CLINICAL AND LABORATORY OBSERVATIONS
Ceftriaxone-induced Hemolytic Anemia:
Case Report and Review of Literature
Michael S. Northrop, MD and Hemant S. Agarwal, MBBS, FAAP
Summary: Ceftriaxone is a frequently used empiric antibiotic in
children. Acute hemolysis is a rare side effect of ceftriaxone therapy
associated with a high mortality rate. A 14-year-old boy suffering
from Crohn disease developed bacterial pneumonia that was
treated with ceftriaxone. We report successful management of
ceftriaxone-induced hemolytic anemia (CIHA) in this patient and
review the CIHA literature in pediatric patients. Early recognition
of CIHA with prompt discontinuation of ceftriaxone therapy may
have a beneficial role in reduction of high mortality seen in these
patients.
Key Words: ceftriaxone, immune hemolytic anemia, acute renal
failure, multiple organ failure, drug induced
(J Pediatr Hematol Oncol 2015;37:e63–e66)
C eftriaxone, a third-generation cephalosporin has been
in use since 1982.1 It is widely used in pediatric patients
because it provides a broad spectrum of activity against
gram-positive and gram-negative bacteria. The prolonged
half-life and once a day administration represent its added
advantages. It is generally well tolerated, and uncommon
adverse effects include diarrhea, skin rash, eosinophilia,
elevation in serum hepatic enzymes, and biliary sludging.2
CIHA in children is a rare and often fatal complication.3,4
Previous reported cases of cardiovascular decompensation
and renal failure in pediatric CIHA patients have been
associated with a high mortality rate.4–7 We report suc-
cessful management of CIHA with multiorgan failure in a
14-year-old boy suffering from Crohn disease by timely
diagnosis of CIHA, immediate discontinuation of cef-
triaxone therapy along with aggressive cardiorespiratory
support. We also review CIHA literature in children.
CASE REPORT
A 14-year-old boy with Crohn disease was admitted to the
hospital for treatment of pneumonia. He was on stable medications
of mesalamine and methotrexate for Crohn disease management.
He developed worsening cough and fever up to 1031C over a 4-day
period that was unresponsive to azithromycin and ceftriaxone
therapy. The rapid influenza and streptococcal antigen tests were
negative and his chest x-ray revealed left lingular pneumonia. There
was no abdominal pain or diarrhea. He was admitted to the hos-
pital and continued on ceftriaxone therapy for the next 3 days
without any significant improvement. He underwent bronchoscopy
Received for publication December 17, 2013; accepted April 30, 2014.
From the Department of Pediatrics, Vanderbilt University Medical
Center, Nashville, TN.
The authors declare no conflict of interest.
Reprints: Hemant S. Agarwal, MBBS, FAAP, Department of Pedia-
trics, Vanderbilt University Medical Center, 5121 Doctor’s Office
Tower, 2200 Children’s Way, Nashville, TN 37232-9075 (e-mail:
hemant.agarwal@vanderbilt.edu).
Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol  Volume 37, Number 1, January 2015
and esophagogastroduodenoscopy with colonoscopy for further
evaluation of his daily high-grade fevers. Bronchoscopy demon-
strated mild erythema of the tracheobronchial tree and bron-
choalveolar lavage fluid was negative for bacterial or fungal
growth. The esophagogastroduodenoscopy and colonoscopy did
not reveal new lesions except for an anal fissure. He tolerated the
procedures well and he received his intravenous ceftriaxone dose
the same night.
He complained of abdominal pain, back pain, headache, and
had 1 episode of nonbloody vomiting within half an hour of
receiving ceftriaxone on day 7 of his antibiotic therapy. His clinical
examination revealed a pulse rate of 162/min, fever of 102.31C, and
significant pallor. His abdomen was mildly distended but soft. He
was quickly transferred to the pediatric intensive care unit since he
continued to remain tachycardic, tachypneic, and diaphoretic. He
was emergently intubated and fluid resuscitated. His laboratory
tests revealed hemoglobin of 2.6 g/dL (hemoglobin before the
procedure: 9 g/dL) and serum lactate level of 11.3 mmol/L. He was
urgently transfused with 2 U of packed red blood cells (RBCs)
followed by another 2 U to give posttransfusion hemoglobin of
10 g/dL. There was no obvious clinical source of acute bleeding.
Studies for evaluation of acute blood loss including computed
tomography scan of his abdomen, chest, and brain and tagged
RBC study of his gastrointestinal tract were negative. His hapta-
globin level tested within 6 hours of suspected hemolysis was
normal (80 mg/dL); however, the direct antibody test (DAT) was
strongly positive (4 +) for complement and negative for immuno-
globulin G (IgG). His plasma was tested against untreated and
enzyme (ficin)-treated RBCs in the presence of ceftriaxone for
suspicion of hemolytic anemia. The untreated RBCs agglutinated
(3 +) in the presence of ceftriaxone; the saline control was non-
reactive. The enzyme-treated RBCs strongly agglutinated (4 +) in
the presence of ceftriaxone. No tests were reactive with anti-IgG.
He developed acute tubular necrosis in the next 2 days with
cola-colored urine, urinalysis was positive for blood but negative
for RBCs on microscopy, serum creatinine rose from 0.65 mg/dL
before his deterioration to peak level of 2.17 mg/dL, and renal
ultrasound revealed normal corticomedullary differentiation. He
also developed acute liver insufficiency in the next 2 days with peak
levels of aspartate aminotransferase of 3978 IU/L, alanine amino-
transferase of 1623 IU/L, and total bilirubin level of 4.2 mg/dL. He
also developed coagulopathy with peak prothrombin time of 18.9
seconds and partial thrombin time of 35 seconds; although he never
developed clinical signs of bleeding. Ceftriaxone was immediately
discontinued after the acute episode of hemolysis and his antibiotic
therapy was changed to vancomycin and piperacillin/tazobactam.
His blood, urine, and endotracheal tube secretion cultures were
negative and his antibiotic regimen was discontinued following
negative culture results. He was extubated within 24 hours of his
acute illness. His renal and liver insufficiency and coagulopathy
gradually improved with supportive care. The patient was trans-
ferred from the intensive care unit in 3 days and discharged home
after 4 days.
DISCUSSION
Drug-induced immune hemolytic anemia (DIIHA) is a
serious but rare adverse reaction with an estimated inci-
dence of 1 to 2 per million individuals per year.8 The
median age of patients for DIIHA is 65 years, 58% are
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Northrop and Agarwal J Pediatr Hematol Oncol  Volume 37, Number 1, January 2015

females and usually there is no direct relationship between
the dose of a drug and the reaction.9,10 Medications
implicated in DIIHA have substantially grown and changed
in the past 50 years.10 In the recent years, anti-infective
drugs (30% of cases) followed by musculoskeletal drugs
(22% of cases) and cardiovascular drugs (20% of cases)
have been associated with DIIHA.9
Drugs can induce hemolytic anemia either by drug
adsorption, red cell membrane modification, immune
complex formation, or positive antibody formation.11
Ceftriaxone causes hemolytic anemia by immune complex
mechanism.12 It is thought that ceftriaxone or its degra-
dation product binds to antibodies in the plasma forming
immune complexes.5 Detectable antibodies to ceftriaxone
are necessary but not sufficient to cause hemolysis in
CIHA.13 Quillen and colleagues found a prevalence of
anticeftriaxone antibodies in 8 of 64 (12.5%) pediatric
patients with human immunodeficiency virus infection and
sickle cell disease exposed to ceftriaxone. Only 2 of these 8
patients with the antibody experienced hemolysis.13 It has
been proposed that the ability of ceftriaxone antibody to fix
complement is an important variable that predicts the
occurrence or severity of hemolysis.14 The immune com-
plexes bind nonspecifically (without antigenic determi-
nation) to red cell membranes and activate complement
that destroy the RBCs.12 The hemolysis due to complement
activation by these antibodies is usually intravascular in
nature. It is often acute, severe, and associated with
hemoglobinemia, hemoglobulinuria, and in serious cases;
there is dramatic drop of hemoglobin following drug
exposure. The resulting hemoglobinuria is nephrotoxic
particularly when intratubular obstruction facilitates
proximal tubular heme uptake.15 Patients can present with
clinical signs and symptoms of jaundice, cardiopulmonary
decompensation, renal failure, and shock.
CIHA has been reported in 23 pediatric patients
(including our case) since 1995 (PubMed online search;
limits: English; terms: ceftriaxone and hemolysis; ceftriax-
one and renal failure)3–7,16–31 (Table 1). CIHA occurs much
more commonly in children as compared with adults.3,32
Children manifesting CIHA commonly have underlying
chronic hematologic or immunological disorders or
chronic/recurrent infections (Table 1). Eighteen of these
patients, including our patient had previous exposure to
ceftriaxone.4,6,7,16–23,25,28–31 There was no information
reported in the remaining 5 patients.3,5,24,26,27 It is unclear
whether the underlying disease processes contribute to the
development of anticeftriaxone antibodies and hemolysis,
or if repeated exposure to the drug is important, or both.13
Hemolysis in pediatric patients with CIHA usually
occurs within 30 minutes (range, 5 to 120 min) of ceftriax-
one administration.4–7,16–19,21,23,28 The hemolysis is often
dramatic and the hemoglobin can acutely drop to 2.5 g/dL
(range, 0.4 to 8.4 g/dL) (Table 1). In adults, the fall in
hemoglobin is much less and occurs over a period of hours
to days.33 Initial symptoms including chills, fever, vomiting,
headache, lumbar and/or abdominal pain, tachycardia, and
dyspnea are nonspecific. In serious cases of CIHA, severe
anemia results in cardiopulmonary decompensation, and/or
shock (Table 1). The massive intravascular hemolysis and
hemoglobinuria may progress to acute tubular necrosis.
Acute renal failure has been reported in at least 40% of
pediatric CIHA patients with an associated mortality rate
of 55% (Table 1). The acute drop in hemoglobin along with

TABLE 1. Ceftriaxone-induced Hemolytic Anemia in Pediatric Patients

Age/ Nadir Hb DAT DAT CVS Renal
References Sex Primary Diagnosis (g/dL) (IgG) (C3) Compromise Failure Outcome
Bernini et al6 2/M Sickle cell anemia 0.9 + + + + Death
Lascari and Amyot16 5/M Chronic myelocytic leukemia 1.4 NR NR + Death
Borgna-Pignatti et al17 8/M HIV 4.1 ? ? Death
Scimeca et al7 3/F Hypereosinophilic syndrome NR NR NR + + Death
Moallem et al18 14/F HIV 4.9 + + + Death
Meyer et al5 16/F Recurrent meningitis 2.4 + + + Death
Viner et al19 6/M Sickle cell anemia 2.8 + Survival
Citak et al20 5/F Recurrent urinary tract infection NR + + Survival
Eastlund et al21 8/M Peter anomaly 4.5 + Survival
Mattis et al22 9/M Crohn disease 2.3 + Survival
Kakaiya et al23 10/M Sickle cell anemia NR + + Survival
Corso and 10/M Sickle cell anemia 2 + + Survival
Ravindranath24
Bell et al25 17/F Hemoglobin SC 5 + + Death
Demirkaya et al26 5/F — 5.1 + + Survival
Kapur et al27 10/M Craniosynostosis 8.4 + Survival
Schuettpelz et al28 6/F Sickle cell anemia 0.4 + + + Survival*
Doratotaj et al29 4/F Infantile astrocytoma 2.4 + + Survival
Tobian et al30 7/M Hemophagocytic 4.4 + + Survival
Lymphohistocystosis
Reis Boto et al31 2/M Congenital nephrotic syndrome 2.8 + + Survival
Goyal et al4 2/M Hemoglobin SC NR NR NR + Survival
Goyal et al4 10/F Hemoglobin SC 4 ? ? + + Death
Boggs et al3 11/F Lyme disease 5.9 + + Survival
This case 14/M Crohn disease 2.4 + + + Survival
*Patient had severe neurological deficit.
? indicates antiglobulin test positive—not specified for IgG and/or C3; CVS, cardiovascular; DAT (C3), direct antibody test for complement; DAT (IgG),
direct antibody test for immunoglobuln G; Hb, hemoglobin levels; NR, not reported.

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J Pediatr Hematol Oncol  Volume 37, Number 1, January 2015
cardiovascular decompensation and acute renal failure has
been previously reported to have high mortality.4–7
The rapid progression of hemolysis leading to death in
a few hours makes early diagnosis difficult. A high index of
DIIHA suspicion is required to promptly diagnose CIHA
with serological tests. Normal haptaglobin levels soon after
the event may be misleading as in our patient. The DAT is
used to determine whether patient’s RBCs have surface-
bound IgG and/or complement. The DAT was positive in
18 of 23 reported cases of CIHA in children (Table 1). A
positive DAT, however, can be found in 1 in 1000 to 14,000
healthy blood donors without hemolysis.34 The significance
of a positive DAT therefore, requires clinical correlation. In
the largest reported series of 25 pediatric and adult DIIHA
cases caused by ceftriaxone, DAT detected RBC-bound
IgG in half of the cases and the DAT was positive for
complement in all the cases suggestive of antibody being
predominantly immunoglobulin M (IgM) in nature.32 In
the laboratory, IgM and/or IgG antibodies almost always
activate complement and cause in vitro hemolysis, agglu-
tination, and sensitization of test RBCs in the presence of
ceftriaxone, and enzyme-treated RBCs react more strongly
than untreated RBCs.8,32
Successful treatment of CIHA as in our patient war-
rants urgent cardiopulmonary support, correction of severe
anemia with blood transfusion, identification of the drug-
induced hemolysis and most importantly, immediate ces-
sation of ceftriaxone therapy. Blood transfusion can usually
be safely administered because the antibodies are drug
dependent.24 Steroid therapy is of questionable efficacy in
treatment of CIHA.19,26 Plasmapheresis has been attempted
as a therapeutic option in few patients with equivocal
outcomes.4,28,29 Immediate discontinuation of ceftriaxone
therapy after evidence of hemolysis seems to be beneficial in
pediatric CIHA patients. In the review of 23 CIHA pedia-
tric patients, 9 patients including our patient did not receive
any further ceftriaxone after hemolysis and 8 (89%) of
these patients survived.19,21–24,26,30,31 Ceftriaxone therapy
was continued in 8 CIHA patients. Four of these 8 patients
died, 1 patient had repeated cardiorespiratory arrests with
subsequent ceftriaxone doses, 1 patient developed severe
renal failure requiring 14 days of hemodialysis, and 1 patient
survived with severe neurological deficit.3,5,6,17,20,25,28
In conclusion, physicians treating pediatric patients
with chronic hematologic or immunologic disorders or
chronic infections should be aware that repeated treatments
with ceftriaxone can lead to erythrocyte sensitization
associated with sudden and unpredictable hemolysis, which
may be fatal. Careful observation is thus required for
pediatric patients receiving ceftriaxone because the risk
factors, if any, for this dramatic complication have not been
clarified, and there is no way to predict its occurrence.
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