Dear Editor,

Ceftolozane-tazobactam, a novel fifth-generation cephalosporin and β-lactamase inhibitor, with activity against multidrug resistant Pseudomonas aeruginosa, has recently been evaluated by Maraolo and colleagues for such infections in the intensive care unit [1]. We describe a cautionary case of fatal Pseudomonal pneumonia, involving the rapid development of ceftolozane-tazobactam resistance in vivo.

An elderly gentleman was admitted with septic shock due to fecal peritonitis associated with Enterococcus faecium bacteraemia, treated with meropenem and vancomycin. A month following admission, sputum cultured P. aeruginosa, resistant to meropenem, aztreonam, and ciprofloxacin (Table 1), with no strains of resistant P. aeruginosa known to be circulating the facility at the time. He was treated with piperacillin-tazobactam followed by ceftazidime for persistent nosocomial pneumonia. Subsequent P. aeruginosa isolated from sputum the following week illustrated additional resistance to piperacillin-tazobactam and ceftazidime, but sensitivity to ceftolozane-tazobactam (MIC 0.5 mg/L). Ceftolozane-tazobactam (1.5g, q8h) was commended with a good response. Monotherapy was chosen based on recent evidence refuting the perceived benefit of dual therapy [2,3]. Five days after completing treatment the nosocomial pneumonia relapsed. Ceftolozane-tazobactam was recommenced, but subsequent respiratory and blood cultures yielded P. aeruginosa resistant to ceftolozane-tazobactam (MIC > 16 mg/L).

Ceftolozane-tazobactam remains active against strains of P. aeruginosa resistant to all other β-lactams, but resistance can develop by plasmid-mediated β-lactamases (most commonly metallo-β-lactamases), or chromosomal reassortment [4]. Metallo-β-lactamases were not found in our patient’s strain of P. aeruginosa, which suggests induction of a modified, non-wild-type AmpC [4]. This latter resistance phenotype is associated with high-level resistance to ceftolozane-tazobactam, but reduced MICs to piperacillin-tazobactam and imipenem when compared to wild-type AmpC; a pattern that can be seen in the antibiogram of our isolates (Table 1) [4].

Our patient was treated with the approved dose for urinary tract or intra-abdominal infection of ceftolozane-tazobactam at 1.5g, q8h [5]. An ongoing phase 3 clinical trial is comparing higher-dose ceftolozane-tazobactam (3g, q8h) with meropenem 1 g, q8h, for the treatment of nosocomial pneumonia, due to concerns that lower doses of the former may insufficiently attain target levels in the lung [6,7]. But, with a ceftolozane-tazobactam MIC of 0.5 mg/L at a dose of 1.5 g, Xiao et al. have shown the drug concentration in lung epithelial lining fluid to well exceed the required time above MIC for satisfactory killing (as observed in healthy volunteers) [7].

Haidar and colleagues have recently published a single-center, retrospective case review of 21 patients treated with ceftolozane-tazobactam for multidrug resistant Pseudomonal infections; 76% of which were respiratory tract infections [8]. A total of 14% of patients developed resistance to ceftolozane-tazobactam, not associated with the dose administered (1.5 or 3 g), site of infection or combination vs. monotherapy [8].

For our case, persistent Pseudomonal pneumonia and refractory abdominal sepsis resulted in continued deterioration and progression to multi-organ failure, leading to a decision with the family for withdrawal of curative treatment. Whilst it is clear ceftolozane-tazobactam is a welcome new addition to our antimicrobial armamentarium, this case illustrates the astute awareness required when considering the problem of anti-Pseudomonal resistance. Further studies detailing the success and failure of this antibiotic, and its use in combination or as monotherapy are greatly encouraged.