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Ceftriaxone-induced hemolysis

Authors:
Vivek Singh Guleria at Post Graduate Institute of Medical Education and Research
Vivek Singh Guleria
Nitin Sharma
Nitin Sharma
Nitin Sharma
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Amitabh Sagar at United Lincolnshire Hospitals NHS Trust
Amitabh Sagar
Lt Gen Dr Velu Nair at COMPREHENSIVE BÖOOD AND CANCER CENTER
Lt Gen Dr Velu Nair
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Immune hemolytic anemia is a rare adverse effect of ceftriaxone, a third-generation cephalosporin, which is a commonly used antibiotic. We describe a 60-years-old lady, a case of community-acquired pneumonia, who developed severe hemolysis after the first dose of ceftriaxone. Her hemoglobin dropped from 9.6 g /dl to 5.5 g /dl. However, she improved after discontinuation of the drug and blood transfusion. This report serves as a reminder to medical fraternity that life-threatening hemolysis can rarely follow administration of ceftriaxone.
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530 Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5
Ceftriaxone-induced hemolysis
Vivek S. Guleria, Nitin Sharma, Sagar Amitabh, Velu Nair
Drug Watch
Department of Internal Medicine,
Armed Forces Medical College,
Pune - 411 040, India
Received: 09-12-2012
Revised: 17-06-2013
Accepted: 07-07-2013
Correspondence to:
Dr. Vivek S Guleria,
E-mail: viveksguleria@gmail.com
ABSTRACT
Immune hemolytic anemia is a rare adverse effect of ceftriaxone, a third-generation
cephalosporin, which is a commonly used antibiotic. We describe a 60-years-old lady,
a case of community-acquired pneumonia, who developed severe hemolysis after the
rst dose of ceftriaxone. Her hemoglobin dropped from 9.6 g /dl to 5.5 g /dl. However,
she improved after discontinuation of the drug and blood transfusion. This report serves
as a reminder to medical fraternity that life-threatening hemolysis can rarely follow
administration of ceftriaxone.
KEY WORDS: ADRs, ceftriaxone, hemolysis
Introduction
About 30 years ago, methyldopa and penicillin were the
two medications most commonly associated with drug-
induced autoimmune hemolytic anemia (DIIHA). Methyldopa
and intravenous penicillin accounted for 67% and 25%, of
all drug-induced immune hemolytic anemia, respectively.[1]
Currently, most cases of DIIHA are attributed to second- and
third-generation cephalosporins, most commonly ceftriaxone,
and this drug has become the most common cause of antibiotic-
induced hemolysis.[2] We present a case of DIIHA following
ceftriaxone use, managed successfully with withdrawal of the
drug and supportive measures. Since this antibiotic is widely
used by clinicians across all specialties, it is important to be
aware of this possibility to enable us to make an early diagnosis.
Case Report
A 60-years-old lady, with no past history of any drug
allergies, presented with fever and productive cough of five
days duration. Clinically, she had fever, tachycardia, tachypnea
with crackles in the right mammary area. X-ray chest confirmed
pneumonia in the right middle zone [Figure 1]. On admission,
her investigation were as in Table 1
A diagnosis of community-acquired pneumonia was made,
and patient was started on intravenous ceftriaxone one gram 12
hourly. Her hemoglobin dropped down to 7.5 g/dL within 24 hrs
and further to 5.5 g/dL after 72 hrs, with peripheral blood smear
showing marked polychromasia with three nucleated red cells
per 100 white blood cells, schistocytes, a corrected reticulocyte
count of 4.0% and LDH of 1221 units/L. Serum bilirubin rose
to 2 mg/dl with indirect of 1.5 mg/dl. Direct Coombs test was
positive. Urine for hemoglobin and hemosiderin was negative.
A diagnosis of ceftriaxone-induced AIHA was made, and the
drug was stopped immediately. Two units of packed red blood
cells were transfused as she had symptomatic anemia, her
hemoglobin increased to 8.6 g/dl and thereafter to 9.8 g/dl
at discharge, after two weeks with no further deterioration.
Bilirubin normalized on day six [Table 1].
Discussion
Ceftriaxone, a third-generation cephalosporin, is being
commonly prescribed since 1984.[3] It is used as an antibiotic
Access this article online
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DOI: 10.4103/0253-7613.117758
Figure 1: X-ray chest of the patient showing consolidation in right
middle zone
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Guleria,
et al
.: Ceftriaxone induced hemolysis
531Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5
across almost all specialties for various conditions. Ceftriaxone-
induced urticaria, rash, exanthem, and pruritus are the most
common adverse effects and occur in about three percent of
patients.[4] The first case of hemolysis induced by ceftriaxone
was reported in 1991 by Garratty et al.[1] in a 52-year-old woman
who was treated with ceftriaxone. This was the first case of
immune hemolytic anemia associated with ceftriaxone, and also
the first case of fatal cephalosporin-induced hemolytic anemia.
Thereafter, in 1995, a case report of a 24-month-old boy with
sickle cell disease who had cardiac arrest and died 36 hours
later from multiple organ failure after starting ceftriaxone.
Another case of a 16-year-old girl was reported in 1999 who
had developed ceftriaxone-induced intravascular hemolysis
leading to acute renal failure and death.
Drug-induced antibodies can be drug-dependent or drug-
independent. Drug-dependent antibodies (antibodies react
in vitro with RBC’s, only in presence of drug) are produced by
antibiotics like ceftriaxone and pipercillin. Antibody produced
can be either IgG or IgM subtypes. These drugs attach to
RBC, but do not bind covalently to RBC membrane proteins.
Combination of drug and antibody creates an immunogen,
which activates complement and results in acute intravascular
hemolysis.[1] Drug-independent antibodies (drug not required
to be present to detect antibodies in vitro) are produced by
drugs as fludarabine, methyldopa, and penicillins. The antibody
produced is mostly IgG.[5] These drugs combine covalently with
RBC membrane proteins, and the antibody-coated RBC are
taken up by macrophages.[3,4]
Ceftriaxone-induced AIHA, though rare, can be fatal if
not thought of. It needs high index of clinical suspicion in
patients treated with ceftriaxone who develop sudden drop
in hemoglobin, hemoglobinuria, and evidence of hemolysis in
peripheral blood smear. Beta lactam antibiotics should be used
with caution in patients who have history of adverse effects to
ceftriaxone because of cross reactivity.[6] According to the World
Health Organization (WHO) system of causality definitions, the
ADR (adverse drug reaction) in this reported case is categorized
as probable with Naranjp algorithm score of six, as the patient
developed hemolysis after intravenous administration of
ceftriaxone. There was no other possible cause of hemolysis
as no other drug was used with ceftriaxone. Rechallenge was
not done due to inherent risk involved, but the patient showed
improvement after stopping the drug.
Conclusion
Though drug-induced autoimmune hemolytic anemia is a
rare adverse reaction, they may be fatal in some cases. Hence,
the physicians should be vigilant while prescribing these drugs.
References
1. Garratty G, Postoway N, Schwellenbach J, McMahill PC. A fatal case of ceftriaxone
(Rocephin)-induced hemolytic anaemia associated with intravascular immune
hemolysis. Transfusion 1991;31:176-9.
2. Arndt PA, Garratty G. The changing spectrum of drug-induced immune hemolytic
anemia. Semin Hematol 2005;42:137-44 .
3. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med 2001;345:804-9.
4. Batchelor FR, Dewdney JM, Weston RD, Wheeler AW. The immunogenicity of
cephalosporin derivatives and their cross-reaction with penicillin. Immunology
1966;10:21-33.
5. Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Rev
2010;24:143-50.
6. Pierce A, Nester T. Pathology consultation on drug-induced hemolytic anemia.
Am J Clin Pathol 2011;136:7-12.
Table 1:
Laboratory parameters of the patient suffering from ceftrixone-induced hemolysis
Investigation On day of admission
(prior to ceftriaxone)
24 hours after
Inj ceftriaxone
After 72
hours
Day 6 Day 14
Hb (Hemoglobin) 9.6 gm/dL 7.5 gm/dL 5.5 gm/dL 8.6 gm/dL 9.8 gm/dL
TLC (Total leukocyte count) 12200/cumm — 9600/cumm — 8000/cumm
Platelet count of 195000/cumm — 180000/cumm — —
Peripheral blood smear Microcytic-hypochromic anemia — — — —
Corrected Reticulocyte count 1.5% — 4.5% 3% 1.6%
Serum Iron 50 microgram/dL — — — —
TIBC 390 microgram/dL — — —
Blood Urea 21 mg/dL — — — —
Serum Creatinine 1.0 mg/dL — — — —
Serum Bilirubin 0.4 mg/dL 1.2 mg/dL 2 mg/dL 1.0 mg/dL 0.8 mg/dL
Blood Sugar Random 138 mg/dL — — — —
Urine RE Normal — — — —
Sputum Examination Normal — — — —
Cite this article as: Guleria VS, Sharma N, Amitabh S, Nair V. Ceftriaxone-
induced hemolysis. Indian J Pharmacol 2013;45:530-1.
Source of Support: Nil, Conict of Interest: No.
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Article
  • Mar 1991
Fatal hemolytic anemia developed in a 52-year-old woman who was treated with a cephalosporin, ceftriaxone. The patient's red cells (RBCs) were coated with C3, but no RBC-bound IgG, IgA, or IgM was detected. Her serum contained an antibody that did not react with cephalosporin-coated RBCs but reacted strongly with RBCs in vitro when her serum was added to drug and RBCs. This is the first case of immune hemolytic anemia associated with ceftriaxone, the first case of fatal cephalosporin-induced hemolytic anemia, and the second case in which a cephalosporin antibody showed in vitro and in vivo characteristics usually thought to be associated with the so-called immune complex mechanism.
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The Changing Spectrum of Drug-Induced Immune Hemolytic Anemia
Article
  • Aug 2005
  • SEMIN HEMATOL
Drug-induced immune hemolytic anemia (DIIHA) occurs rarely. To date, about 100 drugs have been implicated in causing DIIHA and/or a positive direct antiglobulin test (DAT). The most common drugs associated with DIIHA in the 1970s were methyldopa and penicillin; currently, they are cefotetan and ceftriaxone. Drug antibodies fall into two types: drug-independent ("autoantibodies") and drug-dependent ("penicillin type" or "immune complex type"); some patients have combinations of these antibodies. Some drugs cause nonimmunologic protein adsorption onto drug-treated red blood cells (RBCs). This is known to be the cause of positive indirect antiglobulin tests and is suspected to be a cause of positive DATs. This mechanism may be associated with hemolytic anemia. Twelve cephalosporins have been reported to cause DIIHA; five (primarily cefotetan and ceftriaxone) have been associated with fatalites. Patients with DIIHA due to cefotetan may only have received one dose of the drug prophylactically with surgery. Antibodies to cefotetan react to very high titers against drug-treated RBCs (and at lower titers against untreated RBCs without and/or with drug present). Patients with ceftriaxone-induced DIIHA have received the drug previously; reactions in children often occur minutes after ceftriaxone administration. Antibodies to ceftriaxone are only of the "immune complex type."
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