Treatment of Resistant Pseudomonas aeruginosa Infections
For difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA), use ceftolozane/tazobactam (3 g IV every 8 hours for pneumonia, 1.5 g IV every 8 hours for other infections) or ceftazidime/avibactam (2.5 g IV every 8 hours) as first-line therapy when the organism is susceptible to these agents. 1
Understanding Difficult-to-Treat Resistance
DTR-PA is defined as non-susceptibility to all first-line agents: ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, imipenem/cilastatin, meropenem, levofloxacin, and ciprofloxacin. 1 This represents a critical threshold where older agents become ineffective and newer β-lactam/β-lactamase inhibitor combinations become essential. 1
Treatment Algorithm
Step 1: First-Line Therapy Selection
For pneumonia (including hospital-acquired and ventilator-associated): Ceftolozane/tazobactam is the preferred agent at 3 g IV every 8 hours for 10-14 days. 1
For bloodstream infections: Either ceftolozane/tazobactam or ceftazidime/avibactam for 10-14 days. 1
For complicated urinary tract infections: Either agent for 5-10 days. 1
For complicated intra-abdominal infections: Either agent for 5-10 days. 1
Step 2: Alternative Agents When First-Line Options Fail
If metallo-β-lactamases (MBLs) are absent: Imipenem/cilastatin/relebactam may retain activity even when ceftolozane/tazobactam and ceftazidime/avibactam resistance is present. 1
If MBLs are present: Cefiderocol is the preferred alternative. 1
Last-resort option: Colistin-based therapy with loading dose of 5 mg colistin base activity/kg IV, then 2.5 mg CBA × [1.5 × CrCl + 30] IV every 12 hours. 1
Step 3: Combination Therapy Considerations
Combination therapy should not be routine practice but may be considered after infectious diseases consultation for severe infections with limited susceptibility options. 1, 2 The evidence for combination therapy is mixed—while some studies suggest synergy with combinations like piperacillin-tazobactam with levofloxacin (72.7% synergy) or amikacin with levofloxacin (66.7% synergy), in vitro synergy does not always translate to clinical benefit. 3, 2
Combination therapy may be considered when treating with two in vitro active drugs for severe infections. 1
Fosfomycin-containing combinations with meropenem may be effective but should be evaluated case-by-case. 2
For nosocomial pneumonia caused by P. aeruginosa, piperacillin/tazobactam should be combined with an aminoglycoside according to FDA labeling. 4
Critical Pitfalls to Avoid
Do not use older agents (ceftazidime, piperacillin/tazobactam, carbapenems, fluoroquinolones) empirically for DTR-PA—they are ineffective by definition. 1
Avoid carbapenem-based combinations for DTR-PA unless meropenem MIC is ≤8 mg/L and extended infusion (>3 hours) is used. 1
Do not underdose colistin: Use proper loading dose to avoid subtherapeutic levels. 1
Ceftazidime/avibactam monotherapy may increase resistance development during therapy—monitor closely and consider combination therapy if clinical response is inadequate. 1
Frequent antibiotic switching may be an option to prevent resistance development, particularly with prolonged monotherapy. 5, 2
Tailoring Therapy Based on Culture Results
Once culture and susceptibility results are available, tailor therapy immediately. 1, 2 Monotherapy with a highly active antipseudomonal β-lactam is preferred in the absence of compelling indications for combination therapy. 1, 2 The emergence of resistant organisms does not necessarily lead to poor treatment response, but monitoring is essential. 5
Special Considerations
Long-term monotherapy with β-lactam antibiotics can lead to rapid resistance development, especially with agents like ceftazidime. 5, 2
Resistance can develop in 30-40% of organisms during treatment, associated with treatment failure in 10-20% of cases. 6
Amikacin and imipenem historically remained effective as salvage therapy against isolates resistant to other agents, though newer agents now supersede these options for DTR-PA. 7