Ceftolozane/tazobactam for the treatment of multidrug resistant Pseudomonas aeruginosa: experience from the Balearic Islands

Abstract

A prospective, descriptive observational study of consecutive patients treated with ceftolozane/tazobactam in the reference hospital of the Balearic Islands (Spain), between May 2016 and September 2017, was performed. Demographic, clinical, and microbiological variables were recorded. The later included resistance profile, molecular typing, and whole genome sequencing of isolates showing resistance development. Fifty-eight patients were treated with ceftolozane/tazobactam. Thirty-five (60.3%) showed respiratory tract infections, 21 (36.2%) received monotherapy, and 37 (63.8%) combined therapy for ≥ 72 h, mainly with colistin (45.9%). In 46.6% of the patients, a dose of 1/0.5 g/8 h was used, whereas 2/1 g/8 h was used in 41.4%. In 56 of the cases (96.6%), the initial Pseudomonas aeruginosa isolates recovered showed a multidrug resistant (MDR) phenotype, and 50 of them (86.2%) additionally met the extensively drug resistant (XDR) criteria and were only susceptible colistin and/or aminoglycosides (mostly amikacin). The epidemic high-risk clone ST175 was detected in 50% of the patients. Clinical cure was documented in 37 patients (63.8%) and resistance development in 8 (13.8%). Clinical failure was associated with disease severity (SOFA), ventilator-dependent respiratory failure, XDR profile, high-risk clone ST175, negative control culture, and resistance development. In 6 of the 8 cases, resistance development was caused by structural mutations in AmpC, including some mutations described for the first time in vivo, whereas in the other 2, by mutations in OXA-10 leading to the extended spectrum OXA-14. Although further clinical experience is still needed, our results suggest that ceftolozane/tazobactam is an attractive option for the treatment of MDR/XDR P. aeruginosa infections.

Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections

“…The main indication in these series was respiratory tract infection, and different doses of ceftolozane-tazobactam were used, sometimes in combination therapy. Cure rates were close to 70%, with emergence of resistance of 4 to 14% in some studies and mortality rates, measured at different times, ranging from 0% (in small series of cases) to 27% (26,62,165,(281)(282)(283)(284)(285)(286)(287)(288).…”

“…Likewise, the activity of ceftolozane-tazobactam and ceftazidime-avibactam against ESBL-producing P. aeruginosa isolates is variable, but it is generally favorable in the case of ceftazidimeavibactam. Finally, extended-spectrum mutations in horizontally acquired OXA-type ␤-lactamases may lead to the emergence of resistance to both agents (25,62,63).…”

Investigation of Ceftalozan / tazobactam and Ceftazidim / avibaktam invitro activity against Karbapenemaz producing Pseudomonas aeruginosa strains

“…The in vitro efficacy of C/T and CZA against carbapenemresistant P. aeruginosa isolates depends on the type of dominant carbapenemase, which varies globally [13] . In a multicenter study performed in Spain, the rate of susceptibility to C/T was approximately 70% in carbapenemase-producing strains, and their resistance levels were correlated with carbapenemase production [8] . Similarly, Evans et al [13] reported 100% susceptibility to CZA and C/T in carbapenem-susceptible strains.…”

“…Multidrug-resistant was defined as resistance to at least three of the following: antipseudomonal cephalosporin (cefepime), piperacillin-tazobactam, meropenem (MEM), ciprofloxacin, and aminoglycosides [4] . Strains sensitive to only colistin and/ or aminoglycoside were considered to be XDR [8] . The 32 P. aeruginosa isolates classified as MDR were included in the study.…”

<em>Pseudomonas aeruginosa</em> bacteremia among liver transplant recipients

“… 85 , 86 In May 2016, ceftolozane/tazobactam was approved by the Pharmacy and Therapeutics Committee of Balearic Public Health System to treat infections caused by MDR P. aeruginosa in the absence of appropriate therapeutic alternatives according to the patient’s characteristics. 87 Ceftazidime-avibactam (CZA) may also be a valuable option for serious infections due to resistant P. aeruginosa, as a 17-month retrospective descriptive study found that half of their patients with MDR or XDR P. aeruginosa infection who received CZA as initial or continuation therapy were clinical cured. 88 Furthermore, a new study published this year suggest a beneficial role of combination therapy with intravenous CZA and inhaled amikacin when treating pneumonia caused by P. aeruginosa , which indicate that inhaled antimicrobial therapy could be a good auxiliary method.…”