Mupirocin/EDTA/gentamicin

Mupirocin is a topical antibacterial produced by Pseudomonas fluorescens. FDA-approved products are mupirocin 2% ointment, mupirocin calcium 2% cream, and mupirocin calcium 2% nasal ointment (Bactroban Nasal). Mupirocin is also compounded into nasal preparations pursuant to patient-specific prescriptions.

• Mupirocin 2% ointment: topical treatment of impetigo due to Staphylococcus aureus and Streptococcus pyogenes.
• Mupirocin calcium 2% cream: secondarily infected traumatic skin lesions (up to 10 cm in length or 100 cm2 in area) due to susceptible S. aureus and S. pyogenes.
• Mupirocin calcium 2% nasal ointment: eradication of nasal colonization with methicillin-resistant S. aureus (MRSA) in adult patients and health-care workers as part of a comprehensive infection-control program during institutional outbreaks.
• Prescribers use compounded mupirocin in nasal sprays and sinus preparations; these forms are not FDA labeled.

Mupirocin reversibly binds bacterial isoleucyl-transfer RNA synthetase, halting protein and RNA synthesis. It is bacteriostatic at low concentrations and bactericidal at the high concentrations achieved topically. Its unique target means no cross-resistance with other antibiotic classes; low- and high-level resistance arise with prolonged or repeated use.

Systemic absorption through intact skin and nasal mucosa is minimal. Absorbed mupirocin is rapidly metabolized to the inactive metabolite monic acid, which is renally excreted; the plasma half-life after intravenous dosing in studies is under an hour. Absorption may increase through damaged skin or inflamed mucosa.

• Hypersensitivity to mupirocin or any component of the formulation.

• Hypersensitivity: systemic allergic reactions, including anaphylaxis, urticaria and angioedema, have been reported; stop use if they occur.
• Not for ophthalmic use; avoid contact with the eyes.
• Prolonged use may result in overgrowth of nonsusceptible organisms, including fungi, and selection of mupirocin-resistant staphylococci.
• Clostridioides difficile-associated diarrhea has been reported with nearly all antibacterial agents.
• Mupirocin ointment contains polyethylene glycol; absorption from large open wounds can be a concern in moderate or severe renal impairment.

No clinically important drug interactions are known. Labeling for the nasal ointment notes that concurrent use with other intranasal products has not been studied.

Nasal use: headache, rhinitis, nasal congestion, pharyngitis, taste disturbance, burning or stinging, cough and pruritus. Skin use: burning, stinging, pain, itching, rash and contact dermatitis.

Systemic absorption is minimal, and maternal use is not expected to cause meaningful fetal exposure. It is not known whether mupirocin passes into breast milk; if used on the nipple area, the area should be washed before nursing.

Clinical response, local tolerance and signs of superinfection; nasal or wound cultures and susceptibility testing when therapy is prolonged or repeated.

• Bactroban (mupirocin) ointment 2% Prescribing Information, GlaxoSmithKline.
• Bactroban (mupirocin calcium) cream 2% Prescribing Information, GlaxoSmithKline.
• Bactroban Nasal (mupirocin calcium ointment) 2% Prescribing Information, GlaxoSmithKline.

Edetic acid (ethylenediaminetetraacetic acid, EDTA) is a chelating agent used as its salts. Edetate calcium disodium injection (Calcium Disodium Versenate) is FDA approved for lead poisoning. Edetate disodium is widely used as an excipient chelator and stabilizer in ophthalmic, nasal and other preparations; approved edetate disodium injections are no longer marketed in the US. EDTA is compounded into nasal and sinus preparations pursuant to patient-specific prescriptions.

• Edetate calcium disodium injection (IV or IM): reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in pediatric and adult patients.
• Edetate disodium as an excipient: chelation of trace metals to stabilize formulations and enhance preservative activity.
• Prescribers include EDTA in compounded nasal preparations as a chelating agent that may disrupt bacterial biofilm and enhance antimicrobial activity; this use is not FDA labeled.

EDTA forms stable, water-soluble complexes with divalent and trivalent metal ions. Edetate calcium disodium exchanges its calcium for lead and other metals with higher binding affinity, and the chelate is excreted in urine. Against bacteria, EDTA chelates the calcium and magnesium that stabilize outer-membrane lipopolysaccharide and the biofilm matrix, increasing permeability to coadministered antimicrobials.

Oral absorption is poor (under 5%). After parenteral dosing, EDTA distributes mainly in extracellular fluid, does not appreciably enter cells or the cerebrospinal fluid, is not metabolized, and is excreted unchanged by glomerular filtration, about half within an hour and nearly all within 24 hours. Absorption from intact nasal mucosa is expected to be low.

• Edetate calcium disodium injection: anuria, active renal disease and hepatitis.
• Hypersensitivity to edetate salts or any component.

• Nephrotoxicity, including acute tubular necrosis, can occur with parenteral dosing; maintain adequate urine flow and limit dose and duration.
• Product confusion: edetate disodium given in error for edetate calcium disodium has caused fatal hypocalcemia and cardiac arrest.
• Chelation can deplete zinc and other trace metals with repeated parenteral courses.
• Parenteral use can cause hypotension, arrhythmia and ECG changes; monitor cardiac status.
• Topical and nasal use: local irritation can occur; systemic exposure is expected to be low at excipient-range concentrations.

Edetate calcium disodium can interfere with zinc insulin preparations by chelating zinc. Other nephrotoxic drugs add to renal risk with parenteral use. In compounded preparations EDTA chelates metal ions and may enhance the activity of coadministered antimicrobials and preservatives.

Parenteral: nephrotoxicity, fever, chills, malaise, fatigue, myalgia, headache, nausea, vomiting, hypotension, injection-site pain, zinc depletion, and histamine-like reactions such as sneezing, nasal congestion and lacrimation. Topical or nasal: local burning, stinging or irritation.

Adequate human data in pregnancy are lacking; animal studies at high parenteral doses showed fetal effects attributed to zinc depletion. Parenteral edetate calcium disodium in pregnancy is reserved for clear need. Lactation data are not available; systemic exposure from nasal use is expected to be low.

Parenteral use: renal function, urinalysis, serum electrolytes including calcium, blood lead levels, ECG during infusion and zinc status with repeated courses. Nasal use: local tolerance.

• Calcium Disodium Versenate (edetate calcium disodium injection) Prescribing Information.
• FDA Public Health Advisory on edetate disodium and edetate calcium disodium medication errors (2008).
• Handbook of Pharmaceutical Excipients: edetic acid and edetate disodium.

Gentamicin is an aminoglycoside antibiotic derived from Micromonospora purpurea, used as the sulfate salt. FDA-approved products include gentamicin injection (IV or IM), 0.1% cream and ointment, and 0.3% ophthalmic solution and ointment. Gentamicin is compounded into nasal and sinus preparations pursuant to patient-specific prescriptions.

• Injection: serious infections caused by susceptible strains of Pseudomonas aeruginosa, Proteus species, Escherichia coli, Klebsiella, Enterobacter, Serratia, Citrobacter and Staphylococcus species, including bacterial neonatal sepsis, bacterial septicemia, and serious infections of the CNS, urinary tract, respiratory tract, gastrointestinal tract including peritonitis, skin, bone and soft tissue.
• Topical 0.1%: primary and secondary superficial skin infections due to susceptible organisms.
• Ophthalmic 0.3%: external ocular infections such as conjunctivitis, keratitis and blepharitis due to susceptible bacteria.
• Prescribers use compounded gentamicin in nasal sprays and sinus irrigations; these forms are not FDA labeled.

Gentamicin binds the bacterial 30S ribosomal subunit, causing misreading of messenger RNA and production of faulty proteins, and is rapidly bactericidal. Killing is concentration dependent with a post-antibiotic effect. Activity is mainly against aerobic gram-negative bacilli and staphylococci; anaerobes and streptococci alone are resistant.

Gentamicin is poorly absorbed orally and from intact skin, but absorption increases through denuded skin, wounds and inflamed mucosa. After parenteral dosing it distributes into extracellular fluid, with low CNS penetration, and accumulates in the renal cortex and inner-ear fluids. It is not metabolized and is excreted unchanged by glomerular filtration; half-life is about 2 to 3 hours with normal renal function and much longer in renal impairment and neonates.

• Hypersensitivity to gentamicin or any component, or a history of hypersensitivity or serious toxic reaction to other aminoglycosides (cross-sensitivity).

• Use caution in neuromuscular disorders such as myasthenia gravis and parkinsonism because of neuromuscular blockade.
• Some injection products contain sodium metabisulfite, which can cause allergic-type reactions in sulfite-sensitive patients.
• Topical and mucosal use: systemic absorption, with ototoxicity and nephrotoxicity, has been reported with application to large wounds, burns and mucosa; use caution in renal impairment or existing hearing loss.
• Prolonged use can select resistant organisms and cause fungal superinfection. Clostridioides difficile-associated diarrhea has been reported with nearly all antibacterial agents.

Additive nephrotoxicity or ototoxicity with other aminoglycosides, vancomycin, amphotericin B, cisplatin, cyclosporine, polymyxin B, colistin and loop diuretics. Enhanced neuromuscular blockade with anesthetics, neuromuscular blocking agents and botulinum toxin. Penicillins and cephalosporins can inactivate aminoglycosides when mixed in the same solution or in severe renal impairment.

Systemic: nephrotoxicity (rising creatinine, casts, proteinuria), ototoxicity (tinnitus, hearing loss, vertigo, ataxia), neurotoxicity, neuromuscular blockade, rash, fever and electrolyte losses such as hypomagnesemia. Topical: erythema, pruritus and irritation; mucosal use can cause local burning.

Aminoglycosides cross the placenta and can cause fetal harm; total irreversible bilateral congenital deafness has been reported with streptomycin. Gentamicin passes into breast milk in small amounts, and oral absorption by the infant is poor; watch the infant for diarrhea or thrush.

Systemic use: peak and trough serum concentrations, serum creatinine and BUN, urinalysis, electrolytes, and audiometric and vestibular function with prolonged therapy. Topical or nasal use: clinical response, local tolerance, and hearing or balance symptoms, especially with renal impairment or long courses.

• Gentamicin Sulfate Injection USP Prescribing Information.
• Gentamicin Sulfate Cream and Ointment USP 0.1% Prescribing Information.
• Gentamicin Sulfate Ophthalmic Solution USP 0.3% Prescribing Information.