Is fosfomycin (antibiotic) effective for treating urosepsis?

Fosfomycin for Urosepsis

Fosfomycin should NOT be used for urosepsis—it is FDA-approved and guideline-recommended only for uncomplicated cystitis in women, and there is insufficient evidence to support its use in septic patients or complicated urinary tract infections. 1, 2

Why Fosfomycin is Inappropriate for Urosepsis

FDA-Approved Indication is Limited

• Fosfomycin tromethamine is FDA-approved exclusively for uncomplicated urinary tract infections (uncomplicated cystitis), not for systemic infections or sepsis 2
• The drug achieves high urinary concentrations (mean 706 mcg/mL within 2-4 hours) but is designed for bladder-level infections, not bloodstream or systemic infections 2

Guideline Restrictions for Complicated UTI and Sepsis

• The European Association of Urology explicitly states that fosfomycin is not recommended for pyelonephritis or complicated UTIs due to insufficient efficacy data 1
• The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends fosfomycin only for complicated UTI without septic shock, meaning it should be avoided when sepsis is present 3
• Multiple guideline societies (EAU, IDSA) restrict fosfomycin to uncomplicated lower UTI in women, with no endorsement for systemic or septic presentations 1

What to Use Instead for Urosepsis

First-Line Empiric Therapy

• For urosepsis, initiate broad-spectrum intravenous antibiotics immediately—ceftriaxone 1-2 grams IV daily or ciprofloxacin 400 mg IV every 8-12 hours for community-acquired cases 4
• If multidrug-resistant organisms (ESBL-producers, CRE) are suspected based on local epidemiology or prior cultures, consider carbapenems (meropenem 1 gram IV every 8 hours or ertapenem 1 gram IV daily) 4

For Carbapenem-Resistant Enterobacterales (CRE)

• Ceftazidime-avibactam 2.5 grams IV every 8 hours is recommended for CRE-associated complicated intra-abdominal infections and can be extrapolated to urosepsis from abdominal sources 3
• Plazomicin (a novel aminoglycoside) showed lower mortality (24% vs 50%) compared to colistin-based regimens in the CARE trial for serious CRE infections, though this was a small study 3
• Polymyxin-based combination therapy is recommended for CRE when other options are unavailable, with combination agents selected based on susceptibility testing 3

Single-Dose Aminoglycosides for Cystitis Only

• Single-dose aminoglycosides (amikacin or gentamicin) may be considered for CRE-associated cystitis without systemic involvement, but there is insufficient evidence for complicated UTI or sepsis 3, 4
• Aminoglycosides achieve urinary concentrations 25-100 fold higher than plasma levels, making them effective for bladder infections but not reliable for bloodstream infections 3

Clinical Pitfalls to Avoid

Common Mistake: Using Oral Fosfomycin for Serious Infections

• Oral fosfomycin achieves therapeutic levels only in urine and bladder tissue, not in blood or other organs 2, 5
• Even though fosfomycin distributes to kidneys, bladder wall, and prostate, these tissue concentrations (18 mcg/gram at 3 hours) are insufficient for treating sepsis 2

Divergence Between In Vitro Susceptibility and Clinical Outcomes

• A retrospective study showed that while 92% of carbapenem-resistant Klebsiella pneumoniae were susceptible to fosfomycin in vitro, only 46% achieved microbiological cure, highlighting the gap between laboratory results and clinical efficacy 6
• Patients with solid organ transplants (59% vs 21%, p=0.02) and ureteral stents (24% vs 0%, p=0.02) had significantly higher failure rates with fosfomycin, suggesting host factors and anatomical complications limit effectiveness 6

When Fosfomycin Might Be Considered (Not for Sepsis)

• Fosfomycin can be used as step-down oral therapy after clinical improvement from IV antibiotics in uncomplicated cystitis caused by multidrug-resistant organisms, but only after sepsis has resolved 1, 7
• For asymptomatic bacteriuria in pregnant women, fosfomycin is safe and effective, but this is a completely different clinical scenario from urosepsis 1

Algorithm for Urosepsis Management

1. Recognize sepsis: Use qSOFA criteria (altered mental status, systolic BP ≤100 mmHg, respiratory rate ≥22/min) or SIRS criteria with suspected urinary source 4

2. Obtain cultures immediately: Blood cultures (2 sets) and urine culture with susceptibilities before antibiotics, but do not delay treatment 4

3. Initiate IV antibiotics within 1 hour:

   • Community-acquired: Ceftriaxone 1-2g IV daily or ciprofloxacin 400mg IV q8-12h 4
   • Healthcare-associated or MDR risk: Meropenem 1g IV q8h or piperacillin-tazobactam 4.5g IV q6h 4
   • Known CRE: Ceftazidime-avibactam 2.5g IV q8h 3

4. Source control: Remove or replace urinary catheters, address obstruction (stents, nephrostomy) 6

5. De-escalate based on cultures: Narrow to targeted therapy once susceptibilities return, typically at 48-72 hours 4

6. Duration: 7-14 days IV therapy depending on clinical response and source control, then consider oral step-down for uncomplicated cases only after sepsis resolves 4