In vitro activity of ceftolozane/tazobactam alone and in combination with amikacin against MDR/XDR Pseudomonas aeruginosa isolates from Greece

Abstract

Objectives We evaluated the in vitro activity of ceftolozane/tazobactam and comparator agents against MDR non-MBL Pseudomonas aeruginosa isolates collected from nine Greek hospitals and we assessed the potential synergistic interaction between ceftolozane/tazobactam and amikacin. Methods A total of 160 non-MBL P. aeruginosa isolates collected in 2016 were tested for susceptibility to ceftolozane/tazobactam and seven comparator agents including ceftazidime/avibactam. Time–kill assays were performed for synergy testing using ceftolozane/tazobactam 60 or 7.5 mg/L, corresponding to the peak and trough concentrations of a 1.5 g q8h dose, respectively, in combination with 69 mg/L amikacin, corresponding to the free peak plasma concentration. Synergy was defined as a ≥2 log10 cfu/mL reduction compared with the most active agent. Results Overall, ceftolozane/tazobactam inhibited 64.4% of the P. aeruginosa strains at ≤4 mg/L. Colistin was the most active agent (MIC50/90, 0.5/2 mg/L; 96.3% susceptible) followed by ceftazidime/avibactam (MIC50/90, 4/16 mg/L; 80.6% susceptible). GES-type enzymes were predominantly responsible for ceftolozane/tazobactam resistance; 81.6% of the non-producers were susceptible. MICs for the P. aeruginosa isolates selected for synergy testing were 2–32 mg/L ceftolozane/tazobactam and 2–128 mg/L amikacin. The combination of ceftolozane/tazobactam with amikacin was synergistic against 85.0% of all the isolates tested and against 75.0% of the GES producers. No antagonistic interactions were observed. Conclusions Ceftolozane/tazobactam demonstrated good in vitro activity against MDR/XDR P. aeruginosa clinical isolates, including strains with co-resistance to other antipseudomonal drugs. In combination with amikacin, a synergistic interaction at 24 h was observed against 85.0% of P. aeruginosa strains tested, including isolates with ceftolozane/tazobactam MICs of 32 mg/L or GES producers.

Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems

“…Imipenem-relebactam, another option against non-MBL producing P. aeruginosa [ 110 ], is not affected by AmpC mutations that confer resistance to ceftazidime/avibactam and ceftolozane/tazobactam [ 110 ]. However, GES-producing P. aeruginosa strains are resistant to both imipenem/relebactam [ 46 , 47 ] and ceftolozane/tazobactam [ 45 , 111 ], but may be susceptible against ceftazidime/avibactam [ 45 , 111 ].…”

“…Resistance to CAZ/AVI and C/T is usually the result of structural modifications of AmpC (+ overexpression of AmpC) or horizontally acquired carbapenemases [ 108 , 109 ]. GES-type carbapenemases may confer resistance to C/T but not to CAZ/AVI [ 45 ]. 3 IMI/REL is unaffected by the most relevant mutation-driven β-lactam resistance mechanisms of P. aeruginosa [ 110 ].…”

“…6 High-dose aminoglycoside therapy (such as amikacin 50 mg/kg/day) may be a useful option for CACT-resistant P. aeruginosa with borderline MIC (e.g., amikacin MIC = 16 mg/dl) and can be combined with hemodialysis to reduce nephrotoxicity [ 184 , 186 , 187 ]. 7 Until cefiderocol becomes widely available, synergistic combinations (e.g., based on colistin [ 120 , 121 ], fosfomycin [ 122 , 123 ], aminoglycosides [ 45 ] and C/T [ 45 , 122 ]) may sometimes represent the only treatment option, but PK/PD and clinical studies are needed. Other options are ineffective for CAPT-resistant P. aeruginosa : The activity of MVB against P. aeruginosa is similar to that of meropenem alone [ 61 ].…”

Treatment Options for <em>K. pneumoniae</em>, <em>P. aeruginosa</em> and <em>A. baumannii</em> Co-resistant to Carbapenems, Aminoglycosides, Colistin and Tigecycline. An Approach Based on the Mechanisms of Resistance to Carbapenems

“…However, the prevalence of MBL among carbapenem-resistant P. aeruginosa is rising [38] and in some settings the majority (70-88%) of carbapenem-resistant P. aeruginosa isolates are MBL producers [30,31]. Furthermore, GES-type carbapenemases are increasingly being reported in P. aeruginosa [41][42][43][44].…”

“…Both are less prone to outer membrane permeability changes (porin loss/ efflux pumps) and neither is affected by AmpC (ceftolozane is stable against AmpC and avibactam restores the activity of ceftazidime by inhibition of AmpC) [97,98]. Therefore, both ceftazidime/avibactam and ceftolozane/tazobactam remain highly active (81-92% [97,[99][100][101][102]) against non-MBL carbapenem-resistant P. aeruginosa, but susceptibility may be much lower (41-48% [42,99]) in isolates co-resistant to multiple anti-pseudomonal beta-lactams (ceftazidime, piperacillin/tazobactam and cefepime). Generally, ceftolozane/tazobactam appears to be more potent than ceftazidime/avibactam in noncarbapenemase producing P. aeruginosa [97,98], and has been used successfully against ventilator-associated pneumonia by CACT-resistant P. aeruginosa [103].…”