Drug-induced hemolytic anemia Presented by Onnicha Chaisetsumpan, MD. December 24, 2021

1. Drug-induced
Hemolytic Anemia
Onnicha Chaisetsumpan, MD
Division of Allergy, Immunology and Rheumatology unit, Department of Pediatrics
King Chulalongkorn Memorial Hospital

2. Overview
•Introduction
•Mechanism of drug-induced hemolytic anemia
•Diagnosis and investigation
•Management

3. Definition

4. Drug allergy, Middleton’s Allergy: Principle and practice, 9th
edition

5. Altered peptide
Repertoire model
Pharmacologic –
interaction model
Hapten/Prohapten
model
Drug allergy, Middleton’s Allergy: Principle and practice, 9th
edition
Immunopathologic
features of drug allergy

6. Gell and
Cooombs
classification
Drug allergy, Middleton’s Allergy: Principle and practice, 9th
edition

7. Introduction
•Drug-induced immune hemolytic anemia (DIIHA)
•Incidence is unknown
•Estimated incidence about 1 per million of population
•Drug-induced hemolytic anemia is quite rare
• Drug-induced immune thrombocytopenia is more common, 10-18 cases per million
• Neutropenia 2-15 cases per million
Garratty G. Blood Rev. 2010;24(4-5143-50.

8. Introduction
1953 1956 1967 1989 2007
Snapper
• Mephenytoin
• Pancytopenia with
hemolytic anemia
with positive DAT
Harris
First to document
history and serology
of immune hemolytic
anemia due to
stibophen
Dausset and Contu
• Review literature
on DIIHA
• 34 cases due to
15 drugs
50 drugs well-
documented as
causes of IHA
125 drugs with
reasonable evidence
to suggest DIIHA
Garratty G. Blood Rev. 2010;24(4-5143-50.

9. Introduction
Arndt PA. Immunohematology. 2014;30(2):44-54. PMID: 25247622.

10. Drug-induced hemolytic anemia
Drug-induced
hemolytic anemia
Immune-mediated
Non-Immune-mediated
Oxidant injury
Methemoglobinemia
Drug-dependent
Drug-independent
Garratty G. Blood Rev. 2010;24(4-5143-50.

11. Drug-induced
immune
hemolytic anemia
• Immune destruction of RBC
• Generally antibody-mediated
Garratty G. Blood Rev. 2010;24(4-5143-50.

12. Drug-depended immune-
mediated DIIHA
•Hapten reaction
•Immune complex formation
•Protein adsorption
Garratty G. Blood Rev. 2010;24(4-5143-50.
Garratty G. Hematology Am Soc Hematol Educ Program. 2009:73-9

13. Hapten reaction
IgG antibody against drug
Hemolysis
by complement or
phagocytosis
Drug
• Penicillin type
• Drug remains present on RBC surface
• Required for antibody binding
• Limitation: most drugs do not form
stable bond with RBC Garratty G. Blood Rev. 2010;24(4-5143-50.
Garratty G. Hematology Am Soc Hematol Educ Program. 2009:73-9

14. Immune complex
• Drugs cause formation of immune complex
• Bind to RBC and cause complement activation
• Quinidine
Drug
Antibody against drug
Carrier protein
C3b receptors
Hemolysis by complement
Garratty G. Blood Rev. 2010;24(4-5143-50.

15. Passive adsorption
•Nonimmunologic protein adsorption (NIPA)
•Drugs modified the RBC membrane
•Plasma proteins were adosrbed
nonimmunologically
•Cephalothin was the prototype drug for this
mechanism
Garratty G. Blood Rev. 2010;24(4-5143-50.

16. Nonimmunologic protein adsorption (NIPA)
Garratty G. Blood Rev. 2010;24(4-5143-50.

17. • Autoimmune model
• Drug induced autoantibody reacted with normal RBC
• Similar to reactivity seen with autoantibodies found in
idiopathic IgG warm AIHA
• e.g. methyldopa
Drug independent immune-mediated DIIHA
Normal RBC antigen Hemolysis by phagocytosis Garratty G. Blood Rev. 2010;24(4-5143-50.

18. Drug independent
immune-mediated
DIIHA

19. Proposed unifying hypothesis
• Antibody to drug
• Penicillin antibody
• Antibody to mainly membrane
components
• May not need drug to be added to
detect antibody
• Drug-independent autoantibody
• Antibody to drug and membrane
components
• Only react with neoantigen composed
of drug and membrane protein
Garratty G. Blood Rev. 2010;24(4-5143-50.

20. Drug-induced hemolytic anemia
Drug-induced
hemolytic anemia
Immune-mediated
Non-Immune-mediated
Oxidant injury
Methemoglobinemia
Drug-dependent
Drug-independent
Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.

21. Oxidant injury
• RBCs can be affected by oxidant injury from drugs
• Interaction with hemoglobin and oxygen, leading to
intracellular formation of H2O2 and other oxidizing
radicals
• G6PD deficiency
• RBCs protected from oxidant injury by NADPH
• G6PD deficiency increased susceptibility to oxidant drugs
• Hemoglobin H disease
G6PD deficiency
Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.

22. Methemoglobinemia
Decreased tissue oxygenation
• Ferric heme cannot bind oxygen
• Left-shifted hemoglobin-oxygen
dissociation curve
Hemolysis
• Not directly harmful to RBC
• Large oxidative stress, coverted to hemichromes
à formation of Heinz bodies
• Removal of membrane-attached Heinz bodies
can produce hemolysis
Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.

23. Diagnosis
• First step in evaluating suspected drug-
induced hemolytic anemia is to
recognize signs and symptoms of
hemolysis
• Review history of exposure with focus
on new medication, other possible drug
or chemical exposures
• Review medical record to determine
timing of hemolysis (relative to
initiation of new medicines)
Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.

24. Diagnosis
•Does the patient have hemolytic anemia?
•Does the patient have a positive DAT?
•Positive for IgG or C3 (or both) close to the time of observed hemolysis
•If not tested until weeks later, DAT may be weak or negative
•What drug(s) is (are) the patient taking now or recently?
•Is there a temporal relationship between drug administration and
hemolytic anemia?
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

25. Diagnosis
• Peripheral blood smear
• Determine likely causes and appropriate
laboratory testing
• Spherocytes or microspherocyte, MAHA
blood pictures, bite cells
• G6PD testing
• If suspected oxidative hemolysis
• May be negative in setting of severe
hemolysis, repeat testing following
recovery may be warranted
Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.

26. Direct coombs test
• Positive DAT is consistent with
immune hemolysis
• No distinguish between DIIHA, AIHA
unrelated to drug or alloimmune
hemolysis
• Negative DAT in massive acute
intravascular hemolysis or
transfusions before DAT is performed
• Anti-IgG, anti-C3
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

27. Drug-induced immune hemolytic anemia testing
Drug-independent
• Serologic reactivity without
drug being present
• Indistinguishable from
idiopathic IgG warm
autoantibiodies
React with drug-
treated RBCs
React with untreated
RBCs in the presence
of solution of drug
Best to follow techniques
used in relevant report
Useful to avoid future drug-induced hemolytic anemia and especially
helpful in patients with acute-onset, unexplained hemolytic anemia Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

28. Drug-induced immune hemolytic anemia testing
Sample from patient
• Prefer sample from first observed in vivo
hemolysis
• Second sample (2-3 days after drug stopped)
to detect true autoantibody reactivity or drug
antibody reacting with a circulating drug
• True autoantibody: persisent autoantibody
• Drug-immune complex: autoantibody reactivity
disappears when drug has cleared from
patient’s circulation (1-2 days after drug
stopped)
Sample from drug
• Drug under investigation should not be
dissolved before sending
• Caution in pediatric oral suspension formula
due to hemolyze RBC
• Isotonic solution of drug for use with RBCs
(PBS, pH 7.1-7.4)
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

29. DIIHA testing: drug-treated RBCs
• Negative control:
• Normal serum (pooled or several individual
serum and PBS)
• Positive control whenever available
• Drugs known to cause NIPA: positive control
is tested at dilution of ≥ 1:20
1 drop of drug-treated RBCs
or control untreated RBCs
2 drops of patient’s
serum and control
• Incubated at 37 oC for 1 hour
• examined for hemolysis and agglutination
40 mg/ml
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

30. DIIHA testing: drug-treated RBCs
Interpretation of results
Definitive drug antibody
• Reactivity of patient’s serum and eluate
with drug-treated RBCs and no reactivity
with untreated-RBCs
• No reactivity of normal serum and PBS
control
• Reactivity of positive control, if available,
with only the drug-treated RBCs
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

31. DIIHA testing: drug-treated RBCs
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

32. DIIHA testing: drug-treated RBCs
Positive control: drug
truly bounded to test RBCs
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

33. DIIHA testing: drug-treated RBCs
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

34. DIIHA testing: drug-treated RBCs
Antiglobulin reactivity:
NIPA (undiluted and diluted 1:20)
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

35. DIIHA testing: drug-treated RBCs
• Direct agglutination of drug-treated RBCs, but not untreated-
RBCs à low-titer antibody to drug
• Widespread use of antibiotics in agriculture and environmental
contamination = source of exposure to many drugs
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

36. Testing in the presence of the soluble drug
• Testing untreated RBCs in the presence of a
solution of the drug
• Piperacillin and some second- and third-generation
cephalosporins react by this method
• 1 mg/ml solution of drug in PBS, pH 7 to be
compatible with RBCs
Untreated or enzyme-
treated RBCs
Drug Patient’s serum
+ Fresh normal serum for source of complement
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

37. Testing in the presence of the soluble drug
Interpretation of results:
Definitive drug antibody
• Reactivity in the tests with patient’s
serum plus drug and not reactivity in the
control tests of patient’s serum plus PBS
or with complement source without
serum
• No reactivity in any tests indicates no
drug antibody is present
Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.

38. KCMH
หลักการ
Antigen-antibody detection
ตรวจหา antibody ใน plasma
คนไข้ โดยการทําปฏิกิริยากับ
1%cell ของเลือด group O ทีx
coat ด้วยยาทีxสนใจใน gel test

39. KCMH DIIHA (lab hemato med)
1. ปัZนแยก Plasma ของคนไข้ออกมาเก็บไว้ และนํา
RBC ของคนไข้ไปทําการล้างเซลล์ เพืZอกําจัด
สิZงรบกวนออก
2. นํา RBC ของคนไข้มาทําเป็น 1% cell
3. ตรวจ direct antiglobulin test (DAT test)
4. เตรียม 1% cell group O ทีZ coat ด้วยยา
• RBC group O ปัxนล้าง และนํามาผสมกับยาตัวทีxสนใจ +
PBS
• Incubate ทีx 37 oC 1 ชัxวโมง
• นํามาปัxนตกและนํา RBC ทีx coat ยา มาทําเป็น 1% cell
Drug
e.g. Ceftriaxone 40mg/ml
RBC group O
Drug-treated RBC

40. KCMH DIIHA
(lab hemato med)
5. เตรียม Eluate (ใช้ PRC ล้างเซลล์ทีZเหลือ นํามาทํา
Elution เพืZอให้ได้ Eluate)
6. ใส่ Patient’s plasma, eluate, last wash, PBS,
pooled normal plasma และ patient’s plasma
(autoimmune) ผสมกับ 1% cell group O ทีZ coat ด้วย
ยา และ untreated RBC
7. Incubate 37oC เป็นเวลา 15 นาที หลังจากนั‚นปัZน
ด้วยเครืZอง ID-centrifuge 6S 10 นาที
8. อ่านผลจาก ID-cards และลงระดับความแรงของ
ปฏิกิริยา

41. Drug-induced immune hemolytic anemia (DIIHA)
test with Ceftriaxone
• Patient’s plasma + Ceftriaxone
coated RBCs = Positive 4+
• Eluate + Ceftriaxone coated
RBCs = Positive 1+
• PBS + Ceftriaxone coated RBCs
= negative
• Pool normal plasma + Ceftriaxone
coated RBCs = negative
• Patient’s plasma + Patient’s RBC
= negative

42. Drug-induced immune hemolytic anemia (DIIHA)
test with Ceftriaxone

43. Characteristics of common DIIHAs
• 42% anti-mircrobials
• 16% NSAIDs, 13% anti-neoplastics, 6% anti-hypertensive/diuretics
• Most commonly associated with fatal hemolysis was cefotetan (8%)
and ceftriaxone (6%), particularly in young children Garratty G. Blood Rev. 2010;24(4-5143-50.

44. Cephalosporin
•First generation cephalosporins caused positive DATs but rarely caused
drug-induced immune hemolytic anemia
• Cephalothin, cephalexin and cefazolin
•Second and third generation cephalosporins caused DIIHA
• Cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid, cefotetan, cefmetazole
• Cefotaxime, cefoperazone, ceftriaxone, cefixime
•No reports of DIIHA due to fourth generation cephalosporins
Garratty G. Blood Rev. 2010;24(4-5143-50.

45. Cefotetan
• Most common cause of drug-
induced immune hemolytic
anemia
• Associated with prophylactic
use of cefotetan (60% with
surgery)
• Only 18% documented history
of previous cefotetan
Garratty G. Blood Rev. 2010;24(4-5143-50.

46. Ceftriaxone
•Second most common
drug cause DIIHA
•Acute and severe
hemolytic anemia in
children, 50% fatality
•History of previous
ceftriaxone therapy
Garratty G. Blood Rev. 2010;24(4-5143-50.

47. Ceftriaxone-induced immune hemolytic anemia
• Comprehesive literature review according to
PRISMA
• CIIHA: new onset or exacerbation of hemolytic
anemia associated with administration of
ceftriaxone and at least 1 of the following
• New seroconversion from negative to positive DAT
• Presence of drug-dependent anti-ceftriaxone antibody
• Exclusion of other possible triggers such as other
drugs known to cause hemolytic anemia
Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.

48. Ceftriaxone-induced immune hemolytic anemia
•Demographic data
• Median age was 10 years (0.66-80 years), 70% children
• 30% case fatality (27% children, 64% of children were fatal)
•Ceftriaxone exposure
• Previous ceftriaxone exposure 65%
• 3% no prior exposure to ceftriaxone
• Median number of ceftriaxone doses received during current episode = 4
• Elapsed time from initiation of trigger dose and symptoms was 40 minutes and
1 hours (range 5 minutes to 5.6 hours)
Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.

49. Complication
32% presented with an initial, brief, self-
limited hemolytic episode associated with
earlier dose of ceftriaxone
Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.

50. Frequency of laboratory findings
• Anti-ceftriaxone
antibody were positive
68% of cases
• Not reported in 32%
• 5 cases negative both
DAT and antibody
Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.

51. Kapur G, et al. Pediatric blood & cancer. 2008 Jan;50(1):139-42.

52. Serologic characteristics
79 patients suspected DIIHA due to ceftriaxone, 1987-2010
Cases were screened via telephone to exclude those that did
not fit possible DIIHA
• No hemolysis
• Hemolysis not temporally related to administration of drug
• DAT was negative at time of hemolytic anemia
Investigation
• DATs: anti-IgG, anti-C3, anti-IgM, anti-IgA
• Drug-treated RBC
• Untreated or enzyme-treated RBC in presence of drug solution
Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.

53. Drug-treated RBC Untreated RBC in the presence
of drug solution
Group O
donor RBC
Ceftriaxone 40 mg/ml prepared either
PBS or sodium barbital buffer
Incubate 40 1-2 hours at 37 oC
2 drops of patient’s serum
One drop of treated or untreated RBC
Incubate 1 hour 37 oC
Test for hemolysis and agglutination
Negative control= pool normal plasma
Patient’s serum
± pool fresh plasma (complement)
Ceftriaxone
Untreated RBC
2 drops of patient’s serum
2 drops of ceftriaxone (1mg/ml in PBS)
One drop of untreated group O RBC
Incubate 1-2 hour 37 oC
Test for hemolysis and agglutination
Parallel test
• PBS added to serum instead of ceftriaxone
• Fresh normal serum instead of patient’s serum
Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.

54. Results
• Antibody to ceftriaxone were detected
25/79 (32%) of patients suspected of
DIIHA caused by ceftriaxone
• DATs
• Performed 19/25 patients
• 100% reacted with anti-C3 agent
• 47% also reacted with anti-IgG
• 22% reacted with anti-IgM, 6% reacted
with anti-IgA (18/25 patients)
Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.

55. • Drug-treated RBCs
• 7/25 patients were tested against drug-treated RBCs
• All either non-reactive (n=4) or equivalent reactivity (n=3)
with untreated RBCs
• Untreated RBCs in presence of ceftriaxone
• 25/25 patients tested in presence of 1mg/ml ceftriaxone
100% ceftriaxone antibodies detected
• Untreated RBC with no ceftriaxone added
• 64% (16/25) patients’s serum reacted without ceftriaxone
50% weakly reactive, 50% stronger (2-4+)
• Presences of circulating drug or drug-antidrug immune
complexes in patient’s blood
• Immunoglobulin
• 9/14 IgM agglutinin, 2/14 additional IgG, 5/14 non-reactive
or very weakly reactive
Complement can usually be detected on patient’s
RBC and IgM antibody detected in patient’s serum
Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.

56. Piperacillin
• Piperacillin is often used in
combination with tazobactam, beta-
lactamase inhibitor (Tazocin, Zosyn)
• Reactivity for two reasons
• Antibody to piperacillin
• Nonimmunologic protein
adsorption due to BI component
• Not reported: Antibody to BI
component (tazobactam)
Garratty G. Blood Rev. 2010;24(4-5143-50.

57. Other drugs reported DIIHA
•Purine nucleoside analogues
• Fludarabine and cladribine
•Hydrocortisone
• Case report of DIIHA due to hydrocortisone
•DIIHA following transplantation
• No definite data to support suggestions
Garratty G. Blood Rev. 2010;24(4-5143-50.

58. Management
•Discontinuation of presumed offending drug
• Most cases, eliminating exposure to implicated drug is sufficient for
management
• Rate of recovery depends on rate of clearance of drug
•Supportive treatment
• Blood production transfusion in severe and symptomatic anemia
• Hydration and dialysis
• Presumptive treatment of other possible causes until the results of definitive
diagnosis available
Garratty G. Blood Rev. 2010;24(4-5143-50.

59. Drug discontinuation
• 8/9 (89%) Children with ceftriaxone-induced
hemolytic anemia whose ceftriaxone was
stopped immediately, survived
• Children without cessation of ceftriaxone
treatment had mortality of 50%
• Ceftriaxone therapy was continued in 8 patients
• 4/8 patients died
• 1 patients with repeated cardiorespiratory
arrests, 1 patient with severe renal failure
requiring 14 days of hemodialysis and 1 patient
with severe neurological deficit
Stop suspicious drug immediately
23 ceftriaxone-induced hemolytic anemia
Leicht HB, et al. BMC Pharmacol Toxicol. 2018;19(1):67.

60. Management
• Steroid
• No proven benefit and no recommendation for
steroid therpy
• In general, reports of successful use of steroids are
confounded by withdrawal of responsible drug at the
same time
• In case of drug-independent antibodies
(autoantibodies), steroid therapy can be tried
• IVIG
• Evidence of intravascular hemolysis, like treatment of
warm-type AIHA
• Successfully used in child with severe ceftriaxone-
induced hemolytic anemia
• Plasmapheresis or plasma exchange
• Remove drug-induced antibodies from serum
• Drug adsorption-type DIIHA, severe renal failure
• Eculizumab
• Immune complex-type due to complement-
mediated intravascular hemolysis
• Complement inhibitor, hinder formation of
membrane attack complex could be helpful
• No report of the use of eculizumab in patients with
DIIHA
Leicht HB, et al. BMC Pharmacol Toxicol. 2018;19(1):67.

61. Re-exposure and cross-reactivity
•Absolute contraindication for re-exposure of responsible drug
for patient’s lifetime
•Implicated drug should be clearly noted in patient’s medical record
•Application of drugs of same substance class should be
considered very carefully
•Interactions of drug-dependent antibody, cross-reactivity
•Interactions to drug or drug metabolite (more probable cross-reaction to
drugs of same substance class)
Garratty G. Blood Rev. 2010;24(4-5143-50.

62. Cross-reactivity
Garratty G. Hematology Am Soc Hematol Educ Program. 2009:73-9

63. Antibodies
• 7 cefotetan antibodies to react with
cefotetan-treated RBCs and untreated
RBCs in the presence of cefotetan
• 1 ceftriaxone antibody to react with
untreated RBCs in the presence of
ceftriaxone
Drug
• Cefotetan disodium
• Ceftriaxone sodium
• Cephalothin sodium
• Cefazolin sodium
• Cefamandole nafate
• Cefoxitin sodium
• Cefotaxime sodium
• Cefoperazone sodium
• Penicillin G potassium
• Ceftazidime
• Cefepime hydrochloride
Antibody detection
• Drug-treated RBC
• Immune complex method
• Hapten-inhibiton studies
Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.

64. • Cephalothin, cefoxitin-treated RBCs (all)
• Weak reactivity with penicillin-treated RBCs
Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.

65. • Cefotetan
• 1 sample of cetotetan antibody showed reactivity in antiglobulin test with cephalothin
• Ceftriaxone
• Hemolyzed only in the presence of cefotaxime
• Weak agglutination/antiglobulin test in the presence of cetotaxime, cefamandole and cefoperazone
Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.

66. •Serum samples containing cefotetam antibodies showed
• Cross-reactivity with cephalothin and cefoxitin
• Much lesser extent with penicillin and ceftazidime
•Ceftriaxone antibodies showed
• Very weak cross-reactivity with cefotaxime, cefamandole and cefoperazone
•No data to determine in vivo reactivity
Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.

67. • One reported negative reactions with cefotaxime-coated RBCs, 3 reported negative
reactions with cefazolin
• Single reports of positive reactions with cefadroxil, cephalexin, ceftriaxone, cephalothin
• Two reports of positive and two reports of negative reactions with penicillin
Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.

68. Cross-reactivity of ceftriaxone-DIIHA
• Cross-reactivity in structurally similar structures of cephalosporins
• Antibody appeared to cross-react with cefotaxime and cefopodoxime proxetil
• Serological work-up must include tests to determine cross-reactivity of ceftraxone-dependent antibodies
to avoid hemolysis due to administration of structually realted cephalosporins in affected patients
Seltsam A, et al. Intensive care medicine. 2000 Sep;26(9):1390-4.

69. Take home messages
• Drug-induced immune hemolytic anemia (DIIHA) is rare but life-threatening condition
• Drug-dependent, drug-independent
• The most frequent drugs associated with DIIHA are cefotetan, ceftriaxone and
piperacillin
• Early and correct diagnosis of DIIHA is crucial
• Withdrawal of causative drug is essential for patient prognosis