Piperacillin/tazobactam-induced coagulopathy in a patient through a vitamin K-dependent mechanism

Abstract

Haematologic side effects associated with piperacillin/tazobactam (PTZ) treatment are rare but can be fatal. The exact mechanism by which PTZ causes haemorrhages has not been determined. We report the case of a patient who received PTZ treatment and developed a coagulopathy through a vitamin K-dependent mechanism. A 70-year-old female patient was admitted to the intensive care unit because she had a severe case of pneumonia and a pulmonary thromboembolism. Empirical antibiotic treatment using PTZ was started. Her international normalised ratio (INR) was already increased and became elevated again when PTZ was restarted. Her coagulopathy was reversed by supplementation with vitamin K. We conclude that PTZ can induce coagulopathy through a vitamin K-dependent mechanism and, to our knowledge, this is the first case report to suggest that mechanism. We suggest that patients at risk for a vitamin K deficiency should be monitored for coagulopathy when piperacillin or any other board spectrum antibiotic is administered.

Background

Piperacillin/tazobactam (PTZ) is a commonly used antibiotic combination for the empirical treatment of pneumonia and other infections.¹ Haematologic side effects associated with PTZ treatment, including intracranial haemorrhage, are rare but can be fatal.² The exact mechanism by which PTZ causes haemorrhages has not been determined. We report herein the case of a patient who received PTZ treatment and developed a coagulopathy through a vitamin K-dependent mechanism.

Case presentation

A 70-year-old female patient was admitted to the intensive care unit (ICU) because she had severe pneumonia and a pulmonary thromboembolism. The patient had a history of ankylosing spondylitis for 2 years. She had not received any drugs long-term and had no smoking or drinking history. The patient was malnourished because of her age and a decreased appetite due to pneumonia. Her body mass index was 16.7 kg/m². Food and liquids were withheld from the patient because pulmonary aspiration might have resulted.

Investigation

This case reported on any adverse reaction, and this part is integrated in the ‘Outcome and follow-up’ section.

Treatment

Low molecular weight heparin was administered to the patient at a dose of 4100 units every 12 hours for 4 days before admission to the ICU. Empirical antibiotic treatment using PTZ was started on day 1 of her hospitalisation. Warfarin was also administered to prevent a new thromboembolic event.

Outcome and follow-up

On day 2, her international normalised ratio (INR), a measure of coagulation function, had increased to 4.0, at which time she no longer received warfarin but was infused with 300 mL of plasma. Her INR initially fell to 1.8 and then increased slowly over the next 3 days. We assessed whether any of the administered drugs affected her INR values and were able to exclude all except PTZ. The infection was controlled by day 4, and PTZ administration was then stopped to avoid the possibility that she might have a haemorrhage. Her INR value then dropped slowly even though warfarin administration was resumed on day 6. The patient had a recurrent infection on day 8, and PTZ was administered again. Her INR value also increased thereafter. On day 11, administration of PTZ was stopped and imipenem/cilastatin was given instead because the infection remained uncontrolled. The INR increased to 4 on day 12, at which time vitamin K was administered to prevent possible haemorrhagic events. The INR value dropped to 1.8 on day 13, at which time the patient voluntarily left the hospital. The drugs administered to the patient and her INR values during her period of hospitalisation are shown in figure 1. The Naranjo scale is a widely accepted and useful method of evaluating whether an adverse effect may be attributable to a drug in a single case. The adverse reaction was assigned to a probability category from the total score as follows: definite ≥9, probable 5 to 8, possible 1 to 4, doubtful ≤0. Pharmacists used the Naranjo score to assess whether the adverse effect the INR values of the patient could be attributed to PTZ. The final Naranjo score for PTZ was 6; however, the scores of the other drugs were all below 3, indicating a probable relationship of coagulopathy with the use of the suspect drug, PTZ.

Figure 1.

Timelines showing the international normalised ratio (INR) values of the patient and when specific drugs were administered during her hospitalisation. qd, once a day; qid, four times a day; q6h, every 6 hours; q8h, every 8 hours.

Discussion

It is well known that prolonged use of broad-spectrum antibiotics, such as piperacillin, can induce a coagulopathy.³ Hypotheses have been suggested to account for this effect: decreased vitamin K absorption owing to suppression of intestinal flora.⁴ Vitamin K₂ can be synthesised by intestinal flora, thereby providing a portion of the dietary requirement for vitamin K.⁵ Broad-spectrum antibiotic therapy suppresses intestinal flora and may, therefore, contribute to a vitamin K deficiency.⁶ In addition, vitamin K is a co-factor for several intracellular hepatic carboxylases and is necessary for the activation of coagulation factors Ⅱ, VII, IX and X and for prothrombin.

The platelet counts of our patient remained in the normal range, and her coagulopathy was reversed by supplementation with vitamin K. Although the main elimination route of PTZ is renal, it can also be excreted into the bile. In the case of our patient, the administered concentration of PTZ was high enough to suppress the intestinal flora that synthesises vitamin K. Given our experience with this patient, we concluded that PTZ can induce coagulopathy through a vitamin K-dependent mechanism.

To our knowledge, this is the first case report that suggests a mechanism for how PTZ induces a coagulopathy. Piperacillin-induced abnormalities of coagulation usually occur in patients with decreased absorption of vitamin K. Existing reports concerning this side effect involved patients with cystic fibrosis or those who experienced long-term use of piperacillin.⁷ Our patient presented with malnutrition and was fasted during her initial hospital stay; consequently, she would have been expected to store and absorb little vitamin K. We suggest that patients at risk for a vitamin K deficiency should be monitored for coagulopathy when piperacillin or any other broad spectrum antibiotic is administered.

Learning points.

• Piperacillin/tazobactam (PTZ) can induce coagulopathy through a vitamin K-dependent mechanism.

• Piperacillin-induced abnormalities of coagulation usually occur in patients with decreased absorption of vitamin K.

• Patients at risk for a vitamin K deficiency should be monitored for coagulopathy when piperacillin or any other broad spectrum antibiotic is administered.

Data availability statement

All data relevant to the study are included in the article.

Ethics statements

Patient consent for publication

Next of kin consent obtained.