What are the indications, oral and intravenous dosing regimens, contraindications, adverse effects, and alternative agents for fosfomycin?

Fosfomycin: Indications, Dosing, Contraindications, Adverse Effects, and Alternatives

Indications

Fosfomycin is FDA-approved exclusively for uncomplicated cystitis in women and should not be used for pyelonephritis, complicated UTIs, or routine treatment in men. 1, 2

Approved Uses

• Uncomplicated cystitis in women – Single 3-gram oral dose is first-line therapy when trimethoprim-sulfamethoxazole (TMP-SMX) resistance exceeds 20% in the community. 1, 2
• Asymptomatic bacteriuria in pregnancy – Single 3-gram dose is recommended as standard short-course treatment. 2
• Vancomycin-resistant Enterococcus (VRE) uncomplicated UTI – Same single 3-gram oral dose. 1, 2

Off-Label Uses (Intravenous Formulation)

• Carbapenem-resistant Enterobacteriaceae (CRE) infections – IV fosfomycin-containing combination therapy when susceptibility is confirmed (susceptibility rates in carbapenem-resistant K. pneumoniae range 39–99%). 3
• Multidrug-resistant gram-negative infections – IV combination therapy only, never monotherapy, due to rapid resistance development. 3

Explicit Contraindications to Use

• Pyelonephritis or upper UTIs – Insufficient efficacy data; fluoroquinolones or β-lactams are preferred. 1, 2
• Complicated UTIs – Oral fosfomycin lacks adequate tissue penetration; IV formulation may be considered in combination. 2
• Men with UTIs – Limited efficacy data; not recommended for routine use. 2

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Dosing Regimens

Oral Fosfomycin Tromethamine

Standard Regimen for Uncomplicated Cystitis

• 3 grams as a single oral dose – Provides therapeutic urinary concentrations for 24–48 hours, sufficient to eradicate most uropathogens. 1, 2, 4
• Clinical cure rate: 91% at 5–9 days post-treatment. 1
• Microbiological eradication: 78–83% (slightly lower than TMP-SMX or nitrofurantoin but clinically comparable). 1

Off-Label Multi-Dose Regimen

• 3 grams on days 1,3, and 5 – Suggested for gonococcal urethritis (not FDA-approved). 2

Pharmacokinetics

• Oral bioavailability: 34–41%. 4
• Elimination half-life: 5.7 hours (increases to 40–50 hours in anuric patients). 2, 4
• Peak urinary concentrations: >128 mg/L within 4 hours, maintained for 24–48 hours. 4

Intravenous Fosfomycin Disodium

Carbapenem-Resistant Infections (Combination Therapy Only)

• Dosing not standardized in U.S. – IV formulation not FDA-approved; available in Europe and other countries. 5, 6
• Always use in combination with tigecycline, polymyxin, aminoglycosides, or high-dose carbapenems. 3
• Mandatory susceptibility testing before initiation. 3

Renal Dosing Adjustments

• eGFR ≥30 mL/min/1.73 m² – No dose adjustment required for oral formulation. 2
• eGFR <30 mL/min/1.73 m² – Oral fosfomycin not recommended; IV formulation requires dose reduction due to prolonged half-life. 2

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Contraindications

Absolute Contraindications

• Hypernatremia – IV formulation contains high sodium load. 2, 3
• Cardiac insufficiency – Heart failure developed in 8.6% of IV fosfomycin recipients versus 1.4% with meropenem in the FOREST trial. 3
• Severe renal insufficiency (eGFR <30 mL/min/1.73 m²) – Elimination half-life increases from 5.7 to 40–50 hours in anuric patients. 2

Relative Contraindications

• Pyelonephritis or upper UTI – Insufficient tissue penetration and efficacy data. 1, 2
• Complicated UTI – Oral formulation inadequate; IV combination therapy may be considered. 2

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Adverse Effects

Common (Oral Formulation)

• Diarrhea, nausea, headache – Occur in 5.6–28% of patients; transient, mild, and self-limiting. 1, 4, 7
• Gastrointestinal disturbances – Most frequently reported adverse events. 2

Serious (Intravenous Formulation)

• Severe hypokalemia – Reversible; occurred in 3 of 48 ICU patients (6.3%) receiving IV fosfomycin combinations. 3
• Hypocalcemia, hypomagnesemia, hypernatremia – Electrolyte monitoring required during and after IV treatment. 2
• Heart failure – 8.6% incidence with IV fosfomycin versus 1.4% with meropenem. 3

Safety Profile

• Minimal disruption to intestinal flora – Lower risk of C. difficile infection compared to fluoroquinolones or cephalosporins. 1, 2
• Low protein binding – Primarily excreted unchanged in urine. 5
• Pregnancy category B – Safe in pregnancy; recommended for asymptomatic bacteriuria. 2, 4

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Alternative Agents for Uncomplicated Cystitis

First-Line Alternatives

Nitrofurantoin (Preferred)

• 100 mg orally twice daily for 5 days – Clinical cure 93%, microbiological eradication 88%. 1, 2
• Advantages: Excellent E. coli activity (75–95% of cases), <1% resistance worldwide, minimal collateral damage. 1, 2
• Contraindication: eGFR <30 mL/min/1.73 m². 2

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• 160/800 mg orally twice daily for 3 days – Clinical cure 93%, microbiological eradication 94%. 1, 2
• Use only if: Local E. coli resistance <20% AND no TMP-SMX use in prior 3 months. 1, 2
• Resistance threshold: Do not use empirically when resistance ≥20%. 1, 2

Second-Line (Reserve) Agents

Fluoroquinolones

• Ciprofloxacin 250 mg twice daily for 3 days OR levofloxacin 250 mg once daily for 3 days – Clinical cure ~90%, microbiological eradication ~91%. 1
• Reserve for: Culture-proven resistant organisms or when first-line agents contraindicated. 1, 2
• Serious adverse effects: Tendon rupture, C. difficile infection, MRSA promotion. 1

Beta-Lactams

• Amoxicillin-clavulanate, cefdinir, cefpodoxime for 3–7 days – Clinical cure ~89%, microbiological eradication ~82% (inferior to first-line). 1
• Never use amoxicillin or ampicillin alone – Resistance exceeds 55–67% worldwide. 1, 2

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Clinical Decision Algorithm

Step 1: Confirm Uncomplicated Cystitis

• Typical symptoms: Dysuria, frequency, urgency, no fever, no flank pain. 1, 2
• No urine culture required for straightforward cases in healthy women. 1, 2

Step 2: Assess Local TMP-SMX Resistance

• If <20% AND no TMP-SMX in prior 3 months → Prescribe TMP-SMX 160/800 mg twice daily for 3 days. 1, 2
• If ≥20% OR data unavailable → Choose nitrofurantoin (5 days) or fosfomycin (single dose). 1, 2

Step 3: Monitor Response

• If symptoms persist after 2–3 days OR recur within 2 weeks → Obtain urine culture and switch to different antibiotic class for 7 days. 1, 2
• Reserve fluoroquinolones only for culture-proven resistance. 1, 2

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Key Clinical Pitfalls

• Do not use fosfomycin for pyelonephritis – Insufficient tissue penetration; switch to fluoroquinolone or parenteral cephalosporin. 1, 2
• Do not assume susceptibility for CRE – Mandatory susceptibility testing before IV fosfomycin; resistance genes (FosA-like) increasingly prevalent. 3
• Do not use IV fosfomycin as monotherapy – Rapid resistance development; always combine with tigecycline, polymyxin, aminoglycoside, or high-dose carbapenem. 3
• Do not prescribe in severe renal impairment – Elimination half-life increases 7-fold in anuric patients. 2
• Monitor electrolytes with IV formulation – Severe hypokalemia occurred in 6.3% of ICU patients. 3