Plasma Protein Binding and Population Pharmacokinetics and Pharmacodynamics of Total and Unbound Temocillin in Patients With Complicated Urinary Tract Infection or Pyelonephritis, Lower Respiratory Tract Infection, or Abdominal Infection.

1.1. Introduction.

Multidrug resistance towards gram-negative pathogens has been increasing dramatically over the last decades. Due to insufficient discovery of drugs acting on novel targets, re-examination of older compounds, such as temocillin, for which resistance is still low, has proven to be of great therapeutic interest.

As all the β-lactams, temocillin efficacy depends primarily on the time interval during which the plasma concentration remains above the minimal inhibitory concentration (MIC) of the antibiotic against the target organism(s) (Craig, 1998). It is generally accepted that the unbound concentration of the antibiotic must remain above the MIC for at least 40 to 70% of the interval between two successive administrations, and should even reach 100% for severe infections in patients hospitalized in Intensive Care Units (MacGowan, 2011).

Temocillin (Negaban®), a ß-lactamase-resistant penicillin antibiotic, was first marketed in the 1980s but then abandoned due to a lack of activity against anaerobes, gram-positive bacteria and Pseudomonas aeruginosa (Livermore et al., 2006; Zykov et al., 2016). However, temocillin stability to ß-lactamases (including classical and extended-spectrum TEM, SHV, CTX-M enzymes and AmpC ß-lactamase) has found great appreciation amongst a large number of professionals in the field (Balakrishnan et al., 2011; Livermore and Tulkens, 2009). It is approved for intravenous and intramuscular administration at a dose ranging between 1-2 g twice - thrice - a day for the treatment of bacterial infections of the chest, the lungs, the kidney, the bladder, as well as bacterial infections of the bloodstream, abdominal infection, and wound infections (RCP Temocillin, 2014).

Studies performed in critical ill patients show important variations in the level of plasma proteins and rapid and unpredictable fluctuations in renal function (Beumier et al., 2015; Goncalves-Pereira and Povoa, 2011; Roberts and Lipman, 2009), both of which are known to modulate the pharmacokinetics of β-lactams (Goncalves-Pereira and Povoa, 2011; Hayashi et al., 2013; Sime et al., 2012; Udy et al., 2012; Wong et al., 2013). As a consequence, the unbound concentration of β-lactams with high protein binding (Schleibinger et al., 2015; Ulldemolins et al., 2011; Van Dalen et al., 1987; Wong et al., 2013), and renal elimination (Carlier et al., 2013; Simon et al., 2006; Vandecasteele et al., 2015) such as temocillin will be markedly modified in these patients.