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C A S E R E P O R T Open Access
Ceftriaxone-induced hemolytic anemia with
severe renal failure: a case report and
review of literature
Hans Benno Leicht
1
, Elke Weinig
2
, Beate Mayer
3
, Johannes Viebahn
2
, Andreas Geier
1
and Monika Rau
1*
Abstract
Background: Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed.
DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades,
ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic
anemia (IHA) has especially been reported to cause severe complications and fatal outcomes.
Case presentation: A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after
antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was
observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks.
Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with
subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune
hemolytic (DIIHA) anemia to ceftriaxone could be confirmed.
Conclusions: The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but
immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of
DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for
this complication must be raised among treating physicians.
Keywords: Drug-induced immune hemolytic anemia, Ceftriaxone, Hemolysis
Background
Ceftriaxone is a broad-spectrum cephalosporin that is
used for the treatment of diverse bacterial infections. It is
known to cause hemolysis by inducing complement acti-
vating drug-dependent antibodies of mainly immuno-
globulin M (IgM)-type, resulting in “immune-complex”
type immune hemolytic anemia [1–3]. During the last
years, ceftriaxone has been one of the most important
drugs that were shown to be responsible for drug-induced
immune hemolytic anemia (DIIHA) [3–6]. Ceftriaxone-in-
duced immune hemolytic anemia (IHA) is characterized
by sharp decrease of hemoglobin, a high rate of organ fail-
ure and a mortality of at least 30% [2,3,6–8], whereas
children present with a more severe clinical picture and
have a worse prognosis than adults [2,5–7]. Here, we
present the case of a 76-year-old patient with
ceftriaxone-induced IHA who was treated in our depart-
ment and could be managed to survive without persistent
physical impairment. We give an overview of the patho-
physiology and therapeutic options of DIIHA, a rare and
probably underdiagnosed condition. As DIIHA is caused
by frequently used medications like ceftriaxone, it is ne-
cessary to raise awareness of this immediately life-threat-
ening condition among treating physicians. Antibiotic
treatment should be strictly restricted to proper indica-
tions to prevent complications such as DIIHA [9].
Case presentation
In January 2017, a 76-year-old male patient was admitted
to our hospital with ascites and dyspnea. In the patient’s
history, a portal vein thrombosis was known for more
than 10 years due to relapsing, necrotizing biliary pancrea-
titis. At that time a cholecystectomy with biliodigestive
anastomosis was performed. Ascites was analysed after
* Correspondence: rau_m@ukw.de
1
Department of Internal Medicine II, University Hospital Würzburg,
Oberdürrbacherstraße 6, 97080 Würzburg, Germany
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67
https://doi.org/10.1186/s40360-018-0257-7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
large-volume paracentesis without signs of spontaneous
bacterial peritonitis or malignancy. On the second day
after hospitalization, an esophagogastroduodenoscopy was
performed to screen for esophageal varices. After the
intervention, the patient developed fever and chills. Chol-
angitis was suspected due to biliodigestive anastomosis,
increase of cholestasis parameters and an antibiotic treat-
ment with ceftriaxone was started the same day (dose 4 g
intravenously). Immediately after drug application the pa-
tient complained about nausea, vomited and developed
dyspnea, confusion and a positive shock index (systolic
RR < 100 mmHg, cardiac frequency 140 /min). The pa-
tient was referred to our intensive care unit and the anti-
biotic regime was escalated to piperacillin/tazobactam and
ciprofloxacin for sepsis therapy. The patient received no
further dose of ceftriaxone. Laboratory analysis about 1 h
after application of ceftriaxone showed first signs of
hemolysis with an elevated lactate dehydrogenase (LDH)
(1,116 U/L (18.6 μkat/l); baseline 290 U/L (4.83 μkat/l))
and a decrease in hemoglobin (6.4 g/dl (3.97 mmol/l),
baseline 8.5 g/dl (5.28 mmol/l)). Coagulation parameters
were significantly disturbed indicating DIC with an inter-
national normalized ratio (INR) of 3.31 (baseline 1.29), fi-
brinogen not measurable, thrombocytopenia down to
56,000/μl (baseline 203,000/μl). During the next days, the
patient developed an increase in leukocytes (up to 23,000/
μL) and in infection parameters (peak C-reactive protein
(CRP) 9.35 mg/dl (890.48 nmol/l), peak procalcitonin
(PCT) 134 μg/l). Additionally, hemolysis aggravated with a
nadir hemoglobin of 4.8 g/dl (2.98 mmol/l), an elevated
LDH up to 1,734 U/L (28.9 μkat/l) and suppressed hapto-
globin < 0.1 g/l. (course of laboratory parameters is
depicted in Fig. 1). Furthermore, the patient subsequently
developed a severe acute kidney failure with uremia (peak
creatinine 6.29 mg/dl (556.04 μmol/l), urea 192.3 mg/dl
(32.11 mmol/l)) and intermittent hemodialysis was neces-
sary for 14 days. A kidney biopsy was performed and
showed a severe acute tubular damage fitting with
shock-induced injury and/or tubular-toxic effects of free
hemoglobin/hemin.
The massive hemolytic reaction came suddenly and
was unexpected. After exclusion of hematological co-
morbidities, a detailed patient history with current drug
exposure was performed. Before admission to our de-
partment the patient had been hospitalized in our surgi-
cal department due to pneumothorax after pacemaker
implantation. During this hospitalisation (< 3 weeks be-
fore the current admission) the patient had already been
treated with ceftriaxone for at least 6 days and had
already developed mild hemolysis in laboratory analysis
without further consequences at that time. Further de-
tailed diagnostic showed a positive Coombs’direct anti-
globulin test (DAT) for immunoglobulin M (IgM),
immunoglobulin G (IgG) and complement factor C3d.
On Naranjo Scale, a probability scale for adverse drug
reactions, the patient would have reached a value of 9
points (maximal score 13 points, with values ≥9 points
indicating a definite adverse drug reaction) [10]. The
suspected DIIHA was proven by reference laboratory
analysis (Institute of Transfusion Medicine, Charité,
Berlin), confirming the presence of a strongly agglutinat-
ing ceftriaxone-dependent antibody (Fig. 2).
The patient’s situation stabilized with decrease of
hemolysis parameters, stable hemoglobin levels and
Fig. 1 Representative laboratory parameters during disease course
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67 Page 2 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
reconstitution of kidney function after withdrawal of
hemodialysis. At the time of discharge from hospital la-
boratory results were stabilized or even normalized: cre-
atinine 2.04 mg/dl (180.34 μmol/l), bilirubin 0.5 mg/dl
(8.55 μmol/l), LDH 207 U/L (3.45 μkat/l), INR 1.26,
hemoglobin 7.6 g/dl (4.72 mmol/l). In a follow-up visit 4
months later kidney function was also normalized and the
patient had returned to normal daily life.
Discussion
Drug-induced immune hemolysis is a rare (estimated
incidence about 1/1,000,000/year), but potentially life-
threatening complication and therefore an early and
correct diagnosis is crucial [3,6,11]. Several mecha-
nisms causing drug-induced hemolysis have been de-
scribed during the last decades. Basically, it must be
distinguished between direct erythrocytotoxic effects of
drugs causing hemolysis, e.g. hemolysis by the antiviral
drug ribavirin [12]anddrug-induced immunologic reac-
tions leading to extra- or intravascular hemolysis. The
latter is a type of immune-hemolytic anemia (IHA) and
called drug-induced immune hemolytic anemia (DIIHA).
In general, DIIHA can be mediated through drug-induced
antibodies or through a mechanism called nonimmunolo-
gic protein adsorption (NIPA), which is not triggered by
antibodies [1,11,13]. Drug-induced antibodies can be
subdivided into drug-dependent and drug-independent
antibodies [1,5,11,13]. Drug-dependent antibodies need
the presence of the drug (or also of a drug-metabolite) to
bind and lyse erythrocytes. In contrast, drug-independent
antibodies can bind erythrocytes in absence of the causa-
tive drugs and are therefore true autoantibodies that can
serologically not be distinguished from autoantibodies me-
diating warm autoimmune hemolytic anemia (WAIHA),
so diagnosis relies on clinical response to cessation of the
causative drug [1,5,6,11,13,14]. It is considered that
drug-dependent as well as drug-independent antibodies
arise as an immunologic reaction against neoantigens
formed by the binding of drugs to erythrocyte membranes.
The drugs are haptens that need to be attached to a larger
structure to become immunogenic [6,11]. In case of
DIIHA, this neoantigen consists of erythrocyte mem-
brane and drug [1,6,11].Iftheantibodyrecognizes
only the molecular structure of the drug or a struc-
ture formed by membrane and drug together, it re-
sults in a drug-dependent antibody, that will only
bind to erythrocytes and lead to hemolysis in the
presence of the drug [1,6]. In contrast, drug-inde-
pendent autoantibodies are directed predominantly
against a membrane structure and the drug is only a
small and negligible part of the binding site. In this
case, the antibody is able to bind erythrocytes also
in the absence of the drug [1,3]. Drug-dependent
and drug-independent antibodies can be induced in
the same individual during the same anti-drug reac-
tion, supposing that they were generated by the
same underlying mechanism [1]. Concerning
drug-dependent antibodies, a further distinction can
be made considering the binding mechanism of the
drug to the erythrocyte: a covalent binding will result in a
so-called “drug-adsorption mechanism”or “penicillin-type”
reaction, while a rather loose binding will result in a
so-called “immune complex-type”reaction, the latter being
associated with a worse outcome due to formation of
IgM-antibodies, complement activation and intravascular
hemolysis (reviewed in [1,3,11]). Ceftriaxone-induced
IHA is characterized by “immune complex-type”reactions
and in a recent case of ceftriaxone-induced IHA anti-
bodies with Rh specificity were described, that persisted
8monthsafterthedrugreaction[15]. DIIHA by NIPA
does not depend on any drug-induced antibody. NIPA is
caused by some drug-induced, nonimmunologic modifica-
tion of erythrocyte membranes, allowing the unspecific
binding of diverse plasma proteins including IgG and com-
plement factor 3 (C3), which leads to extravasal hemolysis
in spleen [1,5,11]. Furthermore, some drugs can induce
DIIHA by different mechanisms, e.g. platinum-based
chemotherapies cause DIIHA by NIPA as well as
drug-dependent antibodies by “immune complex”-mechan-
ism [16]. An overview of the different mechanisms of drug
induced hemolysis is depicted in Fig. 3.
Massive hemolysis and decrease in hemoglobin level
are typical for ceftriaxone-induced IHA. Mayer et al. re-
ported 12 cases of ceftriaxone-induced IHA with the
Fig. 2 Serological investigation of ceftriaxon-dependent antibody
using gel card technique (BioRad, Cressier sur Morat, Switzerland).
Results showing strong agglutination (4+) of the patient’s plasma
and eluate in the presence of the drug, but negative results without
ceftriaxone added. Patient’s eluate (1) or plasma (2), ceftriaxone and
untreated RBCs; Negative controls: patient’s elutate (1a) or plasma
(2a), saline (instead of ceftriaxone) and untreated RBCs
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67 Page 3 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
nadir hemoglobin < 8 g/dl (4.96 mmol/l) in 9 cases and
in 3 of these cases the nadir was even below 3 g/dl
1.86 mmol/l) [6]. Arndt et al. analyzed 25 cases of
ceftriaxone-induced IHA including 17 children [2].
Ceftriaxone-induced IHA seems to be more frequent
and more severe in children [2,3,6,7,11]. In the series
of Arndt et al., 16 patients had a nadir hemoglobin <
5 g/dl (3.1 mmol/l), and among these 16 patients were
13 children. In three patients, the nadir was even < 1 g/
dl (0.62 mmol/l) and all of them were children [2]. Chil-
dren suffering from serious underlying diseases like HIV
infection or sickle cell disease seem to be predisposed to
develop ceftriaxone-induced IHA [17], and in sickle cell
disease ceftriaxone-dependent antibodies may also lead
to fatal sickle cell-crisis [18]. In our patient, the second
hemolytic episode was much worse than the first one.
This finding is typical for DIIHA [7,11] and is due to a
secondary immune response. The immune system of pa-
tients receiving a drug for the first time in their life
needs some days to produce drug-dependent or also
drug-independent antibodies [19]. In a review of 37
cases of ceftriaxone-induced IHA a weaker and self-lim-
iting hemolytic episode associated with earlier
ceftriaxone-application could be observed in 32% of
these patients [7], underlining the assumption that espe-
cially secondary immune responses are responsible for
severe DIIHA in general. A massive drop in hemoglobin
levels in these patients led to severe complications such
as shock, circulatory arrest, organ ischemia, dissemi-
nated intravascular coagulation (DIC), acute respiratory
distress syndrome (ARDS) in 27 patients and 30% of the
patients died [7]. Surprisingly, drug-dependent anti-
bodies were detected also in healthy persons (blood do-
nors/random patients) in much lower titers than in
patients who developed DIIHA. This interesting finding
might be associated with antibiotic use in industrial ani-
mal breeding [4,5,13], but the clinical relevance of this
phenomenon is still unknown. However, one could
speculate that these persons might be predestinated to
develop clinically relevant antibody-titers and
Fig. 3 Systematic overview of different types of drug-induced immune hemolytic anemia
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67 Page 4 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
subsequent hemolysis after receiving therapeutic doses
of the respective antibiotic [3]. The high prevalence of
acute renal failure in patients with DIIHA in general is
not only because of hypoperfusion/ischemia due to
hemoglobin decrease and shock, but especially because
of the nephrotoxicity of free hemoglobin and hemin
[20]. Beyond their nephrotoxicity there are other proin-
flammatory effects of free hemoglobin and hemin that
have to be considered in patients with DIIHA and might
probably aggravate the clinical course of the patients
(reviewed in [21]).
It has been noticed that ceftriaxone causes more severe
clinical courses and more fatal outcomes than other drugs
responsible for DIIHA [3,6]. Ceftriaxone has been shown
to induce primarily antibodies of IgM-type with accom-
panying IgG-antibodies [1–3]. IgM-type drug-dependent
antibodies lead to binding and activation of complement,
which results in intravascular hemolysis. In fact, intravas-
cular hemolysis through complement-mediated lysis is a
hallmark of “immune-complex-type”DIIHA [1,11]. In
line with this, Coombs’direct antiglobulin test (DCT) in
ceftriaxone-induced IHA is usually positive for C3 and, in
some cases, also for IgG [1–3,22–24]. However, negative
DCT has also been described in ceftriaxone-induced IHA,
probably because of massive hemolysis and therefore lack
of intact complement−/antibody-loaded erythrocytes in
this special case [25]. In our patient a positive DCT was
observed for IgM, IgG and C3d.
Most importantly, if DIIHA is suspected, the suspi-
cious drug must be stopped immediately. Discontinu-
ation of the drug is the most important treatment
measure concerning the patient’s outcome. In children
with ceftriaxone-induced IHA, 8 of 9 patients, whose
ceftriaxone therapy was stopped immediately, survived.
In contrast, children without cessation of ceftriaxone
treatment after diagnosis had a mortality of 50% [8].
DIIHA patients should be admitted to an intensive care
unit to provide optimal supportive care and if required
circulatory support. Transfusion of red blood cells will
be done to the necessary amount. Recently, a case of
ceftriaxone-induced IHA was reported with a patient re-
fusing transfusions for religious reasons (Jehova’s wit-
ness). In this case the patient could be stabilized with
daily application of erythropoietin, ferrous sulfate, folic
acid and vitamin B12 [26]. In many cases, patients are
given steroids. However, there is no proven benefit and
therefore no recommendation for steroid therapy in
DIIHA, at least as far as drug-dependent antibodies are
involved [3,11,14]. In general, reports of successful use
of steroids in DIIHA are usually confounded by the
withdrawal of the responsible drug at the same time [3,
11]. In cases of drug-independent antibodies, which are
autoantibodies, steroid therapy can be tried [3,14], but
also in these cases, the immediate withdrawal of the
responsible drug is the most important therapeutic
measure in order to stop the immunologic stimulation.
Additionally, in cases of drug-independent antibodies,
intravenous immunoglobulins (IVIG) can be given, if
there is evidence of intravascular hemolysis, like in treat-
ment of WAIHA [27]. Administration of high-dose IVIG
has been successfully used in a child with severe
ceftriaxone-induced IHA and a nadir hemoglobin of
2.2 g/dl (1.37 mmol/l) [24]. However, the question re-
mains open whether the positive outcome of the patient
was due to IVIG therapy or due to cessation of ceftriax-
one. In some cases, plasmapheresis/plasma exchange has
been used for treating DIIHA [3,7,8]. It could be specu-
lated that removing drug-induced antibodies from the
patient’s serum actively via plasmapheresis could be
helpful in patients with “drug adsorption-type”DIIHA or
with severe renal failure, where the causative drug is not
eliminated within its normal half-time and might there-
fore trigger a prolonged hemolysis as well as an intensi-
fied immunologic stimulation.
As DIIHA of “immune complex-type”is due to
complement-mediated intravascular hemolysis, one is
tempted to speculate that a therapy with eculizumab, a
complement inhibitor which hinders the formation of the
“membrane attack complex”, could be helpful in these pa-
tients. Eculizumab is successfully used in paroxysmal noc-
turnal hemoglobinuria and (atypical) hemolytic uremic
syndrome, and there have also been reports of its use in
autoimmune hemolytic anemia [28,29]. To our know-
ledge, there is no report of the use of eculizumab in a pa-
tient with DIIHA to date. However, complement
inhibitors might be an effective therapeutic option espe-
cially in cases with severe intravascular hemolysis [30].
After the diagnosis of DIIHA, there is an absolute
contraindication for re-exposure of the responsible drug
for the patient’s lifetime. The application of drugs of the
same substance class should be considered very care-
fully, as there could be interactions of the drug-depend-
ing antibody and these similar drugs. In case of
ceftriaxone-dependent antibodies e.g., cross-reactivity
has been shown with cefotaxime [6,11,23], cefpodox-
ime proxetil [23], with cefamandole [11] and with cefo-
perazone [11]. In addition, drug-dependent antibodies
are not necessarily directed against the drug itself, but
can also be directed against a drug metabolite or against
both the intact drug and its metabolite(s) [3,19,23],
which makes crossreactions to drugs of the same sub-
stance class even more probable.
Antagonizing the toxic effects of free hemoglobin and
free hemin could be an effective therapeutic strategy in
future to prevent renal failure. In animal models of
hemolysis, the application of haptoglobin (binding free
hemoglobin) as well as of hemopexin (binding free he-
min) has proven beneficial [31,32], so maybe purified
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67 Page 5 of 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
haptoglobin or hemopexin might become effective thera-
peutic agents for DIIHA one day.
Conclusions
Our case demonstrates the severity of ceftriaxone-induced
immune hemolytic anemia, a rare, but immediately
life-threatening condition of a frequently used antibiotic
in clinical practice. For the last decades, ceftriaxone has
been one of the most common drugs responsible for
DIIHA and has been associated with particularly severe
outcome. In cases of unclear hemolysis, treating physi-
cians should be aware of DIIHA and check the patient’s
medication carefully. Suspected drugs have to be stopped
immediately in order to prevent severe complications and
fatal outcomes.
Abbreviations
ARDS: Acute respiratory distress syndrome; CRP: C-reactive protein;
DAT: Direct antiglobulin test; DIC: Disseminated intravascular coagulation;
DIIHA: Drug induced immune hemolytic anemia; IgG: Immunoglobulin G;
IgM: Immunoglobulin M; IHA: Immune hemolytic anemia; INR: International
normalized ratio; IVIG: Intravenous immunoglobulins; LDH: Lactate
dehydrogenase; NIPA: Nonimmunologic protein adsorption;
PCT: Procalcitonin; WAIHA: Warm autoimmune hemolytic anemia
Acknowledgements
Not applicable
Funding
None
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated
or analysed during the current study.
Authors’contributions
Conception and design: HBL, MR. Data collection: HBL, MR. Sample analysis:
EW, JV, BM. Data interpretation: HBL, EW, JV, BM, AG, MR. Drafting the article:
HBL, MR, AG. Reviewed and approved: all authors.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent from the patient for this case report was obtained.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Internal Medicine II, University Hospital Würzburg,
Oberdürrbacherstraße 6, 97080 Würzburg, Germany.
2
Institute of Transfusion
Medicine and Haemotherapy, University of Wuerzburg, Wuerzburg, Germany.
3
Institute of Transfusion Medicine, Charité - Universitätsmedizin Berlin,
corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin,
and Berlin Institute of Health, Berlin, Germany.
Received: 24 April 2018 Accepted: 10 October 2018
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