (IgG or IgM) complex
 Activate classical complement pathway.

Massive inflammation
 Influx of neutrophils
 MAC lysis
 Aggregation of platelats

Examples of type III
hypersensitivity:
serum sickness (type I and type III)
 autoimmune acute glomerulonephritis
 rheumatoid arthritis
 systemic lupus erythematosus (SLE)
 some cases of chronic viral hepatitis
 the skin lesions of syphilis and leprosy

Diagnosis of type III
hypersensitivity




ESR, C-reactive protein, Immune complexes
Complement studies
Antinuclear antibody
Tissue biopsy for immunofluorescence studies
Therapeutic
considerations :
Discontinue drug.
Consider NSAIDs, antihistamines, or
systemic corticosteroids.
Type IV: cell-mediated hypersensitivity
Delayed hypersensitivity
 Cell-mediated (NOT Ab-mediated)
 T8-lymphocytes become sensitized to
Ag  differentiate into cytotoxic Tlymphocytes
 Examples:

 Tuberculin
test
 Contact dermatitis
Type IV: cell-mediated hypersensitivity
Type IV: cell-mediated hypersensitivity
Type IV: cell-mediated hypersensitivity
Diagnosis:
Patch testing
Lymphocyte proliferation assay*
Therapeutic considerations:
Discontinue drug
Consider topical corticosteroids,
antihistamines, or systemic corticosteroids if
severe.
Antimicrobial drugs
1st class
Agents that inhibit synthesis of
bacterial cell walls:
Beta Lactams
Glycopeptides
Cycloserine
Azole (antifungal)
Bacitracin
Agents that inhibit synthesis of
bacterial cell walls:
Beta Lactams
 Penicillins (PCN)




Carbapenems
monobactams
Cephalosporins
carbacephems
Sir Alexander Fleming
Agents that inhibit synthesis of
bacterial cell walls:


Toxicity of Beta-lactams:
PCN


All types (I to IV) of hypersensitivity
Low direct toxicity (safe)
Carbapenems seizures
 Monobactams
<<PCN cross-sensitivity

Agents that inhibit synthesis of
bacterial cell walls:
 Toxicity

of Beta-lactams:
Cephalosporins < common
Broader spectrum opportunistic
infections (candidiasis,
C. difficile colitis).
Agents that inhibit synthesis of
bacterial cell walls:

Glycopeptides



Cycloserine CNS toxicity
Azole:



Vancomycin ototoxic
Ketoconazole inhibit CYP 3A3/4
Fluconazole alopecia, hepatitis
Bacitracin  one of the top ten allergens
implicated in contact dermatitis.
2nd class
Agents act directly on the cell
membrane of the
microorganism
polymyxin
polyene
antifungal
agents
Agents act directly on the cell
membrane of the microorganism

polymyxin
 Polymyxin
E (colistin)
 Polymyxin B
Highly nephrotoxic & neurotoxic (only
topical)
 polyene antifungal agents

Nystatin  Rare toxicity (poorly absorbed)

Amphotericin B Nephrotoxicity (80%)
3rd class
Agents that affect the function of 30S
or 50S ribosomal subunit to cause
reversible inhibition of protein
synthesis (bacteriostatic)
Chloramphenicol
Macrolides
Lincosamides
Streptogramins
Oxazolidinones
Fusidic acid
Chloramphenicol
Tetracyclines
Macrolides
Lincosamides
Bone marrow toxicity ,aplastic anemia
& Grey baby syndrome
Photosensitivity (Doxycycline)
Discoloration of permanent teeth &
Tooth enamel in fetuses & children
Low immunogenic potential,
cholestatic jaundice, GI effect &
hepatitis
Rash, anaphylactic shock & GI distress
Streptogramins
Oxazolidinones
Fusidic acid
Rash (rare), Generally well tolerated
adverse effect (Myalgia, arthralgia)
Anaphylaxis (very rare), MAO inhibitor
&Thrombocytopenia
GI disturbance
& Skin eruptions
4th class
Agents that bind to 30S ribosomal
subunit & alter protein synthesis
eventually leads to death
(bactericidal)
aminoglycosides
Aminoglycosides
Amikacin
 Gentamicin
 Neomycin

Main toxicity
 Ototoxicity
 Nephrotoxicity
 neuromuscular blockade.
5th class
Agents that affect bacterial
nucleic acid metabolism
Rifamycins
Quinolones

Rifamycins (Rifampin)


Brownish-red or orange discoloration of the body
secretions.
Induce cyp450 (bad for pts on anticoagulants,
oral contraceptives, anti-convulsants)
Quinolones
 Nalidixic acid, Ciprofloxacin,
Ofloxacin




GI disturbance
CNS side effects
Anaphylactoid react
6th class
Antimetabolites (block essential
enzymes of folate metabolism
Sulfonamides
Trimethoprim
Antimetabolites
Sulfonamides
 Sulfamethoxazole
 Sulfadiazine
 Main toxicity:
• crystalluria, renal failure,
bone marrow suppression
• Kernicterus in infants
• Hypersensitivity 
Rashes (photodermatitis,
Stevens-Johnsons
syndrome).



Trimethoprim
GI disturbance
(nausea, vomiting, and
glossitis)
Folate antagonism
Hypersensitivity 
fever & rash
Bilirubin
deposits in
neonatal brain
7th class
Antiviral agents
Nucleic acid analogs
NNRTIs
Inhibitors of other essential
viral enzymes
Nucleic acid analogs

Selective inhibitors
of viral DNA
polymerase
Acyclovir  Renal &
CNS toxicity
 Ganciclovir  Bone
marrow & CNS toxicity
They cause inflammation or
phlebitis


Nucleoside Reverse
Transcriptase
Inhibitors (NRTIs)

Zidovudine  Bone
marrow suppression, CNS
toxicity, hepatitis, & GI
disturbance
Nonnucleioside Reverse
Transcriptase Inhibitors (NNRTIs)

Nevirapine
 CNS
disturbances (infrequent)
 Dyslipidemia
 Severe rash, including Stevens-Johnson
syndrome, fever, & hepatotoxicity
Inhibitors of other essential
viral enzymes
Protease Inhibitors
(PI)
 Saquinavir
Not life-threatening
toxicity
 GI distress (diarrhea)
 Inhibition of
cytochrome P-450
 Dyslipidemia (leading
to treatment
discontinuation)
Inhibitor of influenza
neuraminidase
 Amantadine



CNS toxicity
Cardiac disturbance
(torsades de pointes)
Urinary retention.
Drug of the case
TMP/SMZ
Trimethoprim-Sulfamethoxazole
(co-trimoxazole)


Class:
Antibiotic (sulfonamide combination)
Mechanism of action
Sulfamethoxazole (SMZ)
Competitively inhibits the synthesis of
dihydropteroic acid from PABA in
microorganisms
 Trimethoprim (TMP)
Inhibit the enzymatic reduction of dihydrofolic
acid to tetrahydrofolic acid.

Therapeutic uses of TMP/SMZ:
Urinary tract infection
 Shigellosis
 Otitis media
 traveler‘s diarrhea

Pharmacokinetic of TMP/SMZ








ADME
Absorption: both are 90-100% absorbed orally.
Distribution: both are widely distributed > lipophilic
Metabolism: SMZ extensively metabolized in the liver
into N4-acetylated and N4-glucuronidated derivatives
Excretion:
TMP  50-75% as unchanged drug.
SMZ  85% as metabolites & 10-30% as unchanged
drug.
Half-life:

TMP = 11 h

SMZ = 10 h
Case report
A 40 year old man presented to outpatient clinic with fever and
diffuse maculopapular rash with erythematous base. His medical
history revealed pyelolithotomy operation 4 weeks earlier and TMP
/SMZ 480 mg po twise daily was prescribed on the postoperative
9th day because of fever. On the 5th day of therapy, erythematous
rash face spreaded all over his body. Though TMP/SMZ had been
withdrawn and replaced with levofloxacin for another 5 days
symptoms not resolved. Anti-Histamines and steroid therapy 
not worked as well.
SOAP Format
Subjective
Upon
admission
Fever
Rash
Fatigue
SOAP Format
Objective
&assessment
↑temperature 38.3˚C (37)
↓BP 100/70 (120/180)
↑Pulse rate 100 bpm (20)
Fever
Decreased BP
Physical examination:
•Diffuse erythematous maculopapular rash
•White plaques & ulcerations resembling
candidiasis in oral mucosa
•Desquamation remarkable in extremities
SOAP Format
Hematologic tests:
↓Hb, 9.6 g/dl (13-18)
↓Hct, 28.2%(45-62)
↓ WBC, 0.7× 103 /dl
(0.7×103)
↓Plt, 133 × 103/dl
(140-440×103)
(N) ESR, 10mm/h (10)
Febrile neutropenia
Erythrodermia
Hemolytic anemia
SOAP Format
↑Glucose 6.8 mmol/l
(3.9- 6.1)
Kidney function tests:
(N) Urea 5.49 mmol/l
(1.7-83)
↑Creatinine 2.57 mmol/l
(0.06-0.115)
Serum electrolytes:
↓Na, 116 mmol/l
(133-152)
↓K, 2.9 mmol/l
(3.5-5.6)
Low serum
Electrolytes
SOAP Format
Liver function tests:
(N) Direct bilirubin 4.79 umol/l
(up to 10 mmol/l)
↑ Indirect bilirubin 6.67 umol/l
(1.7-5 umol/l)
↓Total protein 38 g/l (66-87)
↓Albumin, 23g/l (38-50)
↑ALT, 205 U/l (1-21)
↑AST, 94 U/l (7-27)
↑LDH, 443 U/l (50-150)
(N) CK, 70 U/l (38-174)
(N) ALP, 63 U/l (20-70)
↑GGT, 121 U/l (0-30)
Liver dysfunction
SOAP Format
(N) PT, 13.6 s(11.5-16.5)
(N) aPTT, 36.1 s(26-49)
(N) PT INR, 1 . 19 INR
(0.9-1.3)
↑CRP, 17 mg/dl ( 0-0.5)
(N) Folate, 5.58 ng/ml
(5-25)
(N) Vit B 12, 162 pg/ml
(150-250)
↑Ferritin, 1744 ng/ml
(10-20)
(N) Fe, 53 ug/dl (50-150)
↑Total IgE, 8.36 U/l
SOAP Format
•VDRL & HIV are negative
•Direct microscopic exam.
Of urine → 1-2 leukocytes
+ 10 erythrocytes
•Oral mucosa smear →
candida spp.
•Renal ultrasound →
stone formation of 10 mm
in left collecting system
•Otherwise normal
Leukopenia
Oral candidiasis
SOAP Format
Plan
Cefepime 2 g IV TID
Nystatin mouthwash,
Chlorhexidine mouth rinse
(1% solution)
Supportive therapy
Bone marrow biopsy
SOAP Format
Subjective
Objective,
assessment &plan
2nd hospital day
Subjective The same as before
Objective Bone marrow biopsy
(smear) → hypocellular for all
blood cell series especially
WBC series.
Blood cultureE.coli infection
Assessment leukopenia
Plan Prednisolone 60 mg IM
4 times daily
Sensitivity test
SOAP Format
Subjective Objective,
assessment
&plan
6th hospital day
Subjective The same
Objective E. coli from blood culture
→ cefepime-resistant, meropenemsensitive.
Assessment E. coli infection
Plan Antibiotic changed to
meropenem 1g I.V. 3 times daily
SOAP Format
Subjective Objective,
subjective &
plan
Subjective Mildly improvement of
rash but not dissolved totally
Fever improved ( 24 hours
meropenem )
8th hospital day
Objective The same
Assessment not responding
Plan Fever improved (48 h of meropenem )
D/C steroid therapy
Whole blood, red cell concentrates
& thrombocyte transfusions & filgrastim
(G-CSF, Neupogen) 30 four times daily
SOAP Format
Subjective,
objective ,
assessment &plan
10th hospital day
Subjective The same
Objective WBC ↑ to 0.4×103/dl
Platelet count ↓ to 4×103/dl
Assessment Mild increase in WBC
Plan The same
Refer to university hospital
SOAP Format
Subjective,
objective ,
assessment
&plan
3rd of admission to
university hospital
Subjective same
Objective Not available.
Assessment No improvement
Plan The same
Despite all efforts,
the patient died
Additional SOAP Format
Additional Subjective
•Gastrointestinal irritation
•Megaloplastic anemia
•Agranulocytes, granulosytosis
and eosinophilia.
•Nephrotoxicity (rare)
•QT prolongation
•Allergic skin reactions
•Other rare adverse effects
Additional SOAP Format
Additional Objective
•History
•metabolic pathways
•patients with the slow acetylation
•phenotype and those with glutathione
deficiency
•frequent courses of medications
•Urine test
•Patch test
•Coombs antiglobulin test
•blood smear
•Skin prick test
Additional SOAP Format
Additional
asssement
Drug
interaction
Drugs
Effect
Sulfonylureas
enhanced hypoglycemic
effects
Warfarin
increased risk of bleeding
Methotrexate
increased risk of
methotrexate toxicity
Additional SOAP Format
Drugs
Effect
Cyclosporine
increased nephrotoxicity or
reduced cyclosporine serum
levels and potentially increased
risk of organ rejection
Phenytoin
increased risk of phenytoin
toxicity (ataxia, hyperreflexia,
nystagmus, tremors)
Procainamide
increased risk of cardiotoxicity
(QT prolongation, torsades de
pointes, cardiac arrest)
Additional SOAP Format

Precautions

group A beta-hemolytic strep infections

elderly patients, AIDS patients
patients with
possible folate deficiency
severe allergies,asthma
glucose-6-phosphate dehydrogenase deficiency
Autoimmune disease
Increase bilirubin & jaundice






Additional SOAP Format
Additional Plan
•started on a low dose of
the sulfonamide
•Patient counseling
Comment
A 40 year old man presented to out patient
clinic with fever and a diffuse maculopapular
rash with an erythematous base. on the 5th day
from start taking TMP-SMX an erythematous
rash had appeared on his face, which later
had spreaded all over his body.
Role of pharmacist
The
pharmacist should have
Advised the patient about the use
of antibiotics drug & till him
if appear the rash Should be
discontinue the ABs immediately
Conclusion
When 2 persons take antibiotic drug, the
hypersensitivity reaction not necessarily
appear in both, but sometimes
hypersensitivity reaction developed within
minutes and may lead to death if no
immediate treatment.
For urinary tract infection the trimethoprim
alone is effective and safe than
sulfonamide combination, which may lead
to death due to its action on bone marrow.