Date of Award

Winter 1-1-2020

Document Type

Dissertation

Degree Name

PharmD

First Advisor

Dr. Kavitha Saravu

Abstract

Background: Cefepime is a fourth-generation cephalosporin with broad spectrum of activity. Cefepime continues as a major part of parenteral treatment for neutropenic fever and hospital-associated infections including pneumonia, urinary tract infections, skin and soft tissue infections, etc. The principle mechanism of Cefepime-induced neurotoxicity is via inhibition of GABA-A receptors or GABA release. Neurotoxic adverse drug reactions (ADRs) include unconsciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Risk factors of the ADRs include renal failure, over dosing, pre-existing brain injury, and elevated serum Cefepime levels.

Objectives: Primary objective is to determine incidence of neurotoxic ADRs related to the use Cefepime. Secondary objective is to determine the association of dose of Cefepime treatment and change in renal function with development of neurotoxic ADRs.

Methods: An hospital-based retrospective cohort study was conducted for eight months (August 2019 to March 2020), with a total of 738 patients, selected based on pre-determined inclusion and exclusion criteria. The patients were divided into two cohort groups: study cohort in which all the patients who received Cefepime and reference cohort, in which all the patients who received antibiotics other than Cefepime.

Results: Out of 496 patients who were treated with Cefepime, 53 (10.7%) patients developed ADRs. Similarly, out of 242 patients who were treated with other antibiotics, 12 (4.9%) patients developed ADRs. The age of the patients who developed ADRs with Cefepime were 55.9±17.2 (Mean±SD) and other antibiotics were (53.95±17.1). A significant association was seen between neurotoxicity ADRs and Cefepime use (X2=6.641; p=0.01). Cefepime has 2.29 times increased risk of developing the ADR than the other antibiotics (OR: 2.29; 95%CI: 1.2-4.38). Cefepime 2 grams three times daily is the most frequent dose that caused ADRs. Daily dose of Cefepime was 4.05±1.72 (Mean±SD) grams. Out of 53 ADR patients, 36 patients were having renal failure. Patients with renal failure have 5.5 times greater risk for developing ADRs with Cefepime compared to patient with normal renal function (OR: 5.5; 95% CI: 2.98 - 10.17). Male patients have 18% more likely to develop the neurotoxicity ADR than female patients after Cefepime use (OR: 1.18; 95%CI:0.66-2.1). The 65 neurological ADRs experienced by the patients on Cefepime were disorientation (38.5%), loss of consciousness (23.1%), drowsiness (18.5%), seizures (6.2%), semi-consciousness (6.2%), delirium (3.1%) and extrapyramidal (1.5%). Similarly, 13 neurological ADRs experienced by the patients on other antibiotics experienced were drowsiness (53.8%), disorientation (23.1%), loss of consciousness (7.7%), seizures (7.7%), delirium (7.7%). The calculated number needed to harm (NNH) for Cefepime was 17.2.

Conclusion: Higher incidence of ADR is developed in Cefepime group (10.7%) compared to the other antibiotics group (4.9%). Risk of developing neurotoxicity ADRs by prescribing Cefepime is 2.29 times higher than other antibiotics. The common neurotoxicity ADRs with Cefepime include loss of consciousness, disorientation, seizure, extrapyramidal, alter sensorium, drowsiness and delirium. Renal failure is a risk factor for neurotoxicity ADRs. Male have more likely to develop the ADRs compared to female after Cefepime use. NNH shows that on average 17 patients would have to receive Cefepime for one additional patient to develop the ADR.

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