The General Spectrum of Fosfomycin
Fosfomycin is a bactericidal antibiotic that inhibits bacterial cell wall synthesis. It is known for its broad-spectrum activity against many Gram-positive and Gram-negative pathogens commonly associated with urinary tract infections (UTIs). This includes E. coli (even multidrug-resistant strains), Enterococcus faecalis, and various other Enterobacteriaceae. Its unique mechanism of action and lack of cross-resistance with other antibiotic classes make it a valuable tool, particularly for multidrug-resistant infections.
However, its usefulness is not universal. The coverage of fosfomycin is limited by several groups of bacteria that possess either intrinsic (natural) or acquired resistance mechanisms. Clinicians must be aware of these limitations to avoid treatment failures, particularly in systemic infections where fosfomycin may achieve insufficient tissue concentrations.
Bacteria with Intrinsic Fosfomycin Resistance
Intrinsic resistance refers to a natural characteristic of a bacterial species that makes it unaffected by a particular antibiotic. For fosfomycin, several significant pathogens fall into this category. These bacteria are often considered inherently resistant, meaning fosfomycin is typically ineffective against them and should not be used for treatment.
Common examples of intrinsically resistant bacteria:
- Pseudomonas aeruginosa: A major opportunistic pathogen, P. aeruginosa is intrinsically resistant to fosfomycin. While some studies have explored its use in combination therapy, particularly in treating biofilm infections, it is not a first-line agent due to high resistance rates. P. aeruginosa can also acquire further resistance through mutations in its transport systems.
- Acinetobacter spp.: This group of Gram-negative bacteria, which includes the notorious carbapenem-resistant Acinetobacter baumannii, is known to be inherently resistant. While some intravenous formulations have been studied for combination therapy in severe infections, its standalone use is not recommended.
- Stenotrophomonas maltophilia: This opportunistic pathogen is another example of a bacterium with intrinsic resistance to fosfomycin. Studies have shown that it can acquire increased resistance through mutations affecting its metabolic pathways.
- Burkholderia cepacia complex: Often problematic in patients with cystic fibrosis, the B. cepacia complex is known to be intrinsically resistant to many antibiotics, including fosfomycin.
- Morganella morganii: A member of the Enterobacteriaceae family, M. morganii is also inherently fosfomycin-resistant, distinguishing it from other family members like E. coli which are typically susceptible.
- Bacteroides spp.: Many Gram-negative anaerobic bacteria, including Bacteroides species, are not covered by fosfomycin. This significantly limits its utility in polymicrobial infections involving anaerobes, such as abdominal or pelvic infections.
Acquired Resistance and Limited Susceptibility
In addition to intrinsic resistance, some bacteria that are typically susceptible to fosfomycin can develop resistance over time through genetic mutations or the acquisition of resistance genes. Ongoing surveillance is necessary to monitor these trends.
Notable examples of acquired resistance and limited susceptibility:
- Klebsiella spp.: While often susceptible, certain strains of Klebsiella pneumoniae, especially carbapenem-resistant ones (CRKP), have shown increasing rates of fosfomycin resistance. Resistance can be conferred by plasmid-mediated genes like fosA3 or mutations in chromosomal genes. Fosfomycin susceptibility testing is not always reliable for K. pneumoniae, as resistance genes may not be captured by standard methods.
- Enterococci: Fosfomycin typically shows good activity against vancomycin-resistant enterococci (VRE), but resistant isolates have been identified. High-level resistance has been reported in Enterococcus faecium due to target enzyme mutations.
- Staphylococcus capitis and Staphylococcus saprophyticus: While fosfomycin shows activity against many staphylococci, including MRSA, these two species are known to be inherently resistant. A novel resistance gene, fosSC, has been identified in S. capitis.
- Mycobacterium tuberculosis: The bacteria responsible for tuberculosis are intrinsically resistant to fosfomycin.
Comparison of Fosfomycin Coverage vs. Limitations
| Feature | Covered Pathogens | Non-Covered/Limited Pathogens |
|---|---|---|
| Gram-Negative | E. coli, Proteus mirabilis, Citrobacter spp., Klebsiella spp. (often susceptible) | Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Bacteroides spp., Morganella morganii |
| Gram-Positive | Enterococcus faecalis (including VRE), Staphylococcus aureus (including MRSA) | Staphylococcus capitis, Staphylococcus saprophyticus, Mycobacterium tuberculosis |
| Anaerobes | Peptococcus spp., Peptostreptococcus spp. | Bacteroides spp. |
| Infection Types | Uncomplicated lower UTIs | Systemic infections, pyelonephritis, prostatitis (oral form) |
Clinical Implications of Fosfomycin's Limitations
Fosfomycin's antimicrobial limitations have significant clinical implications, particularly when managing infections beyond simple, uncomplicated cystitis. The oral formulation, for instance, achieves high concentrations in the urine but low serum and tissue concentrations, making it unsuitable for systemic infections like pyelonephritis or prostatitis. For these more complex infections, an intravenous formulation of fosfomycin is sometimes used, often as part of a combination therapy, particularly for multidrug-resistant pathogens.
Awareness of the pathogens that are intrinsically or predictably resistant is key to proper antibiotic stewardship. When dealing with infections potentially caused by organisms like Pseudomonas or Acinetobacter, clinicians should select an alternative antibiotic with a known and effective spectrum of activity. Additionally, in infections with a polymicrobial etiology that may involve anaerobes, fosfomycin is not an appropriate monotherapy.
Finally, ongoing antimicrobial resistance surveillance is crucial. As seen with Klebsiella and Enterococcus, resistance patterns can emerge even in traditionally susceptible species, necessitating susceptibility testing before prescribing, especially for more complex or resistant infections.
Conclusion
In summary, while fosfomycin is an effective and safe antibiotic for specific indications, its antimicrobial spectrum is not all-encompassing. What bacteria does fosfomycin not cover? This includes intrinsically resistant pathogens such as Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Burkholderia cepacia complex, Morganella morganii, and Mycobacterium tuberculosis. Furthermore, it lacks activity against many Gram-negative anaerobes like Bacteroides spp. and faces emerging resistance in traditionally susceptible organisms, including certain strains of Klebsiella and Enterococcus. These limitations highlight the importance of accurate diagnosis, judicious antibiotic selection, and consideration of the infection type and location when prescribing fosfomycin. Further information on the topic is available here.
