Beta-lactam antibiotics in continuous infusion in critically ill patients

We read with great interest Taccone and colleagues’ article [1], published in a recent issue of Critical Care, on the insuffi cient β-lactam concentrations in the early phase of severe sepsis and septic shock. While we fully agree with the authors’ fi ndings, we would like to off er some remarks. Only 18 of their 80 patients (22.5%) were infected with Pseudomonas aeruginosa, but Taccone and colleagues used the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimal inhibitory concentration (MIC) breakpoints of P. aeruginosa to calculate the target pharmacokinetics (PK) profi le in all of the patients. Because Enterobacteriaceae form a substantial part of infectious organisms in intensive care patients, it would be interesting to see how many patients would attain the PK profi le for these microorganisms [2]. For cefepime, for instance, if the EUCAST sensitivity threshold of 1 mg/L were used, 17 of 19 patients (89%) would attain the target PK profi le as compared with 3 of 19 patients (16%) for P. aeruginosa. Of course, we agree that, in an empirically started antibiotic regimen, the organisms, let alone the MIC, are not known to the clinician. Furthermore, the data of Taccone and colleagues should be interpreted in light of local epidemiology and resistance data. In a Belgian multicenter study, all P. aeruginosa strains isolated from patients hospitalized in the intensive care unit (ICU) had an MIC 90 (MIC required to inhibit the growth of 90% of organisms) for meropenem of 0.12 mg/L [3]. With this MIC, even more than 75% of the patients would have attained the target PK profi le. In addition, we think that the initial loading dose should be followed immediately by an extended or continuous infusion in order to obtain an optimal PK/ pharmacodynamics (PK/PD) profi le [4].

We read with great interest Taccone and colleagues' article [1], published in a recent issue of Critical Care, on the insuffi cient β-lactam concentrations in the early phase of severe sepsis and septic shock. While we fully agree with the authors' fi ndings, we would like to off er some remarks.
Only 18 of their 80 patients (22.5%) were infected with Pseudomonas aeruginosa, but Taccone and colleagues used the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimal inhibitory concentration (MIC) breakpoints of P. aeruginosa to calculate the target pharmacokinetics (PK) profi le in all of the patients. Because Enterobacteriaceae form a substantial part of infectious organisms in intensive care patients, it would be interesting to see how many patients would attain the PK profi le for these microorganisms [2]. For cefepime, for instance, if the EUCAST sensitivity thres-hold of 1 mg/L were used, 17 of 19 patients (89%) would attain the target PK profi le as compared with 3 of 19 patients (16%) for P. aeruginosa. Of course, we agree that, in an empirically started antibiotic regimen, the organisms, let alone the MIC, are not known to the clinician.
Furthermore, the data of Taccone and colleagues should be interpreted in light of local epidemiology and resistance data. In a Belgian multicenter study, all P. aeruginosa strains isolated from patients hospitalized in the intensive care unit (ICU) had an MIC 90 (MIC required to inhibit the growth of 90% of organisms) for meropenem of 0.12 mg/L [3]. With this MIC, even more than 75% of the patients would have attained the target PK profi le. In addition, we think that the initial loading dose should be followed immediately by an extended or continuous infusion in order to obtain an optimal PK/ pharmacodynamics (PK/PD) profi le [4].

Fabio Silvio Taccone, Jean-Louis Vincent and Frédérique Jacobs
We thank Jeurissen and Rutsaert for their interest in our study [1] and would like to reply to the important points they raise. In our patient population, one third of documented infections were due to P. aeruginosa as microbiological samples remained negative in 30% of patients with sepsis. Indeed, P. aeruginosa is frequently isolated in patients with comorbid illnesses or indwelling catheters or who are on mechanical ventilation or under going surgery, all of these conditions being typical in ICU patients [5]. Pseudomonas infections are associated with the highest mortality rate in this ICU patient population. For all of these reasons, it seems logical to develop an empirical strategy that targets this pathogen in patients with nosocomial infections.
We agree that in vitro studies on Pseudomonas susceptibility may show MICs that are much lower than the upper threshold of sensibility proposed by the EUCAST for carbapenems. However, in all epidemiologic studies, only the fi rst isolated strain of P. aeruginosa is considered for MIC determination. Besides having an intrinsic resistance to a wide range of antimicrobials, Pseudo mo nas is able to acquire resistance via several mechanisms or under antimicrobial pressure. A recent study showed that Pseudomonas strains isolated from ICU patients are able to progressively increase the in vitro MIC level to diff erent antibiotics during therapy [6].
Finally, we agree that the extended or continuous infusion of β-lactams can optimize the PK/PD profi le of these drugs. Unfortunately, as only retrospective studies have provided evidence in favor of continuous infusion over intermittent infusion (especially in pathogens with higher