FOSFOMYCIN AURO

Indications

• Acute uncomplicated lower urinary tract infections

Mechanism of action

Fosfomycin exerts its bactericidal effects by covalently binding to a cysteine in the active site of the UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme. This inhibition prevents the enzyme from catalyzing the condensation of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine (UNAG), disrupting the production of the peptidoglycan precursor UDP-N-acetylmuramic acid (UDP-MurNAc) and ultimately interfering with bacterial cell wall synthesis. Fosfomycin enters bacterial cells via the L-alpha-glycerophosphate system and the hexose-6-phosphate transporter system. Additionally, it reduces bacterial adhesion to epithelial cells in the urinary and respiratory tracts.

Pharmacodynamics

Fosfomycin is primarily used for treating urinary tract infections but is also effective against various difficult-to-treat strains of bacteria. It has demonstrated the ability to act synergistically with other antibiotics, which enhances its efficacy against clinically relevant pathogens. The drug has low cross-resistance with other antibiotics due to its unique mechanism of action. Furthermore, fosfomycin possesses immunomodulating properties, influencing cytokine responses and enhancing neutrophil activity against pathogens. It effectively penetrates biofilms, reducing microbial load and altering biofilm structure.

Pharmacokinetics

Fosfomycin is administered intravenously and has a bioavailability that can vary depending on the formulation. It is primarily eliminated through renal excretion, with a clearance that may be affected by renal function. The drug's half-life and distribution in body tissues can vary, and monitoring of renal function is advised during treatment, especially in patients with compromised renal function.

Adverse effects

• Abdominal pain
• Diarrhoea
• Headache
• Nausea
• Vomiting
• Skin reactions
• Dizziness
• Vulvovaginal infection
• Antibiotic associated colitis

Precautions

• Monitor electrolytes and fluid balance with intravenous use
• Caution in patients with cardiac insufficiency, elderly patients, hyperaldosteronism, hypernatraemia, hypertension, and pulmonary oedema
• Severe hepatic impairment requires caution

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk-no information available.

Breast-feeding

Present in milk in small amounts, but absorption from gastrointestinal tract is negligible.

Storage

Store in a cool, dry place away from direct sunlight. Follow specific storage instructions on the label.

Formulations

• Fomicyt 2g powder for solution for infusion vials
• Fomicyt 4g powder for solution for infusion vials

Indications

• Metabolic acidosis
• Severe hyperkalaemia
• Renal artery stenosis
• Nephrotic syndrome
• Severe heart failure
• Potassium depletion due to diuretics

Dosage

Children: Dosing in children should be appropriate to the body weight and clinical

Adults: Dosage must be tailored to the individual patient's acid-base status and clinical condition. Refer to the BNF for specific dosing guidelines.

Mechanism of action

Trometamol is a weak base that functions as a proton acceptor. Upon intravenous administration, it binds to hydrogen ions and associated acid anions, leading to their excretion in urine. It is capable of combining with lactic, pyruvic, and other metabolic acids, thereby reducing hydrogen ion concentration in the body. The drug's ionized form predominates at physiological pH, allowing it to penetrate cell membranes and interact with intracellular acids. This action increases bicarbonate concentration and decreases carbon dioxide tension, potentially leading to hypoventilation.

Pharmacodynamics

Trometamol reduces acidity in the body by acting on acid-base buffers, thus shifting the balance towards alkalinity. It increases the flow of alkaline urine, enhancing diuresis and electrolyte excretion. The correction of metabolic acidosis can improve various physiological functions, but caution is required due to the potential for respiratory depression caused by decreased carbon dioxide tension.

Pharmacokinetics

Trometamol is administered intravenously and rapidly distributes into extracellular fluids. It is metabolized primarily in the liver, with renal excretion of the resultant salts. The onset of action is typically quick, and the duration of effect depends on the severity of acidosis and the therapeutic context. Monitoring of plasma potassium levels is essential, particularly in patients with renal impairment.

Contra-indications

• Anuria
• Chronic respiratory acidosis

Adverse effects

• Hepatic necrosis in neonates
• Hypoglycaemia
• Respiratory depression

Interactions

• Potassium salts may cause nausea and vomiting
• Drugs exacerbating hyperkalaemia should be reviewed and stopped as appropriate

Precautions

• Extravasation can cause severe tissue damage
• Use with caution in renal impairment due to risk of hyperkalaemia

Pregnancy

Limited information available, management of hyperkalaemia may harm fetus.

Breast-feeding

No information available.

Storage

Store in a cool, dry place. Protect from light.

Formulations

• Solution for infusion (Trometamol 363.4 mg per 1 ml, Tris 36.34% solution for infusion)

Mechanism of action

Fosfomycin exerts its bactericidal effects by binding covalently to a cysteine in the active site of the UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme, rendering it inactive. By preventing MurA from catalyzing the condensation of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine (UNAG), fosfomycin inhibits the production of the peptidoglycan precursor UDP N-acetylmuramic acid (UDP-MurNAc). Ultimately, the first step of bacterial cell wall synthesis is disrupted. In _Escherichia coli_, fosfomycin gains entry into bacterial cells via two mechanisms: the L-alpha-glycerophosphate system and the hexose-6-phosphate transporter system. Fosfomycin also has important effects on cell adhesion. For example, the adhesion of bacterial cells to urinary epithelial cells is reduced in the presence of fosfomycin. The adhesion of _Streptococcus pneumoniae_ and _Haemophilus influenzae_ to respiratory epithelial cells is also reduced

Pharmacodynamics

Although used primarily to treat urinary tract infections, fosfomycin has been shown to act synergistically with other antibiotics against clinically relevant bacteria. There is also growing interest in the potential of fosfomycin to treat more complex infections since it has retained activity against many difficult-to-treat strains of bacteria including methicillin-resistant _Staphylococcus aureus_ (MRSA) and multidrug-resistant enterobacteria. Further, since fosfomycin has a unique and singular mechanism of action, the risk of cross-resistance with other antibiotics is low. Fosfomycin also demonstrates immunomodulating properties. For example, the antibiotic may influence components of the acute inflammatory cytokine response and enhances neutrophil phagocytic destruction of pathogens. Fosfomycin penetrates biofilms effectively and is capable of not only reducing or eliminating microorganisms in biofilms but can also alter the biofilm structure.

Mechanism of action

Tromethamine is an alkalinizing agent which acts as a proton (hydrogen ion) acceptor. Tromethamine is a weak base; following IV injection, it attracts and combines with hydrogen ions and their associated acid anions and the resulting salts are excreted in urine. Tromethamine can combine with lactic, pyruvic, and other metabolic acids and with carbonic acid. ... At pH 7.4, approximately 70% of the tromethamine present in plasma is in the ionized (protonated) form; if pH is decreased from pH 7.4, the ionized fraction of the drug is increased. In contrast to the ionized fraction of tromethamine, which upon administration reacts only with acid in the extracellular fluids, the fraction of the dose which remains un-ionized at physiologic pH is thought to be capable of penetrating the cell membrane to combine with intracellular acid. Since administration of tromethamine reduces hydrogen ion concentration, there is a decrease in proton donor and an increase in proton acceptor concentrations in body buffers. In the bicarbonate:carbonic acid buffer, the concentration of dissolved carbon dioxide is decreased (at least until regulatory mechanisms compensate) and the concentration of bicarbonate is increased. The reduction of carbon dioxide tension removes a potent stimulus to breathing and may result in hypoventilation and hypoxia. Tromethamine ... acts as a weak, osmotic diuretic, increasing the flow of alkaline urine containing increased amounts of electrolytes. By removing protons from hydronium ions, ionization of carbonic acid is shifted so as to decrease pCO2 and to increase bicarbonate. Excess bicarbonate is then gradually excreted in kidney. /Tromethamine is an/ especially useful way to manage excessively high pCO2 in respiratory acidosis...