IDSA Guideline Recommendations: Treating Multi-Drug Resistant and Difficult to Treat Resistant P. aeruginosa

Pseudomonas aeruginosa (P. aeruginosa) clinical isolates with a difficult-to-treat resistance (DTR) phenotyperepresent a more homogenous group with limited treatment options compared to isolatesexhibiting a multi-drug resistant (MDR) phenotype.¹ DTR P. aeruginosa is defined asresistance to all first line agents, specifically β-lactams and fluoroquinolones antimicrobials.² In the Infectious Disease Society of America (IDSA) guidance document, DTR is defined as P. aeruginosa resistant to piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem/cilistatin, ciprofloxacin, and levofloxacin.³

Resistance

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DTR P. aeruginosa usually develops multiple resistance mechanisms, including decreased expression of outer membrane porins; amino acid substitutions or deletions to penicillin-binding domains or Pseudomonas-derived cephalosporinase (AmpC) enzyme; upregulation of efflux pumps; mutation of penicillin-binding protein (PBP) targets; and expression of expanded β-lactamase enzymes.^4-6 Carbapenemase production is not a resistance mechanism seen in P. aeruginosa.

The IDSA guideline encourages all microbiology laboratories to perform antimicrobial sensitivity testing for MDR and DTR P. aeruginosa isolates against the new β-lactam antimicrobials: ceftolazane/tazobactam (Zerbaxa; Merck), ceftazidime/avibactam (Avycaz; AbbVie), imipenem/cilastatin/relebactam (Recarbrio; Merck), and cefidericol (Fetroja; Shionogi).^3,6

Based on clinical trials for uncomplicated urinary tract infections (UTIs), the preferred agents are ceftolazone/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol. Alternative agents would be single dose tobramycin or amikacin.^7-11 Also based on clinical trial data, the same new β-lactam agents preferred for uUTI are recommended for use in complicated UTIs with daily tobramycin or amikacin as alternatives.^7-10 Based on in-vitro activity and clinical trial data, ceftolazane/tazobactam, ceftazidime/avibactam, and imipenem/cilastatin/relebactam are the preferred agents for treatment of infections outside the urinary tract, with cefiderocol as an alternative.^12-22

There are no clinical trials that compare the newer β-lactam agents (ceftolazane/tazobactam vs ceftazidime/avibactam). There are available clinical trials comparing the newer β-lactam agents with older agents (ceftolazane/tazobactam vs polymyxin) for MDR P. aeruginosa but not DTR P. aeruginosa.

Rationale

Ceftolazane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol are preferred treatment options based on in vitro activity, observational studies, and clinical trials showing noninferiority of these agents vs common comparator agents for the treatment of both uncomplicated and complicated UTIs.^7-10 Tobramycin and amikacin were chosen as alternative agents because aminoglycosides are renally eliminated in the active form with minimal toxicity. However, there is a lack of robust clinical trials.²¹ Most patients in the clinical trials did not have DTR P. aeruginosa infections.

One study compared outcomes of patients with MDR P.aeruginosa receiving ceftolazane/tazobactam vs polymyxin or aminoglycoside therapy. The results showed 81% of patients receiving ceftolazane/tazobactam had a favorable outcome compared to 61% receiving polymyxin or aminoglycoside-based therapy.²⁴ Other studies involved a limited number of patients and included those with MDR P. aeruginosa and not DTR, or had limitations.^25,26

Emergence of Resistance to DTR P. aeruginosa

Ceftazidime/avibactam and ceftolazane/tazobactam resistance is due to amino acid substitutions, insertions, or deletions in the Pseudomonas-derived cephalosporinase.^24-26 Resistance to imipenem/cilastatin/relebactam is related to loss of the outer membrane protein OprD and over-expression of efflux pumps.^27-29 Deficiency of the outer membrane protein OprD confers P. aeruginosa a basal level of resistance to carbapenems, especially imipenem/cilastatin.

There are multiple resistance mechanisms for cefiderocol, including mutations in the modification of the PBP3.^30-35 Ceftolazane/tazobactam and ceftazidime/avibactam appear to be at greater risk of resistance to P. aeruginosa partially due to being used more often in clinical practice.³ There is cross resistance between ceftolazane/tazobactam and ceftazidime/avibactam due to structural similarities.³⁶

In a study by Tamma et al, 78 patients with DTR P. aeruginosa who were treated with ceftolazane/tazobactam had subsequent DTR isolates after the start of therapy.³⁷ Half of the subsequent isolates were no longer sensitive to ceftolazane/tazobactam after a median duration of 15 days of therapy. Most patients with an original isolate sensitive to ceftazidime/avibactam had subsequent isolates displaying resistance to ceftazidime/avibactam after being exposed to ceftolazane/tazobactam and no prior exposure to ceftazidime/avibactam.³⁷ There are limited data for emergence of resistance to imipenem/cilastatin/relebactam or cefiderocol.^9,28,38

Antibiotic susceptibility testing should be done for the 4 new β-lactam agents when a patient previously infected with DTR P. aeruginosa presents with signs and symptoms of sepsis, suggesting a new or relapsed infection. If a patient who was recently treated with ceftolazane/tazobactam or ceftazidime/ avibactam presents with signs and symptoms of a recurrent infection, imipenem/cilastatin/relecbactam cefidericol should be used initially, especially if previous antibiotic susceptibility testing proved sensitive for one of these agents, until antibiotic susceptibility testing results are available for all 4 of the new β-lactam agents.³

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