Flucloxacillin-induced liver injury in elderly patient

Abstract

Flucloxacillin is a penicillin antibiotic used as first-line treatment for soft tissue infections caused by Staphylococcus aureus. It is used frequently in the elderly and is an established cause of cholestatic liver injury. Risk factors for cholestasis include prolonged duration of treatment, female sex and older age. Elderly patients are also more likely to suffer from comorbidities and polypharmacy, which increases the incidence of drug-induced liver injury and hospitalisation, which in turn can lead to irreversible deterioration in functional baseline. Our case report aims to raise awareness of flucloxacillin-induced liver injury in elderly patients and to encourage the use of alternative treatments and/or limited duration. We advocate for further research into individualised treatments and new diagnostic techniques in patients with painless jaundice based on their genotype.

Background

Jaundice (icterus) presents with varying degrees of yellowing of the skin and sclera and occurs when the serum bilirubin level exceeds 3 mg/dL. Bilirubin is formed from the breakdown of red blood cells, which releases haem. Haem is converted to biliverdin and then to unconjugated bilirubin, which binds to albumin for transport to the liver. Hepatocytes metabolise unconjugated bilirubin into water-soluble conjugated bilirubin, which is excreted into the bowels as stercobilinogen. Some conjugated bilirubin is reabsorbed from the intestines and excreted as urobilinogen in urine. Any disruption to this pathway can lead to an increase in either unconjugated or conjugated bilirubin at a prehepatic, intrahepatic or posthepatic level. Prehepatic causes (like haemolysis) lead to an increase in unconjugated bilirubin. Intrahepatic causes include viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, auto-immune disorders, intrahepatic mass lesions (hepatocellular carcinoma, metastasis), genetic diseases (Wilson’s disease and haemochromatosis) and drug-induced liver injury (DILI). These can lead to either a rise in conjugated bilirubin or an impairment of hepatocyte-induced conjugation causing increased levels of unconjugated bilirubin. Posthepatic causes include gallstones, cholangitis, pancreatitis and malignancy involving the bile ducts and pancreas; these causing an increase in levels of conjugated bilirubin. Acute jaundice in adults is mostly caused by intrahepatic disorders (55%) and extrahepatic disorders (45%).¹

DILI is defined by either alanine transaminase (ALT) ≥5× upper limit of normal (ULN), alkaline phosphatase (ALP) ≥2×  ULN or ALT ≥3×  ULN and bilirubin >2×  ULN. DILI can manifest with either a hepatocellular phenotype—where serum ALT and aspartate aminotransferase (AST) rise significantly, a cholestatic phenotype; associated with a significantly higher rise in serum ALP or a mixture of the above. The R value represents the ratio between (ALT/ULN) and (ALP/ULN), and it is used to determine the phenotype of DILI: either hepatocellular (R≥5), mixed (cholestatic hepatitis) (R >2 and<5) or pure cholestatic (R ≤ 2).² There are multiple potential mechanisms and the pathology is poorly understood. Proposed mechanisms for DILI include the release of hepatocyte-toxic metabolites from the breakdown of the drug and immune-mediated reactions where the reactive drug metabolite causes haptenisation and an immune cascade through T and B cells.³ Flucloxacillin is a penicillin antibiotic used as first-line treatment for soft tissue infections caused by Staphylococcus aureus.

Case presentation

A 91-year-old woman presented to the Emergency Department with painless, worsening jaundice for 5 days with associated pruritus, confusion and dark urine. She had no abdominal pain, nausea, anorexia, vomiting, weight loss or fevers and no relevant contact or travel history. She denied alcohol or illicit drug use. Her previous medical history included diabetes mellitus type 2, heart failure, chronic kidney disease, atrial fibrillation, Alzheimer’s dementia and hypertension. She had no history of gastrointestinal or autoimmune conditions. There was no significant family history or previous surgery. She sustained a fall 3 weeks prior, which resulted in pain in the lumbar region, which she took low dose cocodamol (paracetamol/codein) for. Six weeks prior to the onset of icterus, she was treated for bilateral lower leg cellulitis by her general practitioner (GP) with a 1-week course of oral flucloxacillin 500 mg four times a day. A further 5 days of oral flucloxacillin 500 mg four times a day was prescribed by her GP due to a poor clinical response.

On examination, the patient was jaundiced with excoriation marks visible on her arms and back. She was confused. Cardiovascular, respiratory and abdominal examinations were unremarkable. She had no organomegaly. Her vital signs were normal. Blood tests revealed amylase 12 U/L (28–100 u/L), gamma-glutamyl transferase (GGT) 831 IU/L (6–42 IU/L), bilirubin 240 μmol/L (0–21 μmol/L), ALP 1083 IU/L (35–104 IU/L) and ALT 116 IU/L (0–33 IU/L), International Normalised Ratio 1.5 (0.8–1.3) and partial thromboplastin time (PTT) 28.8 s (25–38 s), haemoglobin (Hb) 112 g/L (115–165 g/L), albumin 33 g/L (35–50 g/L). Inflammatory markers were within normal range. The significantly higher increase in ALP, with raised GGT and calculated R value of 0.34, indicated a pure cholestatic phenotype. Given the patient’s age and painless jaundice, a malignancy of the pancreas or bile ducts needed exclusion. An abdominal CT scan was carried out, which revealed a normal appearance of the pancreas with smooth outline of the liver and no intra or extrahepatic duct dilatation. The gallbladder was found to be thin-walled with subtle pericholecystic fluid. A subsequent magnetic resonance cholangiopancreatography (MRCP) did not reveal any abnormality. Hepatitis serology confirmed previous exposure to cytomegalovirus (CMV) and Ebstein-Barr virus (EBV) but no current infection. An autoimmune screen was negative for antineutrophilic antibody, anti-smooth muscle antibody, liver kidney microsomal antibody and anti-mitochondrial antibodies. A diagnosis of flucloxacillin-induced DILI was made.

The patient was managed conservatively by monitoring levels of ALP, bilirubin, ALT, liver synthetic function; and electrolytes were replacement as required. A multidisciplinary approach to optimise nutrition and functional ability was adopted. Cholestyramine was ineffective in alleviating the patient’s severe pruritus. Naltrexone—an opioid antagonist—proved much more effective in alleviating the pruritis by blocking the effect of increased endogenous opioid levels.

Outcome and follow-up

The patient’s liver function settled slowly over the next 4 weeks with a significant improvement in the pruritus and oral intake.

Discussion

The incidence of flucloxacillin-induced liver injury in the UK is estimated at 8.5/100 000.⁴ Female sex, prolonged duration of treatment and older age are risk factors with up to a 14-fold increased risk in patients over the age of 70.⁵ The elderly also have the highest prescribing rates of flucloxacillin; while comorbidities and polypharmacy further compounds the risk of developing DILI and subsequent hospitalisation.⁶ A very high proportion of the elderly will have significant functional decline and worsening frailty following a hospital admission with increased dependency, depression and anxiety.^{7 8} Using alternatives and appropriately limiting the prescribing duration of treatment with flucloxacillin in the elderly may, therefore, have merit.

Certain genotypes increase the risk of DILI with flucloxacillin, with human leukocyte antigen genotype (HLA)-B*5701 being associated with an 80-fold increased risk in developing DILI.⁹ In patients with genotype HLA-B*5701, only 0.2%–0.4% will develop DILI when treated with flucloxacillin and genetic mapping to identify these individuals is, therefore, not currently deemed cost-effective. Research and innovation in the field of genetics may in future prioritise personalised prescriptions in higher risk groups through the identification and testing of patients with clinical risk factors for DILI.¹⁰ This may also reduce unnecessary investigations for elderly patients presenting with painless jaundice. Our case report aims to increase awareness of the risks associated with flucloxacillin in the elderly. We advocate for a limited treatment duration and/or alternative treatments and encourage research in the field of personalised prescriptions in high-risk patient groups.

Learning points.

• Flucloxacillin is commonly used in the elderly.

• Female sex, patients over the age of 70 and prolonged treatment duration with flucloxacillin have been found to increase the risk of developing drug-induced liver injury (DILI).

• DILI can manifest with either a hepatocellular phenotype, a cholestatic phenotype of liver injury, or a mix between the two and can occur between 1 and 45 days from the start of treatment.

• Elderly patients with DILI are likely to require hospitalisation which can lead to an irreversible deterioration in baseline functional status and worsening frailty.