Dapmicin

Uses

Dapmicin is a cyclic lipopeptide antibiotic used to treat complicated skin and skin structure infections by susceptible Gram-positive bacteria and bacteremia due to Staphylococcus aureus.

Dapmicin is indicated for the treatment of complicated skin and skin structure infections (cSSSI) in patients one year of age and older. It is also indicated for the treatment of Staphylococcus aureus bloodstream infections (bacteremia) in patients one year of age and older, including in adult patients with right-sided infective endocarditis.

Dapmicin is not indicated for the treatment of pneumonia or left-sided infective endocarditis due to S. aureus. Use is not recommended in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central).

As with all antibacterial drugs, it is strongly suggested to perform sufficient testing before treatment initiation in order to confirm an infection caused by susceptible bacteria. Failure to do so may result in suboptimal treatment, treatment failure, and the development of drug-resistant bacteria.

Dapmicin is also used to associated treatment for these conditions: Complicated Skin and Skin Structure Infection, Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)

How Dapmicin works

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 Ca^{2+ 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 daptomycin action.

Toxicity

Toxicity information regarding daptomycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as myopathy, rhabdomyolysis, muscular/neurological system symptoms, eosinophilic pneumonia, tubulointerstitial nephritis, vomiting/diarrhea, abdominal pain, headache, dizziness, pyrexia, sweating, and pruritus. Symptomatic and supportive measures are recommended, including maintenance of glomerular filtration. Due to its high serum protein binding, daptomycin is not easily removed by hemodialysis (~15% of a dose over four hours) or peritoneal dialysis (~11% of a dose over 48 hours). High-flux membranes in hemodialysis may improve the quantity of daptomycin removed using this approach.

Food Interaction

Dapmicin Drug Interaction

Unknown: diphenhydramine, diphenhydramine, ciprofloxacin, ciprofloxacin, levofloxacin, levofloxacin, acetaminophen / hydrocodone, acetaminophen / hydrocodone, pantoprazole, pantoprazole, ceftriaxone, ceftriaxone, acetaminophen, acetaminophen, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol, ondansetron, ondansetron

Dapmicin Disease Interaction

Moderate: renal dysfunction

Volume of Distribution

Dapmicin has a very small volume of distribution, averaging ~0.1 L/kg in healthy adult subjects independent of dose. The volume of distribution tends to increase with decreasing renal function, being estimated at ~0.2 L/kg in patients with severe renal impairment.

Elimination Route

Dapmicin administered as a 30 minute IV infusion to healthy volunteers in doses of 4, 6, 8, 10, and 12 mg/kg once daily resulted in a C_max between 57.8 ± 3.0 and 183.7 ± 25.0 μg/mL and an AUC_0-24 of between 494 ± 75 and 1277 ± 253 μg*h/mL. Dapmicin pharmacokinetics are generally linear, with some variation observed above 6 mg/kg, and the C_max and AUC values are approximately 20% higher at steady-state, suggesting some accumulation. Steady-state trough concentrations between 5.9 ± 1.6 and 13.7 ± 5.2 μg/mL are reached following the third once-daily dose.

The data for a single daptomycin dose of 6 mg/kg administered IV over 30 minutes was used to estimate steady-state C_max values for both 4 and 6 mg/kg doses administered over two minutes, which were estimated at 77.7 ± 8.1 and 116.6 ± 12.2 μg/mL, respectively. Administration of IV daptomycin (4 or 6 mg/kg) over two minutes did not allow for measurement of the C_max but resulted in steady-state AUC values of 475 ± 71 and 701 ± 82 μg*h/mL.

Patients with severe renal impairment and those on dialysis had mean steady-state AUC values approximately 2-3 times higher than those with normal renal function. No clinically significant differences in daptomycin pharmacokinetics were observed in patients with mild to moderate hepatic impairment. The mean AUC_0-∞ obtained in healthy elderly individuals (75 years of age and older) was approximately 58% higher than in healthy young adult controls, with no difference in C_max. The AUC_0-∞ is also increased in obese patients by approximately 30%. No significant differences in body weight- and age-adjusted C_max or AUC was observed in pediatric patients.

Half Life

Dapmicin has a relatively long half-life, with ranges of 7.5-9 hours depending on dosing schemes and dose strength. The half-life lengthens in patients with increasing renal impairment, being 27.83 ± 14.85 hours in patients with creatinine clearance 21

Clearance

Dapmicin administered as a 30 minute IV infusion to healthy volunteers in doses of 4, 6, 8, 10, and 12 mg/kg once daily resulted in total plasma clearance values between 7.2 ± 1.1 and 9.6 ± 1.3 mL/h/kg, with no clear dose association. As daptomycin is primarily renally excreted, patients with mild, moderate, and severe renal impairment had reduced total plasma clearance 9, 22, and 46 percent lower than healthy controls, respectively. Dapmicin clearance was also lower in obese (15-23%) and geriatric (aged 75 and older, by 35%) patients, whereas it tended to be higher in pediatric patients, even when normalized for body weight.

Elimination Route

Dapmicin is excreted primarily by the kidneys, approximately 78% of an administered dose recovered in urine and only 5.7% recovered in feces. Approximately 52% of the dose, recovered in urine, retains microbiological activity.

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