Rare complication of ceftriaxone therapy: drug-induced thrombocytopenia (DITP)
- 1 School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA
- 2 Internal Medicine, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA
- 3 Internal Medicine, Sanford Medical Center Fargo, Fargo, North Dakota, USA
- Correspondence to Aishwarya Sharma; aishwaryasharma97@gmail.com
Abstract
A 62-year-old woman with a history of end-stage renal disease on haemodialysis, essential hypertension and type 2 diabetes mellitus was diagnosed with sepsis and placed on 600 mg oral linezolid every 12 hours and 1 g intravenous ceftriaxone every 24 hours. Blood cultures grew Streptococcus dysgalactiae, and she was switched to intravenous ceftriaxone 2 g daily. Platelet counts slowly trended down after starting ceftriaxone reaching 5 K/μL on day 12 of treatment. Ceftriaxone was discontinued and heparin-induced thrombocytopaenia was ruled out. She was switched to vancomycin and her platelet count improved. Given the temporal relationship between changing platelet counts and starting and discontinuing ceftriaxone, a diagnosis of drug-induced thrombocytopaenia was made.
Background
Ceftriaxone is a third-generation cephalosporin antibiotic. It is widely prescribed due to its broad-spectrum coverage of bacterial infections, convenient dosing and limited drug–drug interactions. A rare adverse effect of ceftriaxone is drug-induced thrombocytopaenia (DITP) occurring at an incidence of 10 in 1 million cases.1 Laboratory studies with decreased platelet count and stable haemoglobin and white cell count (WCC) after starting new medication should raise suspicion for cases of DITP. It is important to rule out heparin-induced thrombocytopaenia (HIT) by measuring platelet factor 4 (PF4) levels, followed by serotonin-release assay (SRA) given a heparin exposure. Unlike HIT which is mediated by antibody mediated platelet activation and thrombosis, DITP occurs due to antibody mediated platelet degradation which presents and resolves within 1 week of exposure and discontinuation of the causative medication.2
The rarity of this adverse event leads to diagnosis by exclusion, which often results in delayed recognition, underdiagnosis and worse outcomes. Treatment includes prompt discontinuation of ceftriaxone and replacement with a different antibiotic therapy as indicated. Re-exposure to ceftriaxone is not recommended after a DITP diagnosis. Narrowing down the differential and selecting an effective antibiotic therapy in a timely manner is challenging. This case report demonstrates a life-threatening complication and highlights the importance of high clinical suspicion in formulating a diagnosis and management of unexplained thrombocytopaenia after starting ceftriaxone.
Case presentation
A 62-year-old woman with a history of end-stage renal disease on haemodialysis, essential hypertension and type 2 diabetes mellitus presented to our hospital with fever. She was tachycardiac, and her labs were significant for leucocytosis and lactic acidosis. She was diagnosed with sepsis and started on linezolid 600 mg oral every 12 hours and 1 g ceftriaxone intravenous every 24 hours due to her history of infection with vancomycin-resistant enterococci. Her transoesophageal echocardiogram was negative for endocarditis. Urine cultures grew pansensitive Escherichia coli and Klebsiella pneumoniae; blood cultures grew Streptococcus dysgalactiae. She was switched to ceftriaxone 2 g intravenous every 24 hours and discharged on day 8 of antibiotic therapy with a plan to continue them for a total of 2 weeks.
On day 10, during routine follow-up, she was noted to have a platelet count of 34 K/µL which further dropped to 5 K/µL by day 12 (figure 1). As a result, she was readmitted to the hospital, and ceftriaxone was discontinued the same day. Vital signs on admission were unremarkable (table 1). No external bleeding, confusion or petechiae were present. Her haemoglobin and WCC were unchanged with initiation and discontinuation of ceftriaxone (table 2, figure 2).
Vital signs on admission to our facility
| Vital signs | |
| Temperature: 37.3°C | Blood Pressure: 149/80 mm Hg |
| Pulse: 85 beats per minute | Respiratory rate: 16 per minute |
| Percent oxygen saturation (SpO2): 99% on room air | Weight: 110 kg (242 lbs) |
Lab work on admission to our facility
| Patient’s value | D1 | D8 | D10 | D12 | D13 | D16 | Reference ranges |
| WBC | 12.7 | 6.5 | 4.7 | 6.1 | 5.3 | 5.7 | 4.0–11.0 x 109/L |
| Haemoglobin | 111 | 95 | 93 | 100.0 | 93 | 99 | 11.5–15.8 g/L |
| Platelet count | 143 | 108 | 34 | 5 | 13 | 108 | 140–400 x 109/L |
| Total bilirubin | 0.5 | 0.5 | 0.5 | 0.2–1.2 mg/dL | |||
| Creatinine | 5.30 | 3.83 | 3.85 | 2.01 | 2.88 | 2.76 | 0.60–1.10 mg/dL |
| AST | 21 | 20 | 19 | 0–35 U/L | |||
| ALT | 19 | 30 | 29 | 26 | 0–55 U/L | ||
| Alkaline phosphatase | 145 | 124 | 116 | 30–150 U/L |
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The values in red indicate results outside of the corresponding reference range. The empty boxes indicate days when labs were not drawn.
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; D1, Day 1, etc; WCC, white cell count.
Trend of platelet count during hospital course highlighting causal relationship with the initiation and discontinuation of ceftriaxone.
Haemoglobin levels and WBC remained relatively stable despite initiation and discontinuation of ceftriaxone. WBC, white blood cell count.
Investigations
Infectious disease and haematology were consulted for concerns of DITP secondary to ceftriaxone. Out of the three cell lines, only her platelet count was suppressed.
Differential diagnosis
Given the heparin exposure with the antibiotics, heparin PF4 antibody was measured to be elevated at 0.599 (reference range ≤0.399). However, SRA was negative and HIT was ruled out.
Treatment
Ceftriaxone was discontinued on arrival and the patient was given vancomycin during the hospital stay per infectious disease recommendation. Her platelets improved to 108 K/µL by day 21. Given the clinical presentation and temporal relationship of thrombocytopaenia in the setting of ceftriaxone without any other identifiable etiologies, a diagnosis of DITP was made.
Outcome and follow-up
She completed the remainder of her antibiotic course with vancomycin during her hospital stay and was discharged. No more thrombocytopaenia was noted on subsequent clinic follow-up.
Discussion
DITP is a rare but potentially life-threatening complication, and therefore, an early and correct diagnosis is crucial. Thrombocytopaenia typically results from one of four aetiologies: pseudothrombocytopaenia, platelet underproduction, peripheral destruction and splenic sequestration.3 Peripheral destruction can occur due to disseminated intravascular coagulation, thrombotic thrombocytopaenic purpura, immune thrombocytopaenia and HIT.3
While penicillin, vancomycin and sulfonamides have been shown to trigger DITP, ceftriaxone-induced thrombocytopaenia is rarely mentioned.1 2 In addition, there is a scarcity of published data on cross-reactivity of ceftriaxone-induced thrombocytopaenia with other cephalosporins. Grossjohann et al showed how antibodies with an affinity for epitopes on platelets led to platelet destruction and subsequent thrombocytopaenia in two separate cases, but what remains to be revealed is how ceftriaxone triggered the production of such antibodies.4 An explanation may be the development of antiplatelet antibodies after the drug binds the platelet surface and triggers a conformation change which presents new epitopes on the platelet. Drug-dependent antibodies may target a variety of platelet antigens including surface glycoproteins such as (GP) Ib/V/IX or GP IIb/IIIa.5 Due to laboratory limitations at the healthcare facility, we were unable to test for the presence of ceftriaxone-dependent platelet reactive IgG antibodies. This remains as a limitation of the case.
The preferred treatment of streptococcus bacteraemia is intravenous penicillin G or a third-generation cephalosporin for 4–6 weeks.6 Our patient had a penicillin allergy, so ceftriaxone was used instead. However, in patients who develop ceftriaxone-induced thrombocytopaenia, ceftriaxone must be discontinued, and alternative antibiotic therapy must be considered such as cefotaxime, a different third-generation cephalosporin, or vancomycin, as was done with our patient. For severe bleeding, intravenous immunoglobulin can also be supplemented.3
Learning points
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Ceftriaxone is a third-generation cephalosporin antibiotic that can on rare occasions result in drug-induced thrombocytopaenia (DITP).
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Laboratory studies with decreased platelet count and stable haemoglobin and white cell count after starting ceftriaxone should raise suspicion for cases of DITP after ruling out heparin-induced thrombocytopaenia following heparin exposure.
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Timely discontinuation of ceftriaxone is the most important therapy, followed by subsequent administration of an appropriate antibiotic.
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High clinical suspicion in formulating a diagnosis and management of unexplained thrombocytopaenia after starting ceftriaxone is imperative.
Ethics statements
Patient consent for publication
Footnotes
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Contributors AS: preparation, analysis, drafting and review of manuscript; DM: conception and design, acquisition of data and review of manuscript. AM: analysis, drafting and and review of manuscript. AK: acquisition of data and review of manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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