A Study on Plasma and Pulmonary Pharmacokinetics of High-dose Ceftobiprole Given by Continuous Infusion in Mechanically-ventilated Adult Patients With Severe Community-acquired Pneumonia

Pneumonia is still associated with high morbi-mortality, and rapid treatment with suitable antibiotics is required, i.e. with a broad enough spectrum to cover the activity of all the potentially-incriminated pathogens. These antibiotics must be administered at efficient doses and diffused in sufficient quantity at the infection site.

Unlike other beta-lactams, ceftobiprole is a new-generation broad-spectrum cephalosporin which is active on the majority of pathogens encountered in acute, community-acquired pneumonia (CAP) and also on methicillin-resistant staphylococcus aureus (MRSA) and non-fermenting Gram-negative bacilli (GNB) like pseudomonas aeruginosa. It is indicated for the treatment of CAP and also healthcare-associated pneumonia, other than that acquired under mechanical ventilation.

For any antibiotic administered to critically ill patients it is necessary to ensure that the pharmacokinetic/pharmacodynamic (PK/PD) targets correlated with clinical efficacy can be reached with the recommended doses. The DALI study published in 2014 was the first study to alert on the risk of plasma under-dosing when the standard doses of beta lactams were administered in severely ill patients.

Since then, several PK studies performed in the intensive care unit have confirmed the significant risk of non-optimal doses in this population, linked to physiopathological alterations caused by sepsis. So far there have been no studies specifically aimed at the pharmacokinetics of ceftobiprole in those patients with CAP requiring mechanical ventilation. Furthermore, although there is increasing use in the pharmaceutical industry and in the post-developmental phases of medicines, a population PK analysis to help describe the factors influencing the PK of a molecule and establish new dose regimens optimised for a given population (in this case an ICU population) using Monte Carlo simulations, has never been developed for ceftobiprole given by continuous infusion.

The ultimate aim of so-called adequate antibiotic therapy is to obtain the right therapeutic concentrations at the infection site. During a pulmonary infection, the targeted concentrations of antibiotics in the alveolar liquid must be above the minimal inhibitory concentration value at the end of the dose interval for so-called " time-dependent " antibiotics like cephalosporins. Obtaining these efficient concentrations is often made difficult by the beta-lactams' mediocre pulmonary diffusion and can require an increase in doses in order to reach the PK/PD target at the infection site and/or the use of continuous administration of beta-lactamines. Indeed, this way of administrating is being privileged more and more in order to optimise the time spent above the minimal inhibitory concentration.