Daptomycin for Injection 350mg/vial

Adverse effects

• Aplastic anaemia (reversible or irreversible, with reports of resulting leukaemia)
• Bone marrow disorders
• Circulatory collapse
• Diarrhoea
• Enterocolitis
• Nausea
• Optic neuritis
• Ototoxicity
• Vomiting
• Agra.nulocytosis
• Depression
• Dry mouth
• Fungal superinfection
• Headache
• Muscle pain, tenderness, weakness, or cramps
• Thrombocytopenic purpura
• Urticaria
• Vision disorders

Interactions

• Chloramphenicol: Unknown interactions
• Aspirin: Unknown (increases risk of renal impairment)
• Ciclosporin: Unknown (increases risk of rhabdomyolysis)
• Fibrates: Unknown (increases risk of rhabdomyolysis)
• Statins: Unknown (increases risk of rhabdomyolysis)

Precautions

• Avoid repeated courses and prolonged treatment
• Monitor renal function regularly
• Monitor plasma-chloramphenicol concentration in hepatic impairment
• Caution in patients with obesity
• Consider dose reduction in hepatic impairment

Pregnancy

Manufacturer advises avoiding use, particularly in the third trimester due to risk of neonatal 'grey baby syndrome'.

Breast-feeding

Manufacturer advises avoiding use; alternative antibiotics recommended due to potential bone-marrow toxicity in infants, although concentration in milk is usually insufficient to cause 'grey syndrome'.

Storage

Store in a cool, dry place. Avoid exposure to light. Refer to specific product guidelines for storage conditions.

Formulations

• Powder for solution for injection

Dosage

Children: Refer to specific guidelines for pediatric dosing; consult the BNF for Children for accurate dosage information.

Adults: Refer to specific guidelines for use; dosage may vary based on the context of use.

Mechanism of action

Hydroxide ions act primarily as bases, neutralizing acids to form water and salts. They participate in various biochemical pathways, including selenium metabolism and the degradation of reactive oxygen species. Hydroxide can influence enzyme activity and stability by altering the pH of the environment, thereby affecting metabolic reactions.

Pharmacodynamics

Hydroxide ions can impact biological processes by changing the local pH, which influences enzyme activity, ion transport, and the solubility of other compounds. Their ability to neutralize acids can help regulate physiological pH, contributing to homeostasis in living organisms.

Pharmacokinetics

As an inorganic ion, hydroxide does not undergo traditional pharmacokinetic processes like absorption, distribution, metabolism, or excretion. Instead, it is rapidly equilibrated in biological fluids and participates in acid-base reactions, having immediate effects on the local environment.

Pregnancy

There is limited information regarding the use of hydroxide during pregnancy. Consult a healthcare professional for advice.

Breast-feeding

Limited data is available on the excretion of hydroxide in breast milk. Consult a healthcare professional before use.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Cryotherapy for the destruction of abnormal tissue
• Treatment of warts, moles, and other skin lesions
• Nitrogen narcosis in diving

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations in paediatric patients.

Adults: For cryotherapy, the dosage and duration depend on the specific condition being treated and should be determined by the healthcare provider. Refer to specific guidelines for each condition.

Mechanism of action

In cryotherapy, the mechanism of action involves three stages: heat transfer, cell injury, and inflammation. The boiling point of liquid nitrogen is -196°C, which initiates heat transfer, leading to cell injury during the thawing process. The inflammation stage follows, characterized by edema and erythema, resulting from cellular death and contributing to local cell destruction. Additionally, nitrogen can cause direct toxic effects on brain functions, leading to nitrogen narcosis, which impairs cognitive abilities and motor functions due to its impact on nerve conduction.

Pharmacodynamics

Nitrogen's pharmacodynamics relate to its behavior in cryotherapy and asphyxiation. In cryotherapy, it induces tissue destruction through rapid cooling, leading to apoptosis of abnormal cells. In high-pressure environments, nitrogen narcosis affects the central nervous system, producing symptoms similar to alcohol intoxication, ultimately decreasing reasoning, decision-making abilities, and manual dexterity.

Pharmacokinetics

Nitrogen does not undergo metabolism in the traditional sense, as it is an inert gas at physiological conditions. Its pharmacokinetics involve physical principles of gas exchange and partial pressures. In the case of nitrogen narcosis, the effects are influenced by the partial pressure of nitrogen in the bloodstream, which increases with depth during diving. Nitrogen is primarily eliminated from the body through respiration.

Adverse effects

• Narcotic effect at high pressures
• Stupor or euphoria
• Decreased motor function and manual dexterity
• Asphyxiation due to oxygen displacement

Precautions

• Careful monitoring in environments with high nitrogen pressures
• Avoidance of rapid ascents in diving to prevent nitrogen narcosis
• Use in controlled settings to prevent asphyxiation risks

Pregnancy

Nitrogen is generally considered safe in terms of direct effects during pregnancy; however, the safety of exposure in high-pressure environments should be assessed.

Breast-feeding

Nitrogen is not known to affect breastfeeding; however, caution is recommended in environments where nitrogen levels may displace oxygen.

Storage

Store in a cool, dry place away from heat sources; liquid nitrogen should be handled with care due to extreme cold.

Formulations

• Liquid nitrogen
• Nitrogen gas (compressed)

Mechanism of action

The mechanism of action of daptomycin remains poorly understood. Studies have suggested a direct inhibition of cell membrane/cell wall constituent biosynthesis, including peptidoglycan, uridine diphosphate-N-acid, acetyl-L-alanine, and lipoteichoic acid (LTA). However, no convincing evidence has been presented for any of these models, and an effect on LTA biosynthesis has been ruled out by other studies in _S. aureus_ and _E. faecalis_. It is well understood that free daptomycin (apo-daptomycin) is a trianion at physiological pH, which binds Ca²⁺ in a 1:1 stoichiometric ratio to become a monoanion, which is thought to rely primarily on the Asp(7), Asp(9), and L-3MeGlu12 residues that form a DXDG motif. Calcium-binding facilitates daptomycin's insertion into bacterial membranes preferentially due to their high content of the acidic phospholipids phosphatidylglycerol (PG) and cardiolipin (CL), wherein it is proposed that daptomycin can bind two calcium equivalents and form oligomers. PG is recognized as the main membrane requirement for daptomycin activity; daptomycin preferentially localizes in PG-rich membrane domains, and mutations affecting PG prevalence are linked to daptomycin resistance. Calcium-dependent membrane binding is the generally accepted mechanism of action for daptomycin, but the precise downstream effects are unclear, and numerous models have been proposed. One mechanism proposes that the daptomycin membrane binding alters membrane fluidity, causing dissociation of cell wall biosynthetic enzymes such as the lipid II synthase MurG and the phospholipid synthase PlsX. This is consistent with the observed effects of daptomycin on cell shape in various bacteria at concentrations at or above the minimum inhibitory concentration (MIC). Aberrant cell morphology is also consistent with the observed localization of daptomycin at the division septa and a hypothesized role in inhibiting cell division. A recent study suggested the formation of tripartite complexes containing calcium-bound daptomycin, PG, and various undecaprenyl-coupled cell envelope precursors, which subsequently include lipid II. This complex is proposed to inhibit cell division, lead to the dispersion of cell wall biosynthetic machinery, and eventually cause lysis of the membrane bilayer at the septum causing cell death. Another popular model is based on early observations that daptomycin, in a calcium-dependent manner, caused potassium ion leakage and loss of membrane potential in treated bacterial cells. Although this lead some to suggest that daptomycin could bind PG to form oligomeric pores in the bacterial membrane, no cell lysis was observed in _S. aureus_ or _E. faecalis_, and the daptomycin-induced ion conduction is inconsistent with pore formation. Rather, it has been proposed that daptomycin forms calcium-dependent dimeric complexes in fixed ratios of Dap₂Ca₃PG₂, which can act as transient ionophores. The observed loss of membrane potential is suggested to result in a non-specific loss of gradient-dependent nutrient transport, ATP production, and biosynthesis, leading to cell death. Notably, these models are not strictly mutually exclusive and are supported to varying extents by observed resistance mutations. The strict requirement for PG for daptomycin bactericidal action is supported by mutations in _mprF_, _cls2_, _pgsA_, and the _dlt_ operon in _S. aureus_, _cls_ in various enterococci, and _pgsA_, PG synthase, and the _dlt_ operon in _E. faecium_, all of which alter the bacterial membrane composition and specifically the PG content of bacterial membranes. Other noted mutations in various regulatory systems that control membrane homeostasis also support the cell membrane as the site of daptomycin action. Curiously, in _E. faecalis_, the most commonly observed form of daptomycin resistance is characterized by abnormal division septa, which supports the cell division-based mechanism of daptomyc

Pharmacodynamics

Daptomycin is a cyclic lipopeptide antibacterial agent produced as a fermentation product by the soil microbe _Streptomyces roseosporus_. The daptomycin core consists of 13 amino acids, including three D-amino acids, ornithine, 3-methyl-glutamic acid, and kynurenine, with the C-terminal 10 amino acids forming an ester-linked ring and the N-terminal tryptophan covalently bonded to decanoic acid. Daptomycin is active against aerobic Gram-positive bacteria, including clinically relevant strains such as methicillin-susceptible and -resistant _Staphylococcus aureus_ (MSSA/MRSA), vancomycin-resistant _S. aureus_, vancomycin-resistant Enterococci (VRE), _Staphylococcus_ spp., _Streptococcus_ spp., _Clostridiodes difficile_, _Clostridium perfringens_, _Finegoldia magna_, and _Propionibacterium acnes_, among others. Although daptomycin is active against _Streptococcus pneumoniae_ _in vitro_, it is inhibited by lung surfactant, and hence is not effective for the treatment of pneumonia or other similar lung infections. Daptomycin exhibits rapid concentration-dependent bactericidal activity _in vitro_, which correlates best with the ratio of the area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC) in animal models of infection. Like other antibacterial agents, daptomycin carries a risk of severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). There have been reports of myopathy, rhabdomyolysis, and increased creatine phosphokinase (CPK) levels in patients taking daptomycin, which increased when daptomycin was given more than once per day. Patients should be monitored for CPK levels and, in those with renal impairment, renal function, at least once per week and should consider temporarily suspending the use of HMG-CoA reductase inhibitors. Daptomycin should not be administered more than once per day. Severe adverse reactions such as tubulointerstitial nephritis and peripheral neuropathy have been reported, which may require treatment discontinuation. Based on animal studies, patients less than one year of age may experience serious muscular, neuromuscular, and nervous system effects; daptomycin is not recommended for use in patients under one year of age. Patients undergoing daptomycin treatment may experience eosinophilic pneumonia and _Clostridioides difficile_-associated diarrhea, both of which may require the cessation of antibacterial treatment and initiation of symptomatic/supportive measures. Persisting or relapsing _S. aureus_ bacteremia and endocarditis should be investigated for sequestered foci of infection and the possibility of daptomycin resistance; the dose or treatment regimen may require adjusting. Patients with moderate to severe renal impairment (creatine clearance < 50 mL/min) experienced reduced clinical benefit from daptomycin treatment based on limited data. Clinically relevant daptomycin plasma concentrations have significantly affected prothrombin time and International Normalized Ratio (INR) measurements. As with all antibiotics, daptomycin use may promote the overgrowth of non-susceptible organisms and the development of resistant organisms; daptomycin use should be limited to cases where it is proven or strongly suspected that an infection is caused by susceptible bacteria.

Mechanism of action

In cryotherapy, mechanism of action could be classified into three stages: 1. heat transfer, 2. cell injury and 3. inflammation. Boiling point of liquid nitrogen is -196°C, which is the responsible for creating the initial stage which is heat transfer. The second stage is cell injury which is induced during thawing conditions of the cells. The last step in the cryotherapy is the inflammation stage which is characterized by edema and erythema. Inflammation occurs as a result of cellular death and it helps in local cell destruction. ... Nitrogen also has a direct toxic action of its own, affecting brain functions and inducing a stupor or euphoria. Nitrogen narcosis ("rapture of the deep" or "the martini effect") results from a direct toxic effect of high nitrogen pressure on nerve conduction and produces effects similar to alcohol intoxication. Complex reasoning, decision-making ability, motor function, and manual dexerity decrease. Individuals vary in this response widely, but it typically can be noticed among divers at depths exceeding 100 ft (30 m). For example, certain individuals experience no effect at depths of < or = 130 ft, whereas others feel some effect at around 80 ft. Nonetheless, the narcotic effect increases with increasing depth so that each additional 50 ft incrementally produces the effect of "another martini". A simple asphyxiant, nitrogen's main toxicty arises from its ability to displace O2 and generate an atmosphere that does not support the chemical reactions needed for maintenance of life. The displacement of O2 can be complete or incomplete, leading to varying degrees of hypoxia. Nitrogen is an inert substance and does not exert a direct toxicological effect. Nitrogen acts by the physiological effect of simple asphyxia on the target species within a Controlled Atmosphere Treatment (CAT) bubble. The biocide action of nitrogen is due to its displacement of oxygen from an atmospheric oxygen level of 20.8% to levels < 0.2% v/v in the CAT bubble. The level of oxygen is the critical factor. Victims exposed to atmospheres deficient in oxygen, i.e. < 19%, will begin to display signs and symptoms of oxygen-deficient exposure of air due to an increase in nitrogen.