Daptomycin
Class: Cyclic lipopeptide
Source: Streptomyces roseosporus
Discovered: 1980s; approved for use in 2003 (FDA)
Molecular weight: 1620 DA.
Mechanism of action
The mechanism of action of daptomycin has not been fully elucidated. The current understanding is that the DAP combines with calcium ions to form a positively charged complex that attaches to the bacterial cell membrane (preferably at the nascent septa). This attachment depends upon the presence of the phospholipid phosphatidylglycerol (PG). After attachment, DAP forms oligomers and encroaches on the inner side of the membrane. This process requires the presence of cardiolipin inside the cell membrane. The DAP oligomer for pores leads to the movement of ions and depolarization of the cell membrane. This process leads to cell death.
Another theory suggests that DAP attachment leads to a lipid-extracting effect. Lipid-peptide aggregates exude from the cell membrane, disrupting the cell membrane structure. [Tran, 2015]
Immunomodulatory effect
Daptomycin causes limited/no bacterial cell lysis. It also impairs cell division. This process leads to a milder inflammatory response—suppression of cytokine response and other proinflammatory responses like macrophage stimulation.
Mechanism of resistance
The emergence of resistance has been associated with the use of lower doses (</=6mg/kg/day) and high-inoculum infections (endocarditis, abscess) [Tran,2015]. Phenotypic changes seen in the non-susceptible bacteria are – thickened cell wall, aberrant septal placement, increase in relative cell surface positive charge and reduction of the ability of DAP to depolarize the cell membrane. Mechanisms involved are –
Generating a positive charge on the cell membrane to repel daptomycin
Cell envelope stress response: decrease in PG content of cell membrane, thickening of cell wall, aberrant septum formation, diverting the daptomycin from its preferred site of action.
Increasing the fluidity of the cell membrane
See full details here - including the genes involved in the development of resistance-
Daptomycin tolerance
Daptomycin tolerance has been noted in-
Staph aureus – due to pitA mutation.
Enterococcus – due to liaF (a part of liaFSR) mutation.
Synergy/Combination therapy
Daptomycin resistance increases the susceptibility of many organisms to other antibiotics- especially cell wall active antibiotics (see-saw effect). The combination may prevent the development of resistance to daptomycin as well.
The mechanism of synergy is not well understood. Beta-lactams may modulate the surface charge of the bacteria to make them susceptible to DAP. It is also reported to be specific for those beta-lactams which use PBP1 and are restricted to a specific genetic mutation in Enterococci (liaFSR).
Following combinations were reported beneficial –
Antagonism (in-vitro) has been reported with the following combination (Hindler 2015, Luther 2015)
DAP – Linezolid against MRSA
DAP- Tigecycline & DAP-Rifampicin against Enterococcus
Important PK/PD points
Route: IV, Intraperitoneal (Off-label).
Dose based on actual body weight (for comparison to IBW see Ng et al. – https://aac.asm.org/content/58/1/88).
Pregnancy: Category B, no controlled trial (BookStaver, 2015)
AUC/MIC and Cmax/MIC correlate with efficacy.
Post antibiotic effect – Staph aureus and Enterococcus (6 hours)
Protein binding: high (>90%). reversible.
The volume of distribution: small volume of distribution (1L/kg), does not cross the cell membrane (restricted to plasma, extracellular fluid).
Excretion – via the kidney.
No interaction with the CYP450 system.
T1/2: 8-9 hours.
DAP has no activity in the pulmonary tissue as it is inactivated by the surfactant.
Caution and monitoring
Check creatinine kinase at baseline and weekly [more frequently in patients, who are at a higher risk of myopathy – renal impairment, dialysis, CK > 5 times the upper limit of normal (if prescription deemed necessary) and on drugs which can increase CK (e.g HMG-CoA reductase inhibitors, fibrates, and ciclosporin etc; prescription only if benefit >risk)]. If muscle pain develops, CK should be monitored every 2 days and stopped if CK >5 times the UNL.
Should not be prescribed in children <1 year due to potential muscular, neuromuscular, and/or nervous systems adverse effects.
Eosinophilic pneumonia: the patient may develop eosinophilic pneumonia (fever, dyspnoea, hypoxia, pulmonary infiltrate, organising pneumonia) – usually 2 weeks after treatment. DAP should be stopped. Treatment is systemic steroid. Other causes of pneumonia should be excluded.
Peripheral neuropathy: Patients developing signs and symptoms of peripheral neuropathy should stop DAP.
Adverse effects
Common adverse effects
Fungal/Candida infection, UTI, anaemia, anxiety, insomnia, hypo-/hyper-tension, GI adverse effects, increased liver enzyme, rash, limb pain, increase in CK, infusion site reaction, fever, asthenia.
Serious adverse effects
Hypersensitivity reaction, angioedema, rhabdomyolysis, eosinophilic pneumonia, DRESS syndrome.
Daptomycin indications
Complicated skin and soft-tissue infections (cSSTI) in adults and children > 1-year-old.
Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus.
Staphylococcus aureus bacteraemia associated with RIE or cSSTI in adults.
Staphylococcus aureus bacteraemia associated with cSSTI – Children > 1-year-old.
Spectrum
It is active against gram-positive bacteria only. No meaningful activity against gram-negative bacteria. It also has activity against biofilms of Staph aureus (when combined with rifampicin) and Borrelia burgdorferi (with doxycycline/cefuroxime).