Time–Kill Analysis of Ceftolozane/Tazobactam Efficacy Against Mucoid Pseudomonas aeruginosa Strains from Cystic Fibrosis Patients

Abstract

IntroductionMucoid Pseudomonas aeruginosa (MP) strains in cystic fibrosis (CF) patients are thought to initiate the chronic infection stage of CF and are associated with pulmonary function decline.ObjectivesThe purpose of this study was to assess the susceptibility of MP strains to ceftolozane/tazobactam and the efficacy of ceftolozane/tazobactam against MP strains compared with those for standard-of-care antipseudomonal antibiotics.MethodsTen clinical isolates of MP from CF patients were tested for susceptibility with Etest and time–kill analysis with ceftolozane/tazobactam compared with ceftazidime, cefepime, ciprofloxacin, meropenem, tobramycin, and polymyxin B. The physiologic free peak concentrations were used in the time–kill experiments.ResultsCeftolozane/tazobactam minimum inhibitory concentrations ranged from 0.032 to 1.5 mg/L. In the time–kill analysis, the mean starting inoculum for the isolates was 6.29 ± 0.22 log10 colony forming units (CFU) per milliliter. On average, ceftolozane/tazobactam, cefepime, ciprofloxacin, meropenem, tobramycin, and polymyxin B all demonstrated bactericidal activity. With all isolates taken into account, polymyxin B, tobramycin, meropenem, and ceftolozane/tazobactam 3 g were the most potent, with reductions in inoculum of 5.07 ± 0.45, 4.58 ± 2.2, 4.76 ± 0.71, and 4.17 ± 0.94 log10 CFU/mL, respectively. Ceftolozane/tazobactam 1.5 g, cefepime, and ciprofloxacin reduced the starting inoculum by 3.74 ± 0.99, 3.42 ± 1.4, and 3.23 ± 2.0 log10 CFU/mL, respectively. Despite 90% susceptibility, ceftazidime was bactericidal against seven of ten strains, with an average reduction in starting inoculum of 2.91 ± 2.2 log10 CFU/mL.ConclusionCeftolozane/tazobactam activity against MP strains derived from CF patients was comparable to that of standard-of-care agents at both the 1.5-g dose and the 3-g dose. Further in vitro modeling and clinical trials are warranted.

Polymorphonuclear Leukocytes or Hydrogen Peroxide Enhance Biofilm Development of MucoidPseudomonas aeruginosa

“…P. aeruginosa strains isolated during the initial infection period are likely to be wild strains that are motile and nonmucoid [ 4 ]. After years of infection, strains of P. aeruginosa exhibit an extensive array of altered phenotypes, including a mucoid, nonmotile phenotype [ 40 ]. Mucoid P. aeruginosa exhibits enhanced microcolony formation [ 41 ], and colonization by mucoid P. aeruginosa is recognized as an indicator of a poor prognosis because these bacteria are seldom eradicated.…”

“…Unfortunately, previous studies focused on the effect of activated PMNs or ROS on wild-type P. aeruginosa [ 11 , 33 , 37 , 39 , 42 ]. While P. aeruginosa biofilm formation in the CF airways appears to occur when mucous plugs develop, most strains isolated from the lungs of patients in the advanced stages of CF have a mucoid colony morphology [ 40 , 43 ]. This morphology is usually accompanied by an overproduction of alginate, which makes it difficult to eradicate the P. aeruginosa infection using existing therapies [ 44 ].…”

Optimization of anti‐pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins latest update

“…Microbiological efficacy of ceftolozanetazobactam against P. aeruginosa isolates from CF patients was demonstrated in various studies listed in Table 1. [10][11][12][13][14] Ceftolozanetazobactam was reported to be well-tolerated in CF patients (Table 1).…”

Ceftolozane/Tazobactam for Treating Children With Exacerbations of Cystic Fibrosis Due to Pseudomonas aeruginosa: A Review of Available Data

“…colonization has been established, mucoid, and hypermutable P. aeruginosa strains are highly relevant. Several studies on P. aeruginosa isolates from patients with CF are available, showing a potent, concentration-independent bactericidal activity of C/T also on mucoid and resistant isolates, although percentages of susceptibility to C/T are on average lower than those reported in non-CF strains (10,(22)(23)(24).…”