The main objective of this study was to report our experiences with ceftolozane/tazobactam and to compare its therapeutic properties to colistimethate sodium. Our results confirmed that ceftolozane/tazobactam is an effective and safe drug to treat ventilator-associated pneumonia due to extensively drug-resistant Pseudomonas aeruginosa. The most remarkable observations to emerge from the results were a higher clinical success rate and a lower incidence of AKI and CDi infections associated with C/T, although survival benefit was not demonstrated in this setting.
Even though new antibiotics against multidrug-resistant, Gram-negative bacteria are in development or already approved [26, 27], the treatment of XDR Pseudomonas aeruginosa is still challenging for the clinician at the bedside. For this reason, real-world experiences of the efficacy and tolerability of the novel beta-lactam/beta-lactamase inhibitor ceftolozane/tazobactam is of particular interest for the ICU physician. In our cohort, the use of C/T was associated with clinical cure in 72.2 %. This observation is relatively consistent with those described in previous studies of C/T therapy (between 73.7 % and 86.8 %) [17, 18, 19, 20]. Most of these studies included patients with both MDR and XDR infections. Among them, the work of Escolà-Vergé et al. [18] focused on the treatment of XDR Pseudomonas aeruginosa. They noted an outstanding clinical success rate of 86.8 % at the completion of the treatment. This higher value is likely to be related to the non-critically ill population and the heterogeneous source of infection.
Previous studies showed that higher Simplified Acute Physiology Score II, inadequate source control and continuous renal replacement therapy are associated with clinical failure of C/T treatment [17, 18, 20]. Severity of acute illness was characterized by APACHE II score in our study and was implied in the multivariate analysis. Results indicate that C/T treatment is an independent predictor of clinical cure (OR 4.47). Interestingly, association between CRRT and clinical failure was not observed, despite of a relatively high proportion of all patients having received this therapeutic modality (23.5 %). In a recently published study [28], the influence of CRRT was investigated in 6 critically ill patients treated with C/T against Pseudomonas aeruginosa. They concluded that administration of high dose C/T in extended or continuous infusion and therapeutic drug monitoring should be considered for adequate plasma concentrations. In fact, 3 of 5 patients on CRRT in our study received the high dose of C/T, although clinical success rate did not differ in those who received the standard or high dose of C/T.
In contrast, clinical success was demonstrated in only 30.3 % of CMS-treated patients in our study. These findings significantly differ from previous results reported in the literature by Michalopoulos et al. [7] and Kallel et al. [8]. In the aforementioned studies, intravenous CMS therapy was associated with a favorable clinical response in 69.8 % and 75 % of patients with ICU-acquired infections caused by CMS-only-susceptible Pseudomonas aeruginosa or Acinetobacter baumannii. This apparent lack of correlation can be due to the higher incidence of AKI and nephrotoxicity in our CMS group, which was shown to be an independent risk factor of unfavorable infectious outcome [29]. Another possible explanation of this difference is resistance emergence during CMS therapy, although this option was not investigated in this work, since repeated microbiological samples were not collected routinely.
In those where available, proven microbiological cure rate for C/T (44.4 %) was relatively lower to those reported previously (53.4 % to VAP cases) [19]. Consistently with the results of Gallagher et al. survival was better associated to clinical than microbiological success. Furthermore, since respiratory samples were not collected routinely but when considering a new infection episode, the proven persistence rate of XDR Pseudomonas aeruginosa (22.2 %) may reflect microbiological results better. On the other hand, clinicians should be aware that pneumonia was also shown as a strong predictor of microbiological failure [19].
Mortality benefit was not demonstrated with ceftolzane/tazobactam neither in terms of mortality rate (27.8 % vs 33.3 %), nor by Cox regression analysis (HR = 0.77) and the Kaplan-Meier method. More factors may have contributed to the absence of its impact on mortality. First, the effect of antibiotic therapy may be hidden by the severity of acute illness as an important determinant of outcome. In fact, the predicted mortality by the SOFA score calculated at the time of VAP diagnosis was similar in the two groups. Second, since the estimated attributable mortality of VAP is around 10% [30], a larger study is needed to demonstrate an impact on all-cause mortality. We did not examine the attributable mortality of VAP, because of the potential biases in recording cause of death. This observation is in line with the results of Melsen et al. [31], who found that the attributable mortality of ventilator-associated pneumonia is lower in medical patients, and that it is mainly caused by prolonged exposure to the risk of dying due to prolonged ICU stay. In our study, the majority of patients were medical patients and the length of hospital stay was nearly identical in the two groups, which could explain the lack of survival benefit.
Ceftolozane/tazobactam had a good safety profile in this study. There were no reported cases of Clostridioides difficile colitis, seizures, neuropathy and direct Coombs positivity, despite the fact that half of the C/T patients received the high dose. No new safety signals for ceftolozane/tazobactam were identified.
We are aware that a number of limitations might have influenced our results. Possible sources of error are the retrospective nature and the small sample size of the study. We attempted to mitigate this by enrolling all consecutive patients fitting the enrolment criteria. Furthermore, the single-center design of the study may diminish the applicability of our results to other centers. Finally, the diagnostic criteria of VAP, even if they were defined according to the ECDC guideline, remained very subjective [32], and we may have overestimated the true number of VAP cases. To limit this bias, we included only lower respiratory tract infection episodes microbiologically confirmed and treated with targeted antibiotic therapy. Despite the limitations, our findings support the existing data reported in the only comparative study of ceftolozane/tazobactam and CMS published so far [25]. Nonetheless, our study also has some strengths: the population included only critically ill VAP patients with extensively drug-resistant Pseudomonas aeruginosa, and the results were interpreted in contrast to systemic CMS treatment.