1. Introduction
Complicated urinary infections (cUTI) are among the most frequent health-care associated diseases and a large part of them are caused by multidrug-resistant microorganisms. Infections due to multidrug resistant microorganisms are on the increase. The European Centre for Disease Prevention and Control (ECDC) has shown that antimicrobial resistance is a critical challenge and the fight against the antimicrobial resistance is a public health priority [Citation1]. Among the bacteria listed as WHO priority list for research and development of new antibiotics, Acinetobacter baumanii carbapenem-resistant, P. aeruginosa carbapenem-resistant and carbapenem-resistant third-generation cephalosporin-resistant Enterobacterales are at the highest critical level [Citation2]. Multidrug-resistant uropathogens bacteria represent a major global concern [Citation3].
Ceftolozane/tazobactam (C/T) is a new cephalosporin beta-lactam combined to a beta-lactamase inhibitor as a fixed combination. It has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and cUTI, by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). C/T activity was very high against multidrug resistant (MDR) P. aeruginosa. Several studies demonstrated a very high level of activity of C/T (more than 95%) also against extended-spectrum beta-lactamase (ESBL)-E. coli [Citation4,Citation5].
C/T was approved for the treatment of cUTI, based on a randomized clinical trial (ASPECT-cUTI) [Citation6]. The ASPECT-cUTI study was a multicenter, double-blind, double-dummy, noninferiority randomized trial comparing C/T vs. levofloxacin for the treatment of cUTI, including pyelonephritis. In this study, C/T was shown to be not inferior to high-dose, levofloxacin for the primary endpoint of composite outcome.
2. C/T activity against MDR organisms
2.1. C/T activity against MDR P. aeruginosa
Among Gram negative bacteria, P. aeruginosa remains one of the most frequently isolated microorganism of healthcare-associated infections [Citation1]. In Europe, P. aeruginosa isolates with multidrug resistance (defined as combined resistance to at least three antimicrobial groups among piperacillin/tazobactam, ceftazidime, carbapenems, fluoroquinolones and aminoglycosides) were 12.1% in 2019 [Citation1]. Sensitivity to C/T in P. aeruginosa isolates is around 95% [Citation7,Citation8] and activity of C/T remains also for extensively drug resistant (XDR) P. aeruginosa (around 80%) [Citation4,Citation5]. C/T has a decreased susceptibility to AmpC beta-lactamases. Moreover, C/T was not influenced by upregulation of the efflux pumps activity or deletion of the membrane protein OprD. These mechanisms are associated with resistance to P. aeruginosa. However, additional acquired resistance can complicate the treatment of P. aeruginosa infections. C/T showed no activity against P. aeruginosa isolates producing metallo-beta-lactamase carbapenemase production, the overexpression of AmpC beta-lactamases or onset of mutations in OprD are major limitations of the efficacy of C/T against carbapenemase-producers P. aeruginosa [Citation9].
2.2. C/T activity against extended-spectrum beta-lactamases (ESBL)-producers Enterobacterales
According to ECDC, 12.4% of E. coli and 26% of Klebsiella pneumoniae in Europe are ESBL-producers [Citation1]. Among Enterobacterales, about 90% of the isolates in patients with cUTI were susceptible to C/T [Citation4,Citation8] and the activity of C/T against ESBL-producers Enterobacterales was successful in 97.4% of the cases [Citation10]. The activity of C/T against ESBL-producers Enterobacterales was higher than other beta-lactams [Citation11] but decreased against ESBL–producing K. pneumoniae [Citation8]. Sensitivity to C/T in Klebsiella spp with an ESBL phenotype was between 60% (using EUCAST criteria) [Citation8] and 70-75% [Citation5].
Many beta-lactamases (SHV, TEM, OXA) hydrolyze piperacillin and, even though tazobactam is protective, susceptibility is reduced compared with wildtype strains.
2.3. C/T activity against carbapenemase-producers Enterobacterales
Activity of C/T in carbapenemase-producers was almost nothing, as previously reported [Citation5]. Resistance of Enterobacterales isolates to C/T has been associated, in particular, with carbapenemase-producers [Citation12]. However, OXA-48 producers may persist to be susceptible since ceftolozane is stable to the enzyme and ESBL, if present, are inhibited by tazobactam
3. Expert opinion
In the present Section, we describe the possible place of C/T in the treatment of cUTI. In our opinion, the most appropriate place of C/T in the treatment of cUTI are infections due to MDR and XDR isolates of P. aeruginosa including carbapenem-resistant isolates and infections due to ESBL-producers Enterobacterales when isolates have high MIC for piperacillin/tazobactam. C/T is a valuable resource in settings with very high rate of carbapenemase-producers microorganisms. In these cases, a carbapenem-sparing is largely desirable and C/T may be appropriate. In serious infections, such as sepsis from a cUTI source, initiating an appropriate antimicrobial regimen is pivotal for a successful outcome. Then, C/T may have a place when starting an empiric therapy in sepsis with a cUTI source till the microbiologic results are available, especially in settings where the prevalence of MDR/XDR P. aeruginosa is high.
C/T susceptibility testing of confirmed P. aeruginosa or ESBL-producers E. coli infections should be strongly considered for de-escalation purposes.
C/T is the most active beta-lactam against MDR and XDR P. aeruginosa. The use of an antibiotic within an empiric regimen, with a strong activity against almost all isolates of P. aeruginosa, could be very useful in patients at risk of infections due to P. aeruginosa, such as people with hematological malignancies and neutropenia febrile. People with cystic fibrosis, for whom mucoid strains of P. aeruginosa represents a danger, are another target population for the empirical use of C/T. C/T might remain active due to escape resistance mechanisms [Citation13] and it has activity also against carbapenem-resistant isolates in the absence of carbapenemase. It demonstrates good stability against several resistance mechanisms put in place by P. aeruginosa, including overexpression of AmpC beta-lactamase, efflux pumps and loss of porin channels. It should be noted that treatment failed in all cases of infections due to P. aeruginosa with MIC to C/T > 4 mg/L. Resistance to C/T associated with de novo mutations occurred in 14% of the cases [Citation14]. Continuous infusion of C/T has been demonstrated to have significantly higher probability of target attainment. Achieving optimal PK/PD targets could be of particular benefit in difficult-to-treat co-infections, such as cUTI and diabetic foot, in which P. aeruginosa is frequently isolated.
The treatment of severe infections due to Enterobacterales ESBL-producers is currently under debate. In 2018, the MERINO trial showed that carbapenems are superior to piperacillin/tazobactam in the treatment of bloodstream infections caused by ceftriaxone-resistant E. coli or K. pneumoniae [Citation15]. However, concerns remain about the validity of the study conclusions. Subgroup analysis of the MERINO trial and observational data failed to demonstrate the superiority of carbapenems over piperacillin/tazobactam in lower risk sources of infection such as UTIs. Therefore, piperacillin/tazobactam remains a valid option for treatment of UTIs due to ESBL-producers E. coli. C/T is the first cephalosporin active against Enterobacterales ESBL-producers, positioning the drug in therapy of severe infections due to ESBL-producers pathogens, especially when a carbapenem-sparing approach is desirable. The activity of C/T was altogether superior than that of piperacillin/tazobactam. Furthermore, the place of C/T is in the treatment of infections due to Enterobacterales ESBL-producers with high MIC to piperacillin/tazobactam. It should be noted that in most cases of infections caused by Enterobacterales ESBL-producers, the MICs of ceftazidime/avibactam are lower than those of C/T and that the activity of C/T decreased against ESBL-producing K. pneumoniae. Since C/T was not active against carbapenem-resistant Enterobacterales (CRE), its place in infections caused by CRE is null.
The probability of clinically significant drug–drug interaction of C/T is probably very low, since at therapeutic concentrations it cannot be a substrate or an adjuster of the cytochrome P450 system. C/T can be safely administered in patients with renal impairment.
In conclusion, the microbiological evidences promote C/T as a therapeutic option in patients with cUTI or sepsis with a cUTI source due to P. aeruginosa or Enterobacterales ESBL-producers isolates (especially those with high MIC to piperacillin/tazobactam and in geographical areas with high incidence of infections due to CRE), but not for carbapenemase producers.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
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