Systematic overdosing of oxa- and cloxacillin in severe infections treated in ICU: risk factors and side effects

Abstract

BackgroundOxacillin and cloxacillin are the most frequently used penicillins for the treatment of severe methicillin-susceptible Staphylococcus aureus infections in intensive care units (ICUs), especially endocarditis. International recommendations do not suggest any adaptation of the dosage in case of renal impairment. We wanted to assess the risk factors for overdosing in ICU and the related observed side effects.MethodsAll patients with a therapeutic drug monitoring of oxa- or cloxacillin between 2008 and 2014 were included. The target range of trough concentration for total antibiotic activity was considered to be 20–50 mg/L. Data concerning the infection, the given treatment, the renal function, and the attributed side effects of overdosing were collected. A logistic regression model was used to compute the measured trough concentrations.ResultsSixty-two patients were included in this study. We found a median trough plasma concentration of 134.3 mg/L (IQR 65.3–201 mg/L). Ten patients (16.1%) reached the target concentration; all other patients (83.9%) were overdosed. Eleven patients (17.7%) experienced neurological side effects attributed to a high antibiotic concentration, i.e. persistent coma and delirium. When adjusted on the dosage used, the risk of overdosing was significantly associated with a creatinine clearance <10 mL/min (with or without hemodialysis).ConclusionWith the suggested dose of 12 g/day for cloxacillin treatment in case of endocarditis and severe infections occurring in ICU, 83.9% of patients are largely overdosed. Considering the observed side effects, doses should be accurately monitored and reduced, particularly when renal replacement therapy is needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-017-0255-8) contains supplementary material, which is available to authorized users.

Acute kidney injury during treatment with high-dose cloxacillin: a report of 23 cases and literature review

“…We found that, despite patients were prescribed the cloxacillin dose recommended by guidelines, taking into account their eGFR, 57% had trough plasma concentration > 50 µg/mL. This result is consistent with a recent study that reported trough plasma concentration > 50 µg/mL in 83.9% of 62 patients treated by oxacillin or cloxacillin in intensive care unit [6]. Of note, intravenous cloxacillin is mainly bound to plasma proteins (>90%) [23], and the active metabolite is the unbound fraction.…”

“…Cloxacillin plasma concentration was determined by high-performance liquid chromatography method with UV detection, as previously described [5]. The target range of trough concentration (or steady-state concentration, in case of continuous administration), was 20-50 µg/mL, as previously described [6].…”

The 2014 updated version of the Confusion Assessment Method for the Intensive Care Unit compared to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders and other current methods used by intensivists

“…Delirium is multifactorial and frequent in critically ill ICU patients [ 6 , 27 – 35 ]. It is diagnosed in 10–90% of ICU patients, depending on the diagnosis tool, the timing of assessment (during or after interrupting sedation), as well as the frequency of assessment (one-point assessment for validation studies or throughout the ICU stay) [ 6 , 36 ].…”

“…Even in such an “a priori” favorable setting for the early recognition of delirium, bedside–clinicians still need to use a validated tool during their routine practice, repeatedly during the day and throughout the ICU stay. This is paramount for treating the factors associated with delirium [ 6 , 27 – 35 ] as soon as possible, especially when taking into account the negative outcomes associated with delirium [ 5 , 6 ]. A comprehensive approach [ 48 ] integrating delirium management with analgesia, sedation, mechanical ventilation, mobility/exercise and family engagement/empowerment has shown a positive impact on increasing ventilatory-free days [ 49 , 50 ], decreasing delirium incidence [ 49 – 51 ] and improving hospital mortality [ 51 ].…”

Serum biomarkers of delirium in the elderly: a narrative review

“…Although the pathophysiology of delirium remains poorly understood, we know that the pathogenesis of the cognitive impairments associated with delirium is multifactorial. Certain entities such as drug overdose [16] but also drug withdrawal [17] bear delirium risk. As with so many disparate etiologies, it is highly unlikely that a single mechanism is solely responsible [18].…”