Fosfomycin

Overview

Mechanism of Action

• This mechanism is entirely unique among antibacterials, so cross-resistance to other drug classes is rarely encountered.
• The drug is bactericidal.
• Beyond cell wall inhibition, fosfomycin also reduces bacterial adherence to uroepithelial cells, which is therapeutically relevant for UTIs.
• Note: optimal in vitro susceptibility testing requires supplementation of media with glucose-6-phosphate (which facilitates fosfomycin uptake via the GlpT and UhpT transporters).

Spectrum of Activity

Pharmacokinetics

Available Formulations

• United States: Oral only - fosfomycin tromethamine powder (3 g sachet dissolved in water). IV formulation is NOT FDA-approved in the US.
• Outside the US: Intravenous formulation is widely available (fosfomycin disodium) for systemic use, often in combination with other agents.

Clinical Uses

1. Uncomplicated Cystitis (Primary Indication)

• Single 3-g oral dose - the FDA-approved regimen.
• Considered first-line therapy alongside nitrofurantoin and TMP-SMX.
• Especially valuable when other first-line options are contraindicated (e.g., in pregnancy, renal impairment limiting nitrofurantoin use, or areas of high TMP-SMX resistance).
• Highly effective against ESBL-producing E. coli and VRE UTIs.

2. Complicated UTI / Recurrent UTI Prophylaxis (Off-label in US)

• Some clinicians use 3 g every other day for 3 doses for complicated UTI.
• 3 g every 10 days for recurrent UTI prophylaxis.

3. Systemic/Serious Infections (IV formulation, outside US)

• Used in combination (never monotherapy) for:
  • ESBL- and KPC-producing Enterobacterales bloodstream infections
  • MRSA infections
  • Carbapenem-resistant organisms
  • Osteomyelitis, endocarditis (as combination partner)
• Monotherapy risks rapid resistance emergence with IV use for systemic infections.

Resistance Mechanisms

• Chromosomal mutations in MurA (target modification) or the transport proteins GlpT and UhpT (reduced uptake).
• Plasmid-mediated resistance via FosA, FosB, FosC, and FosX enzymes (glutathione transferases that inactivate fosfomycin).
• Key clinical point: resistance emergence has NOT been observed during treatment of cystitis with the oral single-dose regimen, but has been documented during IV treatment of respiratory tract infections and osteomyelitis.

Adverse Effects

• GI distress (nausea, diarrhea) - most common
• Headache
• Dizziness
• Vaginitis (in women treated for UTI)
• No significant nephrotoxicity or hepatotoxicity

Key Clinical Pearls

1. Single-dose oral therapy for uncomplicated cystitis achieves very high compliance rates.
2. ESBL coverage makes it one of very few oral options for ESBL UTIs - a critical advantage in outpatient settings.
3. VRE (E. faecalis) UTIs are often susceptible - an important niche use.
4. Avoid for pyelonephritis - systemic concentrations after oral dosing are too low.
5. Do not use as monotherapy for systemic infections - resistance emerges rapidly.
6. No dose adjustment needed for mild-moderate renal impairment for cystitis treatment (drug is excreted in urine as active drug), but should be used cautiously in severe renal failure.
7. Overuse risks selecting for resistance - reserve for situations where other first-line agents cannot be used per Rosen's Emergency Medicine.

Recent Evidence (PubMed 2024-2026)

Tetanus Toxoid (TT) Vaccine - Complete Regimen

1. Routine Childhood Immunization (CDC / Red Book Schedule)

• 5 doses of DTaP complete the primary childhood series.
• The 11-12 year Tdap replaces one Td booster and adds pertussis coverage.
• Every subsequent adult booster is Td (or Tdap if Tdap has not been given before).

2. WHO Primary Schedule (Universal / Developing Countries)

• Minimum 4 years between booster doses.
• 5 doses total provide long-term (possibly lifelong) protection.

3. Antenatal (Pregnancy) TT Schedule

Previously unimmunized pregnant woman:

• Minimum interval between TT1 and TT2: 4 weeks.
• TT2 must be given ≥3 weeks before delivery to allow adequate transfer of maternal antibodies to the fetus.
• If the woman is seen late in pregnancy and may not return: give at least 1 dose regardless of gestational age - no evidence that TT is harmful to the fetus.

Previously immunized pregnant woman:

• If last dose was ≤10 years ago: 1 booster dose is sufficient.
• No need for a booster at every consecutive pregnancy (risk of hyper-immunization).

WHO 5-dose maternal schedule (for areas of high neonatal tetanus incidence):

4. Catch-up Schedule (Unvaccinated / Incompletely Vaccinated)

Children 7-10 years (incomplete prior DTaP):

• Preferred: Tdap → Td/Tdap at 2 months → Td/Tdap at 6-12 months
• Still receive the adolescent Tdap booster at 11-12 years.

Adolescents and Adults (never vaccinated or unknown history):

• 3-dose primary series: Dose 1 (Tdap) → Dose 2 at 4 weeks → Dose 3 at 6-12 months
• Then Td/Tdap booster every 10 years.

5. Wound Prophylaxis (Post-Exposure Management)

Wound classification:

• Clean wound: <6 hours old, non-penetrating, negligible tissue damage
• Tetanus-prone wound: >6 hours, puncture/crush injury, contaminated (soil, feces, rust), devitalized tissue, burns, frostbite
• High-risk tetanus-prone: Heavily contaminated, delayed presentation, extensive devitalized tissue

Management guide:

• TIG (Tetanus Immunoglobulin): 250 IU IM (up to 500 IU for high-risk), given at a different site from the toxoid.
• If TIG is unavailable: Human Normal Immunoglobulin (HNIG) can be used as an alternative.
• Patients with HIV or severe immunosuppression should receive TIG regardless of vaccination history.
• Tetanus disease does NOT confer immunity - always vaccinate during convalescence.

6. Special Populations

Key Points to Remember

1. Standalone TT is mainly used in antenatal/maternal programs; in all other settings, combination vaccines (DTaP, Tdap, Td) are preferred.
2. The standard childhood series is 5 doses of DTaP (at 2, 4, 6 months; 15-18 months; 4-6 years).
3. Tdap at 11-12 years is the recommended adolescent booster (adds pertussis coverage).
4. Adult boosters: every 10 years (Td or Tdap).
5. In pregnancy: Tdap every pregnancy (27-36 weeks); unimmunized women need a 3-dose series.
6. For wound management: the decision to give TIG depends on wound type and number of prior doses.
7. Resistance emerging during IV treatment (wound-associated): always ensure immunization since disease itself does not confer immunity.