Highlights•

CRO administration can cause encephalopathy due to high blood levels of CRO

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The CRO concentration in blood at the onset of encephalopathy was about 60 μg/mL

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The patient's pharmacokinetic parameters differed from those of healthy adults

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Patients’ renal function or the use of diuretics may affect the blood level of CRO

Abstract

Ceftriaxone (CRO) is a long-acting third-generation cephalosporin antibiotic. We present a case of CRO-induced encephalopathy in an 84-year-old male patient with a solitary right kidney, admitted with bilateral pneumonia and right pyelonephritis. Intravenous CRO (2 g, every 24 hr) was started for the infection, but tonic-clonic seizures of the left face and left upper extremity appeared on the 8th day. To examine the relationship between CRO administration and the seizures, we measured CRO concentrations in the patients' plasma/serum and cerebrospinal fluid (CSF). The CRO concentration in blood at the onset of encephalopathy was estimated to have been approximately 60 μg/mL based on a simulation curve. We also calculated the pharmacokinetic parameters after CRO administration. The patient had about one-tenth of the total body clearance and one-third of the volume of distribution compared with healthy adults, and the elimination half-life was about 3 times longer.

KeywordsAbbreviations: CRO (Ceftriaxone), CSF (Cerebrospinal fluid)

Introduction

Ceftriaxone (CRO) is a long-acting third-generation cephalosporin antibiotic that can be administered once daily (Lamb et al., 2002). CRO is excreted in both urine and bile, while most other cephalosporins are excreted mainly in urine as the unchanged drug (Brogard et al., 1978; Brogard et al., 1982; Balant et al., 1985). However, cephalosporins can cause adverse effects on the central nervous system (CNS), called cephalosporin-related encephalopathy, in patients with renal dysfunction (Bhattacharyya et al., 2016).

With regard to CRO, there are some reports describing the drug concentration in blood or cerebrospinal fluid (CSF) at the time of the drug-induced encephalopathy (Suzuki et al., 2019; Yokoyama et al., 2020; Inoue et al., 2017; Jadot et al., 2021). However, the kinetic parameters of CRO in patients with drug-induced encephalopathy have not been reported. To clarify the threshold CRO concentrations in blood and CSF for inducing encephalopathy, further cases will need to be accumulated.

Here, we present a case of encephalopathy in a patient with a solitary kidney who was treated with CRO for pneumonia and pyelonephritis. Our findings shed light on the relationship between CRO pharmacokinetics and the development of encephalopathy.

Results

This 84-year-old male patient (height: 174 cm, weight: 89 kg) with a solitary right kidney was admitted with bilateral pneumonia, right pyelonephritis, and congestive heart failure. The patient's medical history included hypertension and diabetes mellitus. On the day of admission, antibiotic therapy with intravenous CRO (2 g, every 24 hr) was started for the infection. Because of the elevation of C-reactive protein (CRP) despite the administration of CRO (Table S1), the patient's physician discontinued the administration of CRO after day 8. In the evening of the same day, disturbance of consciousness started to be observed, and at 23:00, tonic-clonic seizures of the left face and left upper extremity occurred. The patient had no previous history of CNS lesions and was therefore admitted to the intensive care unit. The seizure disappeared quickly after the administration of propofol at about 3:30 on day 9. Head computed tomography and head magnetic resonance imaging, performed on day 9, showed no intracranial organic lesions. There were no abnormalities in the electrolytes, but mild hepatic dysfunction was observed (Table S1). The daily medication history of the patient was tamsulosin 0.2 mg, nifedipine 20 mg, rebamipide 200 mg, cilnidipine 20 mg, carvedilol 10 mg, methyldopa 500 mg, telmisartan 40 mg, furosemide 20 mg. Nifedipine and furosemide had been started within 2 days before the onset of seizures. Azosemide 30 mg and rivaroxaban 10 mg per day had been discontinued within 2 days before the onset of convulsions. Since the laboratory findings or imaging examinations did not reveal the cause of the disturbance in consciousness, we suspected an elevated CRO concentration in the patient's blood.

To examine the relationship between CRO administration and the seizures, we measured CRO concentrations in the patients' plasma/serum and CSF (Fig. 1). CRO concentrations in the plasma and CSF samples on day 14 were below the lower limit of quantification (LLOQ, 0.78 μg/mL). Simulation of the patient's blood CRO concentration curve based on the measurement results suggested that the CRO concentration would have reached a maximum on days 4 to 7 and decreased rapidly after discontinuation of CRO. The calculated pharmacokinetic parameters after CRO administration are shown in Table S3. The patient had about one-tenth of the total body clearance and one-third of the volume of distribution compared with healthy adults (Pollock et al., 1982), and the elimination half-life of CRO was about 3 times longer.

Fig. 1Concentration-time profile of CRO in the patient.

Show full caption

Plots of CRO concentrations in serum/plasma and CSF are shown on linear (a) and semi-log (b) scales. Kinetic data were analyzed as described in Supplemental materials and methods.

CRO, Ceftriaxone; CSF, cerebrospinal fluid; LLOQ, lower limit of quantification.

Discussion and conclusions

In the present case, the encephalopathy appeared to have been caused by the administration of CRO to a patient with a solitary kidney. The patient had no history of CNS lesions and no abnormalities were noted in the laboratory findings or imaging examinations. The patient's blood CRO trough level prior to discontinuation of CRO was approximately 90 μg/mL, which is about 6 times higher than the trough level seen in healthy adults receiving CRO (2 g, every 24 hr) (Pollock et al., 1982). In general, the blood concentration of a drug is determined by the dose, dosage interval, total body clearance, and distribution volume. In this case, the total body clearance and distribution volume were decreased compared with those of healthy adults, and these factors are thought to have contributed to the increase in blood CRO concentration. About 45–60% of administered CRO is excreted in urine as the unchanged drug, and the rest is excreted in bile and feces (Lamb et al., 2002). The decreased total body clearance observed in the patient could be attributed to the combination of a low urinary excretion rate of CRO in this patient with a solitary kidney and decreased bile excretion of CRO due to hepatic dysfunction. Since the serum creatinine (Scr) and urea nitrogen (UN) levels before the seizure were higher than after the event, the decreased distribution volume in the patient may have been due to dehydration caused by the diuretics (azosemide or furosemide) that were administered concomitantly with CRO. Generally, CRO dose adjustment is not required in patients with impaired renal function (Lamb et al., 2002), but hepatic dysfunction in combination with a solitary kidney or the concomitant use of diuretics may synergistically increase the blood level of CRO. Indeed, there have been reports of encephalopathy in patients receiving both diuretics and cephalosporins (Plensa et al., 2004; Pingue et al., 2021).

The mechanism of β-lactam antibiotics-induced encephalopathy is less clear, but may involve suppression of inhibitory neurotransmission associated with inhibition of GABAA receptors (Deshayes et al., 2017). In previous reports of CRO-induced encephalopathy, CRO concentrations in blood (110 μg/mL (Suzuki et al., 2019), 450 μg/mL (Yokoyama et al., 2019), 422, 472 μg/mL (Inoue et al., 2017)) and CSF (10.2 μg/mL (Suzuki et al., 2019), 27.9 μg/mL (Jadot et al., 2021)) were measured at the time of encephalopathy. In addition, a survey of CNS adverse drug reactions reports for cephalosporins found that the median plasma CRO concentration at the time of CRO-induced CNS adverse drug reactions was 81.4 μg/mL (Lacroix et al., 2019). The CRO concentration in blood at the onset of encephalopathy in our patient was predicted to have been approximately 60 μg/mL based on the simulation curve. Since the concentration ratio of CRO in CSF and serum on day 9 in this patient was 1:10, the CRO concentration in CSF at the time of the event is considered to have been approximately 6 μg/mL. Thus, the present encephalopathy occurred at a lower CRO concentration than in previous reports of CRO-induced encephalopathy, and the administration of diuretics might have contributed to this. Considering that renal function improved over time as the disease improved, CRO concentrations in the early treatment period may have been higher than indicated by the simulation curve, and this may also have contributed to the development of the encephalopathy.

To our knowledge, this is the first report to describe the kinetic parameters of CRO in a patient with CRO-induced encephalopathy. CRO is a widely used antimicrobial agent, and our results suggest that measurement of the drug blood level might be helpful for predicting the possibility of adverse CNS effects.

Author contributions

YF designed the study, collected and analyzed data, and wrote the first draft of the manuscript.

YI, JN, AF, TS MY, YT, MK and TT designed the study, collected and analyzed data, and contributed to the writing of the manuscript. TS and YS supervised the project and contributed to the writing of the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Conflict of interest

The authors have no conflicts of interest to declare.

Funding Source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval

Not required.

Acknowledgments

We would like to thank W R S Steele for English language editing.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

References

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Accepted: July 11, 2022

Received in revised form: July 8, 2022

Received: May 26, 2022

Publication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.ijid.2022.07.036

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© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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