Role of Fosfomycin in Management of Pseudomonas Infections
Fosfomycin should primarily be used as part of combination therapy rather than monotherapy for Pseudomonas aeruginosa infections, particularly for carbapenem-resistant strains, due to the high risk of resistance development with monotherapy and improved efficacy when combined with other antipseudomonal agents. 1, 2, 3
Mechanism and Activity Against Pseudomonas
- Fosfomycin inhibits bacterial cell wall synthesis through a unique mechanism by targeting MurA, which initiates peptidoglycan biosynthesis at a step prior to that inhibited by β-lactams 4
- Fosfomycin demonstrates variable in vitro activity against P. aeruginosa with MIC50/90 values of 48/≥1024 mg/L reported in clinical isolates of carbapenem-resistant P. aeruginosa 2
- P. aeruginosa develops resistance to fosfomycin more readily than Enterobacteriaceae both in vitro and in clinical studies, limiting its utility as monotherapy 5, 4
Combination Therapy Applications
- Synergistic interactions between fosfomycin and other antibiotics have been demonstrated in approximately 21.7% of tested combinations against carbapenem-resistant P. aeruginosa 2
- Highest synergy rates were observed when fosfomycin was combined with ceftazidime (51.9%) and ceftolozane/tazobactam (50%) 2
- Combinations of fosfomycin with polymyxin B or tobramycin showed enhanced killing against fosfomycin-susceptible P. aeruginosa isolates, while fosfomycin with ciprofloxacin improved activity against fosfomycin-resistant isolates 6
- Meropenem susceptibility was restored in 13.7% of carbapenem-resistant P. aeruginosa isolates when combined with fosfomycin 2
Resistance Concerns
- Resistance to fosfomycin develops rapidly in P. aeruginosa during monotherapy, primarily through modifications of membrane transporters that prevent fosfomycin from entering the bacterial cell 5, 4
- The mutation frequency for fosfomycin resistance is higher in P. aeruginosa compared to E. coli and is associated with fosfomycin concentration 4
- Even when used in combination therapy, fosfomycin resistance can still emerge in P. aeruginosa, though the clinical impact may be mitigated by the synergistic effects with other agents 6
- Unlike in Enterobacteriaceae, mutations conferring fosfomycin resistance in Pseudomonas do not appear to have a significant biological cost, making resistance more stable 4
Clinical Applications
- For carbapenem-resistant P. aeruginosa infections, fosfomycin may be considered as part of combination therapy with agents such as polymyxins, aminoglycosides, or carbapenems 1, 3
- Intravenous fosfomycin has favorable pharmacokinetic properties for both bloodstream and deep-seated infections, including antibiofilm activity that may be beneficial for biofilm-producing P. aeruginosa 3
- Observational studies suggest that fosfomycin-containing combination therapies may reduce mortality in infections caused by multidrug-resistant gram-negative bacteria, though evidence quality is very low 1
- Fosfomycin has minimal propensity for collateral damage to intestinal flora, making it advantageous from an antibiotic stewardship perspective 1
Practical Recommendations
- For serious P. aeruginosa infections, particularly carbapenem-resistant strains, fosfomycin should be used as part of combination therapy rather than as monotherapy 1, 2, 3
- The choice of companion agent should be guided by susceptibility testing, with ceftazidime, ceftolozane/tazobactam, polymyxins, or aminoglycosides being potential options based on synergy studies 2, 6
- Regular monitoring for the emergence of resistance is essential during treatment, as resistance can develop despite combination therapy 4, 6
- Consider fosfomycin as a carbapenem-sparing option in settings with high incidence of carbapenem-resistant P. aeruginosa to reduce selective pressure for carbapenem resistance 1
Limitations
- The bacterial efficacy of fosfomycin is generally lower than that of other first-line agents for uncomplicated infections 1
- Fosfomycin susceptibility testing is not routinely performed in many clinical laboratories, which may limit its targeted use 1
- Evidence for clinical efficacy against P. aeruginosa infections is primarily based on in vitro and observational studies rather than randomized controlled trials 1, 2, 3