A Bit of Caution in the Empirical Treatment of Complicated Urinary Tract Infections

To the Editor: U rinary tract infections are among the most common bacterial infections, with over 150 million annual cases globally. The most implicated bacterial species are Escherichia coli and other Enterobacteriaceae (Klebsiella and Proteus), Pseudomonas aeruginosa, and Staphylococcus aureus. Complicated urinary tract infection (cUTI) is defined if there are factors related to the host (e.g., immunosuppression, diabetes mellitus) or the urinary tract (e.g., obstruction or alterations of the detrusor muscle). An infection that involves the upper urinary tract (pyelonephritis) or causes a systemic involvement (urosepsis) can be considered a cUTI. The most recent data report an increase in the rates of uropathogenic resistant bacteria species. In the United States, from 2000 to 2009, the proportion of extended-spectrum betalactamases (ESBL)-producing Enterobacteriaceae in hospitalized patients with urinary tract infections has tripled. Many strains of E. coli are now producers of ESBL, and species resistant to fluoroquinolones and producer of ESBL is now widespread globally. Since the mortality rate from urosepsis has reached percentages ranging from 20% to 40%, new antibiotic drugs are more necessary than ever. On the other hand, carbapenem-resistant species are also increasing, constituting a danger that is currently difficult to address due to the absence of real pharmaceutical competitors: carbapenem-resistant strains of Klebsiella grew from 1% to 34% in the period 2006 to 2013. The need to spare carbapenems for severe infections has led the pharmaceutical industry to develop new association molecules capable of eradicating these multiresistant species. Ceftolozane-tazobactam (C/T) is a new combination of advanced cephalosporin and a beta-lactamase inhibitor. C/T is effective in the treatment of nosocomial pneumonia and intra-abdominal infections by Gram-negative bacteria. Ceftolozane-tazobactam is superior to levofloxacin in the treatment of cUTIs, as demonstrated by a multicenter trial, the ASPECTcUTI, published in Lancet in 2015. We must point out that ASPECT-cUTI is a noninferiority trial. A noninferiority trial is often difficult to interpret and is based on assumptions often challenging to prove. Furthermore, theASPECT-cUTI trial is the pooling of 2 different trials conducted in 2 different regions of the world: North and South America and Central and Eastern Europe. The authors did not specify whether the 2 populations are comparable in terms of drug resistance. C/T has not shown superiority over ceftazidime or piperacillin/tazobactam against cUTIs. The cost of these new molecules is often high: a pack of C/T costs around € 1000, a box of piperacillin/tazobactam around € 80, a box of meropenem € 60. Only a cost-benefit study in Taiwan compared C/T with piperacillin/tazobactam in terms of economic sustainability. The result was favorable for C/T. Although studies on this are lacking, the use of C/T is likely to be beneficial in the long term despite higher costs in the short term. For the reasons we mentioned, it would be desirable that the clinician was aware of the bacterial epidemiology of his hospital, primarily if he works in an intensive care unit. Remembering what the risk factors for a urinary infection with multidrug-resistant bacteria are is crucial: the age of the patient, an immunosuppressive condition, the presence of a urinary catheter, frequent hospitalization, or long-term hospitalization.