Mixed hepatocellular-cholestatic liver injury from cefepime: A case report

Abstract

BACKGROUND

Cefepime is a fourth-generation cephalosporin antibiotic widely used to treat a variety of serious bacterial infections, including febrile neutropenia, pneumonia, complicated intra-abdominal infections, urinary tract infections, and skin infections. It possesses broad-spectrum action against both gram-positive and gram-negative bacteria, with favorable pharmacokinetics and clinical efficacy, making it a cornerstone in the management of infections, especially in the hospital setting, where resistant organisms are prevalent. Well-known adverse effects include local reactions, gastrointestinal symptoms, and neurologic complications. However, instances of liver injury are rare.

CASE SUMMARY

We report the case of a 73-year-old male who presented to the emergency department (ED) with a 1-week history of productive cough, shortness of breath, and fatigue. Laboratory findings in the ED included leukocytosis, hyponatremia, and elevated procalcitonin. Computed tomography chest without contrast showed a new right-sided pleural effusion and worsening consolidative opacities in both lungs. He was admitted and started vancomycin and cefepime for infected bronchiectasis. Liver function tests subsequently worsened and improved with the discontinuation of cefepime. The patient ultimately died from acute hypoxic respiratory failure two weeks after hospitalization.

CONCLUSION

This case report highlights a rare adverse effect of a commonly used antimicrobial in the hospital setting for various bacterial infections. Prompt cessation of the medication is the primary treatment in cefepime-induced liver injury, and most cases resolve without complications.

Key Words: Drug-induced liver injury; Cefepime; Hepatitis; Inflammation; Transaminitis; Cephalosporins; Case report

Core Tip: Cefepime is a fourth-generation cephalosporin commonly used to treat various bacterial infections. It is safe and generally well-tolerated. While frequently associated with adverse effects such as neurotoxicity and nephrotoxicity, cases of hepatotoxicity are rare. Prompt cessation of the medication is the primary approach in management.

INTRODUCTION

Drug-induced liver injury (DILI) commonly occurs in the hospital setting with several classes of medication. The approximate annual incidence of DILI in the general public is 15-20 per 100000 in the United States and globally[1,2]. However, because it is frequently underreported, it is challenging to verify its true incidence. Over 25% of DILI cases are caused by antibiotic-associated liver injury, which is the most common cause of acute liver failure in the United States[3,4]. Cephalosporins account for about 1% of DILI cases in prospective trials, despite the fact that they are often well-tolerated and linked to few adverse drug responses[5,6]. Hospital settings employ cefepime, a fourth-generation cephalosporin with broad-spectrum antibiotic coverage, for a number of bacterial illnesses, such as intra-abdominal infections, pneumonias, urinary tract infections, and febrile neutropenia[7]. Although commonly associated with neurotoxicity and nephrotoxicity, it is rarely linked to liver injury[7,8]. In fact, cefepime-induced liver toxicity is a rare adverse reaction to the drug that is infrequently seen by providers. A literature review unmasked only five reported cases of cefepime-induced liver injury, including a prospective study, a retrospective study, and three case reports[9-12]. We present a rare case of cefepime-induced liver injury that resolved with medication cessation. Prompt recognition of this adverse drug reaction can prevent fulminant liver failure and the development of chronic liver disease.

CASE PRESENTATION

Chief complaints

Cough, shortness of breath, and fatigue.

History of present illness

A 73-year-old male arrived to the emergency department (ED) due to a 1-week history of shortness of breath, cough with greenish sputum, and worsening fatigue. The patient was seen by his pulmonologist for a routine visit, who subsequently recommended ED evaluation for his symptoms. On arrival to the ED, vital signs were within normal limits.

History of past illness

His medical history included hypothyroidism, gastroesophageal reflux disease, paroxysmal atrial fibrillation, atopic dermatitis, benign prostatic hyperplasia, and bronchiectasis.

Personal and family history

No personal or family history.

Physical examination

Physical examination revealed an ill-appearing, cachectic man in mild distress who responded to questions adequately. S1 and S2 heart sounds were present with normal rate and rhythm. Lung auscultation revealed coarse referred airway sounds throughout the bilateral lung fields, more greatly appreciated on the right. The abdomen was soft and non-tender to palpation, and extremities were symmetric without edema.

Laboratory examinations

Laboratory tests in the ED revealed leukocytosis (white blood cells 11.9/mm³), hypoglycemia (72), hyponatremia (129 mmol/L), hyperbilirubinemia (1.8 mg/dL), and elevated procalcitonin (1.395 ng/mL). All other values, such as coagulation profile, blood gas, creatinine clearance, and liver function tests (LFTs) [aspartate aminotransferase (AST) 45 U/L and alanine aminotransferase (ALT) 24 U/L] were within normal limits. A respiratory pathogen panel detected rhinovirus and methicillin-resistant Staphylococcus aureus were present in the nares. Blood cultures were negative. Sputum culture drawn ultimately revealed Staphylococcus aureus and Pseudomonas aeruginosa. Liver enzymes (Figure 1) subsequently worsened over the following days after initiation of cefepime for infected bronchiectasis.

Figure 1 Line graph showing liver enzyme trend following the initiation and cessation of cefepime. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase.

Imaging examinations

A computed tomography scan of the chest without contrast was done on arrival, which showed new and worsening consolidative opacities in both lungs, extensive airway thickening with numerous occluded bronchi, and a new right-sided pleural effusion (Figure 2). A right upper quadrant ultrasound was done on the following day due to worsening LFTs, which showed nonspecific hepatitis.

Figure 2 Computed tomography of the abdomen and pelvis without contrast showing new and worsening consolidative opacities in both lungs, which include a consolidative opacity in the right hilum that appears to be enlarging and a new mass-like consolidative opacity in the right lower lobe. A: Axial lung window showing consolidative opacities, more notable on the right; B: Axial lung window showing a right lower lobe lung mass; C: Axial view showing consolidative opacities in the left lung; D: Coronary view showing consolidative opacities, predominantly in the left lung. Additionally, there is a new right-sided pleural effusion and extensive airway thickening with numerous occluded bronchi.

FINAL DIAGNOSIS

Cefepime-induced mixed hepatocellular-cholestatic liver injury.

TREATMENT

The patient was hospitalized, where he was initiated on vancomycin and cefepime for infected bronchiectasis. AST and ALT were elevated the following day and continued to worsen, prompting cessation of cefepime and a transition to piperacillin-tazobactam for continued management. Vancomycin was continued.

OUTCOME AND FOLLOW-UP

LFTs ultimately trended to baseline normal values within 11 days after cefepime cessation. He ultimately died from acute hypoxic respiratory failure two weeks after admission.

DISCUSSION

Cefepime, an antibiotic wide-spectrum antibacterial activity, is considered safe with few side effects[1-4]. Although the medication has been linked to incidences of nephrotoxicity and neurotoxicity, DILI is uncommon[9,10]. A precise diagnosis of DILI necessitates a thorough review, including detailed laboratory and history data. This procedure includes noting the date of symptom development, measuring the pace of resolution following medication discontinuation, comparing clinical features to documented patterns associated with the culprit drug, and ruling out other potential causes of liver damage. Acute viral hepatitis should always be considered as a differential diagnosis and should be ruled out with serological hepatitis A, B, C, and E testing[13]. Ischemia and viral illnesses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), should also be tested for and excluded as possible causes. Based on the R value, which uses the ratio of serum ALT to alkaline phosphatase (ALP), DILI can be categorized as hepatocellular, cholestatic, or mixed[9-12,14]. In this case, the R value was 2.2 (257/114) with elevated serum ALP indicating a mixed pattern of hepatic injury. There have been previously documented cases of acute hepatotoxicity following cefepime therapy, including Liao et al[9], who reported on a similar scenario in which liver enzymes normalized within a few days.

Our patient in this case developed hepatic injury as noted above within 24 hours of starting cefepime therapy (2 g every 8 hours). The causal relationship between cefepime and DILI was assessed using the Naranjo adverse drug reaction probability scale[15,16]. This accountability scale encompasses various criteria, including the time link between drug exposure and the onset of liver damage, the progression of liver enzymes after discontinuation of the drug, prior case documentation of DILI, concurrent medications, and other potential causes that might have led to the reaction. In our case, the Naranjo score (Table 1) was 7 on a scale of 0 to 12, with a score of ≥ 9 indicating that the drug was the likely cause of the reaction. The score of 7 correlated with the probable category. Some questions on the probability scale, such as “Was the drug detected in any body fluid in toxic concentrations”? were not feasible to answer, which partially accounted for the observed lower score. Other causes of liver injury were ruled out. Testing for hepatitis A, B, and C with a hepatitis panel was negative. Additional serological testing included EBV, CMV, anti-smooth muscle, and anti-liver-kidney microsomal-1 antibodies, all of which were negative. Other drugs as a culprit of liver injury were also ruled out, as the patient was not taking any medications that are commonly associated with liver injury. Vancomycin, which can occasionally cause hepatoxicity, was continued despite the cessation of cefepime, ruling it out as a confounding factor. Transaminitis ultimately improved with cessation of drug therapy, and LFTs went back to baseline.

Table 1 Naranjo adverse drug reaction probability scale for the patient.

Question	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did the adverse event appear after the suspected drug was administered?	+2	-1	0	+2
Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?	+1	0	0	+1
Did the adverse reaction reappear when the drug was readministered?	+2	-1	0	0
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	-1	+2	0	+2
Did the reaction reappear when a placebo was given?	-1	+1	0	0
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score				7

Cefepime-induced liver injury is rare but commonly presents as cholestatic or mixed hepatocellular-cholestatic hepatitis, often resembling an immune-mediated reaction with rash, eosinophilia, and fever, though the precise mechanism of liver injury isn’t fully understood. It is likely due to an idiosyncratic event in which the drug molecule or its metabolites trigger an immune-mediated cascade that damages hepatocytes, leading to inflammation and bile flow obstruction[17]. While there is no universal treatment protocol, the primary approach typically involves cessation of the medication and providing supportive care. The patient ultimately died from respiratory failure during the admission, which was unrelated to his liver injury.

CONCLUSION

In summary, our case illustrates a rare but true hepatotoxicity associated with cefepime therapy. Although cefepime is usually well-tolerated, it can lead to DILI especially in older patients with comorbid conditions. This article underscores the importance of careful monitoring of liver enzymes in patients receiving cefepime therapy. Worsening LFTs typically occur prior to symptoms and prompt cessation of therapy is important in preventing the development of fulminant liver failure and chronic liver disease. Clinicians should be aware of this rare adverse effect and intervene with medication cessation when necessary.