key: cord-0740076-9pcfgi8m
authors: Novy, E.; Scala-Bertola, J.; Roger, C.; Guerci, P.
title: Preliminary therapeutic drug monitoring data of β-lactams in critically ill patients with SARS-CoV-2 infection
date: 2020-04-18
journal: Anaesth Crit Care Pain Med
DOI: 10.1016/j.accpm.2020.04.005
sha: 4ec49821207991fe7ae1247c0e2c87003f6b7a81
doc_id: 740076
cord_uid: 9pcfgi8m

nan

Dear Editor, Among the treatment strategies recommended for the management of SARS-CoV-2 critically ill patients, early administration of antibiotics is suggested [1] . In the intensive care unit (ICU), β-Lactam antibiotic therapy remains the first choice and can be optimised by a continuous infusion combined with therapeutic drug monitoring (TDM) [2, 3] . However, in the context of COVID-19 disease outbreak, the feasibility of routine TDM could be challenged by the work overload associated with the surge of patients.

Herein, we present pooled routine TDM data obtained from the first days of β-lactam therapy in 20 critically ill patients with a confirmed SARS CoV-2 viral infection. Our local stewardship program included systematic invasive respiratory samples before the start of antibiotics (β-lactams administered continuously after intravenous bolus dose in association with spiramycin), blood sampling for TDM of β-lactams after 24 hours and reassessment of the treatment at 48 hours.

The clinical patient characteristics and TDM data are reported in Table 1 . None of the patients presented with septic shock. All the patients were managed using protective mechanical ventilation, early use of prone positioning and conservative fluid management.

Overall, unbound β-lactam concentrations were above 4 x MIC when considering bacteria commonly involved in community acquired pneumonia (namely Streptococcus, Staphylococcus aureus and Enterobacteriaceae). Cefotaxime (6 g/24 h) was the most used antibiotic. Piperacillin/tazobactam and cefepime were used for patient with previous antibiotic exposure within the last 3 months. No initial severe acute renal failure was observed. Within the first 24 hours, serum albumin concentrations were low despite conservative fluid management, which may increase unbound fraction of antibiotics.

Interestingly, all patients manifested neurological dysfunction (confusion or delirium after first cessation of sedative drugs. Although several confounding factors may explain or contribute to the observed neurological state (advanced age, severe hypoxemia, sedative drugs, SARS-Cov-2 related encephalopathy), β-lactam neurotoxicity as contributing factor could not be excluded. Considering the high risk for healthcare workers to be contaminated, electro-encephalograms were not performed.

Trough cefepime concentrations were consistently above the thresholds associated with toxicity [4] .

Thus, this cephalosporin should be used with extreme cautious in these patients. Concerning cefotaxime and piperacillin, the concentrations were below the published range of neurotoxicity [5, 6] .

As previously described, few patients presented early bacterial coinfection [7] . Herein, only one patient presented a documented pneumonia due to Streptococcus pneumoniae and Staphylococcus aureus.

To conclude, the low prevalence of early bacterial coinfection and the peculiarities of β-lactam pharmacokinetics during the early phase of SARS CoV-2 infection should be considered for antibiotic stewardship. Indeed, since a high interindividual variability of β-lactam concentrations was observed despite apparent similarities in clinical features, β-lactam TDM should be advised. Moreover, as many patients will require long duration of invasive mechanical ventilation [8] exposing them to a high risk of ventilator-associated pneumonia, these patients should not be exposed to inadequate antibiotics drug dosing. However, since the prevalence of augmented renal clearance was low, the risk of β-lactam underdosage is probably low and conventional doses of β-lactams should be sufficient. Finally, clinicians should be aware of a shifted risk of overdosage after the first days of admission, when Page 3 of 6 J o u r n a l P r e -p r o o f 3 approaching the period of weaning from mechanical ventilation. In view of the apparently high prevalence of neurological disorder that affects patients suffering from SARS-CoV-2, TDM should be performed at least to screen possible β-lactam overexposure.

TDM of β-lactams is performed routinely in our ICU. Approval to analyse these data was granted by the local ethic committee. The need for informed consent was waived in view of the retrospective nature of the study. 

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

Update in antibiotic therapy in intensive care unit: report from the 2019 Nîmes International Symposium

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR)

A retrospective cohort study

Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients

Simultaneous determination of eight β-lactam antibiotics in human plasma and cerebrospinal fluid by liquid chromatography coupled to tandem mass spectrometry

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists