3. DISCUSSION
Here, we describe the case of a patient with a history of COPD, who
required
antimicrobial
therapy for pulmonary bacterial infection, but the treatment was
complicated by
thrombocytopenia
association with antibiotics. We found our patient
with
piperacillin-tazobactam-induced thrombocytopenia was able to
successfully challenge meropenem and cefotiam, but cannot tolerant with
cefoperazone-sulbactam for the treatment of pneumonia.
Due to the etiology of DIT still remains complex and multifactorial, its
diagnosis remains a challenge. This case suggested that doctors should
be aware of the risks of drug-induced thrombocytopenia, and that drugs
should be discontinued following detection of drug-induced
thrombocytopenia. The Naranjo scale was employed for assessing the
causal relationship between the development of thrombocytopenia and
piperacillin-tazobactam and cefoperazone-sulbactam treatment. This
yielded a probability score of +9
for piperacillin-tazobactam, suggesting that it was the definite cause
of thrombocytopenia, and a probability score of +7 for
cefoperazone-sulbactam,
suggesting that it was the probable cause of thrombocytopenia (Table 1).
Two mechanisms underlying
beta-lactam
antibiotics-induced thrombocytopenia have been proposed, including
drug-induced bone marrow suppression and
DITP, but
DITP
is more common.3 DITP is attributed to accelerated
platelet destruction secondary to an immune response. Moreover, two
different mechanisms have been elucidated for beta-lactam antibiotics
DITP.8 Thus, a limited number of case reports have
previously documented confirmation of piperacillin-tazobactam DITP by
identification of positive drug-induced antiplatelet
antibodies.5 Unfortunately, it was unfeasible to
collect and test of piperacillin-tazobactam antiplatelet antibodies at
our site. However, bone marrow suppression is often accompanied by a
simultaneous decrease in leukocytes, hemoglobin, and platelets. In
addition, given the nature of the mechanism, bone marrow suppression
tends to develop more gradually over a few weeks, while
DITP
typically develops more quickly, often after 7 to 14 days of therapy,
and even after 1 to 3 days of therapy in patients with prior
exposure.8Therefore,
due
to the absence of decrease of white blood cells and hemoglobin and rapid
platelet decline, DITP associated with piperacillin-tazobactam and
cefoperazone-sulbactam was considered for our patient.
To date, previous reports have described the use of other beta-lactam
antibiotics, such as carbapenems,9–12cefepime,3,13,14 cefoperazone,9aztreonam,10 in patients with
piperacillin-tazobactam-induced thrombocytopenia. However, although our
patient with piperacillin-tazobactam DITP was able to successfully
challenge merropenem and cefatiam,
cefoperazone-sulbactam
was not tolerated. Thus, due to the immunogenic nature of DITP and the
structural similarities between beta-lactam antibiotics, identifying the
structural moiety of
piperacillin-tazobactam
responsible antibodies for this immunogenic response and evaluating the
safety of other beta-lactam antibiotics in this clinical setting are of
crucial importance. To the best of our knowledge, only three reports
describing studies of drug cross-reactions in beta-lactam DITP have been
reported. In one,4 two ceftriaxone-dependent
platelet-reactive antibodies failed to cross-react with any of five
other cephalosporins. In two,5 three
piperacillin-induced antibodies failed to cross-react with two other
penam and five cephem beta-lactam drugs. In three,6among 14 antibodies specific for penam drugs, five “strong”
cross-reactions with other penam drugs were found; among 18 antibodies
specific for cephem drugs, eight “strong” cross-reactions were
identified. But antibodies induced by penam drugs did not cross-react
strongly with cephem drugs and vice versa. These reports however covered
very few different beta-lactam antibiotics, did not involve piperacillin
and cefoperazone.
In our case, we
hypothesized
the possible platelet-reactive antibodies of beta-lactam antibiotics and
presented in table 2. Firstly, previous reports observed a strong
correlation between cross-reactions and similar or identical R1 side
groups of the beta-lactams.6 So we hypothesized that
identical R1 side chains between piperacillin and cefoperazone maybe the
underlying reason why our patient experienced thrombocytopenia during
using piperacillin-tazobactam and cefoperazone-sulbactam. However, a
case reported cefoperazone can successfully challenged in a patient with
piperacillin-tazobactam DITP.9 Therefore, R1 side
chain considered as
platelet-reactive
antibodies was questioned. Secondly, we found sulbactam, like
piperacillin, contains a beta-lactam structure, which may become the
responsible of platelet-reactive antibodies. This may be similar to
patients with an allergy to sulbactam will cross-react with other
beta-lactams with the similar core.15 And finally,
previous study showed tazobactam-specific antibiotic had been obtained
in a patient with piperacillin-tazobactam DITP.16Thus, tazobactam may be crucial drug in our case. In addition, the
structural similarity between tazobactam and sulbactam provided the
possibility of cross-reaction between piperacillin-tazobactam and
cefoperazone-sulbactam. However, as multiple pathways may be involved in
immune reaction, the exact responsible antibodies of beta-lactam
antibiotics DITP have not been clearly defined and require further
investigation in future research.
The proper treatment of DITP usually entails the withdrawal of the
suspected drug, and supportive care with platelet transfusions as
bleeding complications can be severe.17 To data, there
is no evidence that corticosteroids are efficacious in
DITP,17 which may be the reason why our patient still
experienced DITP despite continuous methylprednisolone use. However,
previous case reported where the drop in platelet count was minimized or
mitigated when the patient was receiving higher doses of
corticosteroids.18