Treatment of Resistant Pseudomonas aeruginosa Infections
For difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA), use ceftolozane-tazobactam 3g IV every 8 hours for pneumonia or ceftazidime-avibactam 2.5g IV every 8 hours for non-pulmonary infections as first-line monotherapy when the organism is susceptible to these agents. 1, 2
Defining Resistant Pseudomonas
Difficult-to-treat resistance in P. aeruginosa means non-susceptibility to all of the following first-line agents: ceftazidime, cefepime, piperacillin-tazobactam, aztreonam, imipenem, meropenem, levofloxacin, and ciprofloxacin. 1 This definition is critical because it determines when you need to escalate to newer agents rather than conventional antipseudomonal antibiotics.
First-Line Treatment Algorithm for DTR-PA
When Susceptibility is Known:
For pneumonia (including HAP/VAP):
- Ceftolozane-tazobactam is preferred at 3g IV every 8 hours for 10-14 days 1, 2
- This agent demonstrates superior outcomes in pulmonary infections compared to ceftazidime-avibactam 1
For non-pulmonary infections (bacteremia, UTI, intra-abdominal):
- Either ceftolozane-tazobactam 1.5g IV every 8 hours OR ceftazidime-avibactam 2.5g IV every 8 hours 1, 2
- Both are equally effective for these infection types 1
- Duration: 10-14 days for bacteremia/bone infections, 5-10 days for UTI/intra-abdominal infections 1
When First-Line Agents Show Resistance:
If resistant to ceftolozane-tazobactam AND ceftazidime-avibactam:
- Use imipenem-cilastatin-relebactam when metallo-β-lactamases (MBLs) are absent 1, 2
- Use cefiderocol when MBLs are present or as an alternative when other novel agents show resistance 1, 2, 3
For MBL-producing strains:
- Cefiderocol is the preferred agent 1, 2
- Alternative options include aztreonam-avibactam or ceftazidime-avibactam combined with aztreonam, though evidence is limited 2
Role of Combination Therapy
Combination therapy should NOT be routine practice for DTR-PA. 1 Despite in vitro synergy demonstrations, there is no clinical evidence supporting combination therapy as a general approach. 2 However, consider combination therapy on a case-by-case basis after infectious diseases consultation for:
- Severe infections with limited susceptibility options 1
- Situations requiring treatment with two in vitro active drugs 1
The older evidence suggesting combination therapy prevents resistance emergence (from CF populations) 4 does not apply to modern DTR-PA management with newer agents. 1, 2
Last-Resort Options
Colistin-based therapy is reserved for situations where all other options have failed:
- Loading dose: 5 mg colistin base activity/kg IV 1
- Maintenance: 2.5 mg CBA × [1.5 × CrCl + 30] IV every 12 hours 1
- Critical pitfall: Use proper loading dose to avoid subtherapeutic levels 1
- May combine with meropenem for MBL-producing strains, though evidence is limited 2
Critical Pitfalls to Avoid
Do not use older conventional antipseudomonal agents empirically for DTR-PA (ceftazidime, cefepime, piperacillin-tazobactam, carbapenems) as they are ineffective by definition. 1 This is the most common error in DTR-PA management.
Avoid carbapenem-based combinations for DTR-PA unless meropenem MIC is ≤8 mg/L and extended infusion (>3 hours) is used. 1
Ceftazidime-avibactam monotherapy may increase resistance development during therapy, so ensure close monitoring and susceptibility retesting if clinical response is inadequate. 1
Never assume monotherapy with conventional agents will work - the resistance mechanisms in DTR-PA (AmpC β-lactamases, efflux pumps, porin mutations) make treatment failure nearly certain. 5
Tailoring Therapy
Always tailor therapy once culture and susceptibility results are available. 1 Monotherapy with a highly active antipseudomonal β-lactam is preferred in the absence of compelling indications for combination therapy. 1 This approach differs from older CF-based guidelines that routinely recommended combination therapy. 4
Obtain infectious diseases consultation for all DTR-PA infections to optimize agent selection and dosing strategies. 1