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  • CLASSES

    Urinary Antibiotics and/or Sulfonamides

    DEA CLASS

    Rx

    DESCRIPTION

    Antibiotic; used for uncomplicated UTIs; may be synergistic with beta-lactam antibiotics; sustains effective urinary concentrations for over 3 days; efficacy as a single dose appears to be less than that for fluoroquinolones or co-trimoxazole.

    COMMON BRAND NAMES

    Monurol

    HOW SUPPLIED

    Monurol Oral Gran: 3g

    DOSAGE & INDICATIONS

    For the treatment of uncomplicated urinary tract infection (UTI), including cystitis.
    Oral dosage
    Adult women

    3 g PO as a single dose.

    MAXIMUM DOSAGE

    Adults

    Women: 3 g PO as a single dose.
    Men: Safety and efficacy have not been established.

    Elderly

    Women: 3 g PO as a single dose.
    Men: Safety and efficacy have not been established.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. The half-life of fosfomycin increases and urinary excretion decreases as renal impairment progresses.

    ADMINISTRATION

    Oral Administration

    Fosfomycin is administered orally without regard to meals.

    Oral Liquid Formulations

    Do not administer dry powder. Pour the entire contents of a sachet containing the equivalent of 3 g of fosfomycin into 3—4 oz (1/2 cup) of water; do not use hot water. Stir to dissolve. Take immediately after dissolving.

    STORAGE

    Monurol:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Breast-feeding

    Limited data indicate that fosfomycin produces low levels in milk. The manufacturer recommends that the use of fosfomycin in breast-feeding mothers should be undertaken with caution. In 2 women, after 1—2 grams of fosfomycin given by injection, colostrum concentrations were 4.8 mg/L and milk concentrations were 3.6 mg/L. Cephalexin, nitrofurantoin, or sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Trimethoprim (in combination with sulfamethoxazole) and nitrofurantoin are considered to be usually compatible with breast-feeding by the AAP. Cephalosporins, such as cephalexin, are generally considered to be compatible with breast-feeding. If fosfomycin is used, alterations to the infants' gut flora may be altered; monitor appropriately. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safe and effective use of fosfomycin in neonates, infants, and children under 12 years of age has not been established in adequate and well-controlled studies.

    Pregnancy

    Fosfomycin crosses the placental barrier. The FDA labeling suggests that fosfomycin should be used during pregnancy only if clearly needed. While there are no adequate and well-controlled studies with fosfomycin in pregnant women, observational data suggest that the single-dose use during pregnancy may be well tolerated during pregnancy.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following fosfomycin administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Geriatric

    Because fosfomycin is given in a single-dose regimen, no particular dose adjustments have been recommended for geriatric patients. Repeated daily doses do not improve the clinical success or microbiological eradication rates compared to single dose therapy, but do increase the incidence of adverse events. Diarrhea is a particularly common side effect. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    ADVERSE REACTIONS

    Severe

    toxic megacolon / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    hearing loss / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0

    Moderate

    vaginitis / Delayed / 5.5-7.6
    constipation / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    migraine / Early / 0-1.0
    dysuria / Early / 0-1.0
    hematuria / Delayed / 0-1.0
    lymphadenopathy / Delayed / 0-1.0
    pseudomembranous colitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known

    Mild

    diarrhea / Early / 9.0-10.4
    headache / Early / 3.9-10.3
    nausea / Early / 4.1-5.2
    rhinitis / Early / 4.5-4.5
    back pain / Delayed / 3.0-3.0
    dysmenorrhea / Delayed / 2.6-2.6
    pharyngitis / Delayed / 2.5-2.5
    dizziness / Early / 1.3-2.3
    abdominal pain / Early / 2.2-2.2
    dyspepsia / Early / 1.1-1.8
    asthenia / Delayed / 1.1-1.7
    rash / Early / 1.4-1.4
    anorexia / Delayed / 0-1.0
    xerostomia / Early / 0-1.0
    vomiting / Early / 0-1.0
    flatulence / Early / 0-1.0
    influenza / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    drowsiness / Early / 0-1.0
    insomnia / Early / 0-1.0
    myalgia / Early / 0-1.0
    fever / Early / 0-1.0
    pruritus / Rapid / 0-1.0

    DRUG INTERACTIONS

    Bethanechol: (Moderate) Bethanechol increases gastrointestinal motility and may decrease the systemic absorption of fosfomycin when the drugs are coadministered. This may result in lower fosfomycin serum concentrations and urinary excretion. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
    Cisapride: (Moderate) Cisapride may decrease the systemic absorption of fosfomycin due to the prokinetic action of cisapride. This may result in lower fosfomycin serum concentrations and urinary excretion. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
    Metoclopramide: (Moderate) When coadministered with fosfomycin, metoclopramide, a drug which increases gastrointestinal motility, lowers the serum concentration and urinary excretion of fosfomycin. Other drugs that increase gastrointestinal motility may produce similar effects. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.
    Prucalopride: (Moderate) Prucalopride may decrease the systemic absorption of fosfomycin due to the prokinetic action of prucalopride. This may result in lower fosfomycin serum concentrations and urinary excretion. Monitor for evidence of clinical effectiveness of fosfomycin. Since fosfomycin is given as a single dose, separating times of administration may limit the interaction.

    PREGNANCY AND LACTATION

    Pregnancy

    Fosfomycin crosses the placental barrier. The FDA labeling suggests that fosfomycin should be used during pregnancy only if clearly needed. While there are no adequate and well-controlled studies with fosfomycin in pregnant women, observational data suggest that the single-dose use during pregnancy may be well tolerated during pregnancy.

    Limited data indicate that fosfomycin produces low levels in milk. The manufacturer recommends that the use of fosfomycin in breast-feeding mothers should be undertaken with caution. In 2 women, after 1—2 grams of fosfomycin given by injection, colostrum concentrations were 4.8 mg/L and milk concentrations were 3.6 mg/L. Cephalexin, nitrofurantoin, or sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Trimethoprim (in combination with sulfamethoxazole) and nitrofurantoin are considered to be usually compatible with breast-feeding by the AAP. Cephalosporins, such as cephalexin, are generally considered to be compatible with breast-feeding. If fosfomycin is used, alterations to the infants' gut flora may be altered; monitor appropriately. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Fosfomycin inhibits one of the first steps in the synthesis of peptidoglycan. After transport into bacterial cells via glycerol-3-phosphate or glucose-6-phosphate transport systems, fosfomycin, through its epoxide group, irreversibly inactivates the enzyme enolpyruvyl transferase by taking the place of phosphoenolpyruvate. Inactivation of this enzyme blocks the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate, a key first step in bacterial cell wall synthesis. Fosfomycin also binds other p-enolpyruvate dependent enzymes, but irreversible inactivation does not occur. Inhibition of peptidoglycan synthesis results in accumulation of the nucleotide precursors and subsequent death and bacterial cell lysis. Fosfomycin is bactericidal in the urine at therapeutic doses. Clinicians are advised to consult susceptibility data at the institution in which they practice to determine fosfomycin activity.

    PHARMACOKINETICS

    Fosfomycin is administered orally as fosfomycin tromethamine. In the systemic circulation, fosfomycin is not bound to plasma proteins. The drug is distributed to the kidneys, bladder wall, prostate, and seminal vesicles. Fosfomycin has been shown to cross the placenta. Fosfomycin is not metabolized and excretion occurs via both urine and feces. Approximately 38% of a dose is recovered from urine and 18% from feces. A mean urinary concentration of 706 +/- 466 mcg/mL was attained within 2—4 hours after a single 3-gram oral dose under fasting conditions. After a high-fat meal, a mean urinary concentration of 537 +/- 252 mcg/mL was achieved within 6—8 hours. The cumulative amount of fosfomycin excreted in the urine was the same under fed and fasting conditions. Urinary concentrations >= 100 mcg/mL were maintained for 26 hours. The mean elimination half-life is 5.7 +/- 2.8 hours.

    Oral Route

    Following administration, fosfomycin tromethamine is rapidly absorbed and converted to the free acid, fosfomycin. The absolute oral bioavailability under fasting conditions is 37% and is reduced to 30% under fed conditions. Following a single 3-gram oral dose, mean maximum serum concentrations were achieved within 2 hours or 4 hours on an empty stomach or with a high-fat meal, respectively.