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