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Abstract
A man in his late 70s, retired and independent, generally fit and well with a history of normal cognitive function baseline presented with liver abscess and acute kidney injury. He received meropenem 1 g three times a day for 15 days then subsequently changed to ertapenem 1 g one time a day in preparation for outpatient antibiotic treatment. After 2 days of starting ertapenem, the patient developed night-time delirium, decreased orientation and insomnia, loss of appetite, jerking and hallucination. Investigations have been done to investigate the cause of acute delirium, including lumbar puncture, CT brain, MRI brain, repeat CT abdomen and pelvis to monitor the liver abscess, and electroencephalogram but results were all unremarkable. Medication history during admission was reviewed and discontinued one by one the medications that were suspected to have caused the encephalopathy. Two days following the discontinuation of ertapenem, the patient’s symptoms improved with a rapid return to his baseline and without neurological deficit.
- Respiratory system
- Infections
- Renal system
- Geriatric medicine
- Drugs: CNS (not psychiatric)
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Background
Carbapenem antibiotics are used in critically-ill patients in which other broad-spectrum antibiotics have been given but no favourable response.It is used for the treatment of complicated and serious bacterial infections caused by Gram-positive and Gram-negative organisms,especially extended-spectrum beta-lactamase (ESBL)-producing microorganisms. Neurotoxicity is its rare adverse reaction in patients who are elderly with comorbidities and/or existing neurological problems.1–3 The highest incidence of neurotoxicity among carbapenems is imipenem.2 4 5 A type of neurotoxicity is encephalopathy is a diffuse disease of the brain that alters brain function or structure. It is characterised by an altered mental state with additional symptoms including progressive loss of memory and cognitive ability, personality changes, myoclonus, nystagmus, tremor and seizures.6 In the world of literature, it is widely believed that the reason behind this phenomenon can be attributed to the similarity between the β-lactam ring and the structure of the ɣ-aminobutyric acid (GABA) neurotransmitter. As a result, these agents have the ability to counteract the GABA receptor. Chemically speaking, all carbapenems share a common organic heterocyclic compound known as (5R)−1-azabicyclo[3.2.0]hept-2-ene with a 7-keto substituent. However, it seems that the potential for neurotoxicity varies depending on the basicity of the C2 side chain. While imipenem contains the most basic substituent, specifically 2-(iminomethylamino)ethylthio, the C2 side chains of ertapenem ((3-carboxyphenyl)carbamoyl pyrrolidin-3-sulfanyl) and meropenem (dimethylcarbamoyl pyrrolidin-3-sulfanyl) are less basic. Consequently, imipenem-cilastatin exhibits a higher rate of neurotoxicity compared with other carbapenems. For ertapenem, neurotoxicity is a rare adverse event, especially in patients with advanced age, renal insufficiency, pre-existing neurological disease and hypoalbuminaemia. Epileptiform seizures (42.4%), visual hallucinations (36.4%), altered mental status (25.8%) and confusion (22.7%) were the most common symptoms of ertapenem-induced neurotoxicity.7 We report a patient with normal cognitive function admitted with a liver abscess and acute kidney injury who developed ertapenem-induced encephalopathy.
Case presentation
A man in his late 70s, retired and independent, generally fit and well with a history of normal cognitive function baseline. He presented in our A&E with a cough, shortness of breath, and a new oxygen requirement. A review of the system did not reveal any headache, abdominal pain, vomiting, diarrhoea and dysuria. Initial investigation in table 1 showed raised inflammatory markers and acute kidney injury. His chest radiograph showed right basal consolidation. He was treated for community-acquired pneumonia in the A&E. The patient initially had acute renal failure with an eGFR (Estimated glomerular filtration rate) of 32 mL/min/1.73 m2. He had a penicillin allergy; hence, he was started with teicoplanin 1 g with a loading dose every 12 hours for 3 doses then one time a day (penicillin allergy) and clarithromycin 500 mg two times a day as per hospital policy (see table 2). On day 3, the patient had deteriorated and developed into septic shock. A CT abdomen and pelvis revealed liver abscess within segments 7 and 8 (see figure 1). The antibiotics were escalated to meropenem 1 g three times a day with an eGFR of 38 mL/min/1.73 m2 while waiting for the rest of the investigation to exclude the cause of the liver abscess (see table 3) The dose of meropenem was further adjusted to renal dose to 1 g two times a day as eGFR still not improving at 39 mL/min/1.73 m2. His 2D echo revealed an ejection fraction between 50% and 55%, the aortic valve is tri-leaflet and there is mild focal calcification. A blood culture was sent but no growth. He was seen by endocrine for hyperthyroidism (see table 1) and was started on carbimazole 10 mg one time a day. On day 15, the patient was clinically improving and acute kidney injury improved with an eGFR of 58 mL/min/1.73 m2. Meropenem was subsequently switched to ertapenem 1 g one time a day as per microbiologist advice in preparation for outpatient antibiotic treatment (OPAT) to complete a total of 6 weeks duration (table 3). On the seventeenth hospital day, the patient started to experience night-time delirium, decrease orientation, insomnia, loss of appetite, jerking, as well as a hallucination. He has been placed on hospital non-pharmacological delirium precautions with the goal of maintaining his sleep-wake cycle. He was started on midodrine 2.5 mg three times a day for postural hypotension. Our mental health and liaison services (MHLS) input was noted, and the patient was placed on a delirium pathway. The patient received his first dose of haloperidol and lorazepam 12 days after ertapenem was started (see table 3).
Summary of the blood test results of our patient on admission
Medication history at hospital admission
CT abdomen and pelvis. Arrow (yellow) showing the liver abscess within segments 7 and 8.
Delirium investigations for our patient
After discontinuing ertapenem, we carefully assessed the patient’s condition, taking into account the persistent delirium, hallucinations and functional decline. As part of the treatment plan, we gradually discontinued medications such as midodrine, haloperidol and lorazepam, and eventually stopped administering antibiotics. Since the infection marker and liver abscess were nearly resolved, we made the decision to completely discontinue the use of ertapenem and refrain from initiating any other antibiotics. Surprisingly, just 2 days after discontinuing the antibiotic, the patient experienced a rapid recovery. To ensure appropriate management, we sought the advice of a microbiologist who recommended closely monitoring the patient due to normal blood test results and the resolution of the abscess as observed on the abdominal CT scan (see figure 2). Following this guidance, the patient underwent a follow-up appointment in the outpatient clinic and a repeat CT scan, which confirmed complete regression and resolution of the abscess. During this period, no new antibiotic was initiated after discontinuing ertapenem, except regular medication, felodpine, fludrocortisone and carbimazole.
CT scan of abdomen showing resolution of abscess.
No significant side effects were observed from any other medications, except for an episode of delirium. Prior to admission, the patient had been taking felodipine as their only reported medication and did not exhibit any cognitive impairment. On admission for a chest infection, the patient received teicoplanin and clarithromycin. However,2 days after starting this treatment, the patient developed septic shock and a liver abscess was identified on a CT scan. Consequently, the antibiotic regimen was switched to meropenem based on the CT report (see figure 1). To complete the remaining treatment, the decision was made to switch to ertapenem, which the patient could continue at home. During the course of treatment, no allergic reactions, anaphylaxis, or side effects like skin rash were observed. Additionally, the patient received a 3-day course of haloperidol and lorazepam, as mentioned previously.
Prior to the administration of haloperidol and lorazepam, the patient was already experiencing delirium. These medications were prescribed during the period when the lumbar puncture (LP) was performed. However, the administration of haloperidol for 3 days and subsequent discontinuation had no noticeable impact on the patient’s condition. Similarly, the discontinuation of lorazepam also did not yield any significant changes.
Ultimately, it was the discontinuation of ertapenem that resulted in a rapid recovery and the absence of further symptoms. This observation strongly suggests that ertapenem was the primary cause of the patient’s delirium.
Investigations
He had raised inflammatory markers and acute kidney injury with a creatinine of 153 umol/L, urea of 14.5 mmol/L and eGFR of 39 mL/min/1.73 m2. The other laboratory parameters on admission are tabulated in table 1.
Table 2 summarises the investigations done when the patient developed acute delirium. These investigations were tailored based on our differential diagnoses and advice from neurology.
Differential
Prior to admission, the patient had a stable baseline functioning and did not report any cognitive impairment. They were taking felodipine as their sole medication. During the delirium workup, we conducted a comprehensive assessment to explore various potential. Possible differential diagnoses for the cause of his delirium include meningoencephalitis, status epilepticus, infection-induced delirium, acute psychosis, insomnia-induced psychosis and other medication-induced psychosis. A repeat imaging was performed to rule out worsening of the liver abscess but CT abdomen showed further improvement of liver abscess.
This involved reviewing the patient’s medical history, conducting cognitive screenings and ordering laboratory tests to rule out underlying infections, metabolic imbalances. During this process, it was discovered that the patient had an overactive thyroid. The endocrine team provided guidance, and appropriate medication was initiated for the treatment of the thyroid condition. Unfortunately, despite this intervention, the patient did not show any improvement. We also considered the possibility of medication-related side effects. Despite thorough investigations, the exact cause of the delirium episode remained unclear. At the time of admission, the CRP level was 268 and the WBC count was 14, with inflammatory changes observed in the right chest on the X-ray. The patient required 2 L of supplemental oxygen. Two days later, the patient developed septic shock with a lactate level of 4.1. The CRP increased to 385, the WBC count rose to 16 and the eGFR dropped to 34. A CT scan revealed the presence of multiple liver abscesses.
The patient received treatment with meropenem for approximately 10 days, during which time the CRP levels gradually decreased from 384 to 13. Meropenem was then switched to ertapenem, with adjusted doses based on renal function. The eGFR gradually improved to above 60 before discharge. On days 16–17 after receiving ertapenem, the patient experienced a delirium episode characterised by restlessness, reaching for non-existent objects, and jerky movements.
To further investigate the situation, we sought input from mental health and neurology specialists. They recommended performing a LP, an electroencephalogram, and a series of blood tests, MRI brain. However, all results came back within the normal range. Eventually, it was decided to discontinue ertapenem based on repeat CT scans showing almost resolution of the liver abscess (see figure 2), as well as improved CRP levels (9) and WBC count (5.4), with an eGFR above 60. Two days after discontinuing ertapenem, the patient rapidly improved with no further hallucinations or jerky movements. It strongly suggested that ertapenem was the primary cause of the encephalopathy.
Consultation with a microbiologist at the local hospital advised holding off further antibiotics and closely monitoring the patient for any signs of infection deterioration. Fortunately, the patient remained well and was discharged home. At this point, we focused on reviewing the patient’s medication regimen to determine if any of the prescribed drugs could be causing the delirium. In an effort to identify the root cause of the delirium, we decided to gradually discontinue the recently added medications one by one. This included haloperidol, lorazepam, midodrine and eventually ertapenem. Notably, the patient experienced a rapid recovery following the discontinuation of ertapenem, which strongly suggests that it was the cause of the delirium in this case.
Treatment
The patient presented initially with a working diagnosis of pneumonia but further deterioration leads to the diagnosis of severe sepsis secondary to liver abscess. He was given a broad-spectrum antibiotic in the family of carbapenem. He was started on meropenem 1 g three times a day then switch to ertapenem 1 g one time a day as per microbiologist advice in preparation for OPAT to complete a total of 6 weeks duration on day 16. When the patient developed acute delirium, medical treatment commenced including haloperidol 0.5 mg three times a day and lorazepam 0.5 mg one time a day after advice from our MHLS. The patient was also found to have hyperthyroidism, hence, started on carbimazole 10 mg one time a day. Midodrine 2.5 mg three times a day was started after he developed postural hypotension. Following a tailored investigation for delirium and all results return to normal, we have concluded that the cause for the patient’s delirium is due to medications. All medications were carefully considered and stopped one by one until arriving in the conclusion that the offending drug is ertapenem. Table 3 summarises all the medications given on admission.
Outcome and follow-up
Following discharge from the hospital after being diagnosed with ertapenem-induced encephalopathy, the patient returned home and remained well. There were no further signs of insomnia, hallucination, or agitation observed during the patient’s recovery. The patient underwent a reconditioning process to aid in their recovery from ertapenem-induced encephalopathy, which was encouraging to support the initial diagnosis. It is recommended that the patient continue to monitor their symptoms and attend all follow-up appointments to ensure a full recovery.
Despite conducting extensive investigations, including MRI head, ECHO and MRI spine, the exact cause of the liver abscess could not be determined. These diagnostic tests did not provide conclusive findings. However, during the patient’s admission, we observed that they were anaemic on admission. As a result, we sought input from the surgical team, who recommended a CT colon scan. The scan revealed the presence of rectal polyps, which were subsequently biopsied. The biopsy results revealed a diagnosis of colon cancer, providing insight into the potential cause of the liver abscess. Currently, the patient is receiving ongoing follow-up care from the surgical team.
Discussion
Our case report demonstrates a manifestation of ertapenem-induced encephalopathy who presented with night-time delirium, decreased orientation and insomnia, loss of appetite, jerking, and hallucination. The patient’s rapid improvement of symptoms on discontinuation of ertapenem is consistent with other case reports describing ertapenem neurotoxicity in renal dysfunction.1 2 8 We have excluded other drugs that could possibly cause the patient’s delirium by stopping it one by one with the observation of the patient’s resolution of symptoms. Supporting our diagnosis to estimate the probability of an adverse drug reaction to ertapenem, the patient’s Naranjo scale9 score was 7. Following strictly the points asked, we answered yes or no based on the clinical evidence available to us (see table 4).
Naranjo Adverse Drug Probability Scale
Ertapenem, a long-acting carbapenem, is highly protein bound with a mean half-life of 3.8–4.4 hours in a healthy individual.2 It is mainly excreted in kidneys (80%) with half unchanged and half as a beta-lactam open-ring metabolite and the remaining percentage is excreted via faeces.10 11 In our patient, the presence of acute kidney injury has precipitated the neurotoxicity of this drug. It can be explained as the half-life of ertapenem can be increased to 6.1–14.1 hours in the presence of renal impairment.10 12 13 Furthermore, the study of Mistry and colleagues showed that the estimated clearance of ertapenem via the non-renal routes was lower in patients with kidney dysfunction, as compared with the estimated clearance of ertapenem via the non-renal route in healthy young adults with normal kidney function.10 The risk factors for carbapenem neurotoxic adverse reactions include the basicity strength of the C-2 amino group for carbapenems, accumulation in the CNS, specifically in cases of excessive dosage or impaired renal clearance, and the patients with CNS disorders (eg, medical history of seizure disorder).14–16
In addition, ertapenem is highly protein bound (92%–95%), and data suggest that in critically ill patients with hypoalbuminaemia, ertapenem dosed according to current guidelines is associated with higher mortality than alternative carbapenems.17 The dose of ertapenem should therefore be guided by serum albumin concentrations, with dose intervals or continuous infusion considered with the aim of achieving optimal free drug concentrations in patients with severe hypoalbuminaemia. In a retrospective, observational, single-centred, cohort study of hospitalised patients done by Gavaghan et al, of the 146 subjects that were included, 73 patients had serum albumin levels of <2.5 g/dL during treatment with ertapenem. 30Thirty-day all-cause mortality was 19.7% for subjects with low albumin and 9.6% for subjects with normal albumin levels (p=0.09). Our study found that although not statistically significant, there is potentially a clinical significance between hypoalbuminaemia and our primary endpoint, 30-day all-cause mortality, with higher rates of mortality in the low albumin group and a 9.6% between group differences. The study data suggest that in subjects with hypoalbuminaemia, treatment with ertapenem dosed as a one time a day intravenous infusion may be associated with suboptimal clinical outcomes that may include an increased mortality, hospital readmission and length of stay.18
Case report published by Lin et al also described status epilepticus and delirium associated with ertapenem in a very elderly patient with chronic kidney disease and silent ischaemic cerebrovascular disease.1 They presented an 85-year-old woman with chronic kidney disease and newly acquired seizures on oral phenytoin who received intravenous ertapenem 500 mg one time a day for a urinary tract infection and bacteraemia involving ESBL-producing Escherichia coli. After three ertapenem doses, she developed seizures which self-aborted. Corrected phenytoin level was subtherapeutic initially, but became therapeutic following a phenytoin dose increase. The patient suffered another episode of seizure on day 14 of ertapenem. They eventually stopped ertapenem. On day 15, she developed status epilepticus lasting 2 days, requiring intravenous lorazepam, sodium valproate and phenytoin. The last episode of seizure occurred 3 days after discontinuation of ertapenem, with a dramatic recovery of her Glasgow Coma Scale and resolution of delirium.
Contrary to the above case report, our patient previously does not have previous cerebrovascular disease. However, characteristics of our patient that might have contributed to developing neurotoxicity include his age, low albumin with ongoing liver abscess and acute kidney injury as ertapenem is highly protein bound and its half-life is increased in ongoing renal dysfunction. It is also important to mention that the timing of neurotoxicity development, that is, 2 weeks after initiation of ertapenem, in our patient was almost similar to Lin et al patient.
Learning points
This case highlights the importance of considering adverse drug reactions as a potential cause of a patient’s deterioration. As healthcare professionals, we should always keep in mind the possibility of medication-related adverse effects, especially in elderly patients who are more vulnerable to such reactions. In this case, the patient’s symptoms were initially thought to be due to septic shock, and extensive investigations were conducted to identify the cause of the acute delirium. However, a medication review led to the identification of ertapenem as the culprit, and the discontinuation of the drug resulted in the patient’s rapid improvement.
The case also emphasises the need to carefully consider the risks and benefits of investigations, especially in elderly patients who may be more sensitive to the stress and discomfort associated with such procedures.
By avoiding unnecessary investigations, we can save valuable resources, reduce the burden on the healthcare system and improve patient outcomes by minimising the risk of complications and adverse events.
Therefore, this case provides a valuable lesson on the importance of considering medication-related adverse effects in the differential diagnosis of acute delirium and the need to balance the risks and benefits of investigations in elderly patients.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors SF: contributions to the case report were extensive and diverse, encompassing various essential aspects of the research and publication process. A played a vital role in providing direct patient care, leveraging my expertise in diagnosing and treating the patient. SF: accurate recognition of the diagnosis and appropriate care added significant value to the case report. Furthermore, I took the lead in meticulously collecting the necessary data for the study. Through my diligence and attention to detail, I ensured the completeness and accuracy of the collected data, thereby enhancing the reliability of the findings. Additionally, I conducted a comprehensive comparative analysis by thoroughly examining other relevant cases and existing research. This comparative approach allowed for a comprehensive understanding of the case and provided valuable insights into its unique aspects. Moreover, SF, actively engaged with the patient’s family by initiating contact and obtaining their perspectives and insights into the case. This patient-centered approach enriched the report by incorporating personal experiences and viewpoints of those directly affected. In terms of ethics, SF, took responsibility for addressing the ethical implications of the research findings. My consideration of the ethical aspects demonstrated a firm commitment to upholding ethical standards and protecting patient confidentiality. Moreover, I obtained consent from the patient and their family for publication. Overall, SF, contributions as the main author encompassed patient care, accurate diagnosis recognition, meticulous data collection, comprehensive comparative analysis, substantive manuscript drafting and revision, incorporation of patient perspectives and ethical considerations. Through my multidimensional involvement, I played a pivotal role in the successful completion and acceptance of the case report, showcasing my expertise and dedication in advancing medical knowledge. AA, substantively, made significant contributions to the drafting and revision of the manuscript. By paying meticulous attention to detail, maintaining scientific rigour, and employing clear communication, I enhanced the clarity and readability of the manuscript, readying it for publication. AA, as the second author, made invaluable contributions to this project. Firstly, AA played a crucial role in formatting the publication. Their attention to detail and expertise in publication guidelines ensured that the case report adhered to the required format. Additionally, AA actively participated in the daily ward rounds, providing valuable insights and assistance in managing the patient. Furthermore, AA’s assistance in finding different articles for the comparative study was instrumental. Their ability to identify and access relevant literature enriched the research findings and provided a broader context for the case report. Overall, AA’s contributions have made a significant difference in the publication of this case report.
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.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.