Class: Cyclic lipopeptide
Source: Streptomyces roseosporus
Discovered: 1980s; approved for use in 2003 (FDA)
Molecular weight: 1620 DA.

Immunomodulatory effect:

Daptomycin causes limited/no bacterial cell lysis. It also impairs the cell division. This process leads to a milder inflammatory response. Suppression of cytokine response, and other proinflammatory response like macrophage stimulation.

Mechanism of action:

Daptomycin (DAP) mechanism of action is not been fully elucidated. Current understanding is that the DAP combines with Calcium ion to form a positively charged complex which attaches to the bacterial cell membrane (preferably at the nascent septa). This attachment depends upon the presence of phospholipid phosphatidylglycerol (PG). After attachment DAP form oligomers and move encroaches the inner side of the membrane. This process requires the presence of cardiolipin inside the cell membrane. The DAP oligomer for pores which lead to the movement of ions and depolarization of the cell membrane. This process leads to cell death.
Another theory suggest that DAP attachment leads to a lipid extracting effect. lipid-peptide aggregates exude from the cell membrane causing a disruption in the cell membrane structure. [Tran, 2015]

Mechanism of resistance:

The emergence of resistance has been associated with the use of lower dose (</=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 –

Mutation in the mprF genegenerating positively charged cell membrane phosphatidylglycerol (PG) through lysinylation (L-PG) and translocating the L-PG from inner to the outer side of the cell membrane. This result in a positive charged outer side of the cell membrane which repulses calcium-DAP complex (Bayer 2013).
Activation of liaFSR regulatory systemThis is a cell envelope stress response – decrease in the PG content of the cell membrane. It also causes thickening of the cell wall and aberrant septum placement. Cross-resistance has been noted with vancomycin and bacitracin. This system may play a role in diverting the DAP from the preferred septal target to other areas of the cell membrane.
Overexpression of the dlt operonpositively charged amino acid D-alanine is incorporated into teichoic acids in cell wall causing positive surface charge and repulsion of DAP.
Altered PG/cardiolipin metabolismcls genes mutation- decreases the level of cardiolipin in the cell membrane
pgsA gene mutationencode for a transferase responsible for PG synthesis. Decreased level of PG in the cell membrane.
GdpD mutation – potentiate liaFSR mediated resistance in Enterococci.
Increase the thickness of the cell wall; altered homeostasisThis mechanism is responsible for vancomycin-intermediate Staph aureus (VISA), often responsible for daptomycin resistance as well.
TagA mediated – responsible for the synthesis of teichoic acid.
RpoB mutation – also plays a part in hVISA.
yycFG [walKR] and vraSR mutation – thickening of the cell wall, altered homeostasis.
Increase fluidity of the cell membranee.g. altered staphyloxanthin (carotenoid pigment) in Staph aureus may alter the fluidity resulting in resistance.
Loss of an 81 kDa membrane proteinwhich acts as a chaperone for daptomycin interaction. (Kaatz 2006)

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.
Following combinations were reported beneficial –

Strep mitisDaptomycin -gentamicin
Staph aureusDaptomycin-oxacillin/cloxacillin (MSSA)
Daptomycin- gentamicin
Daptomycin-Clarithromycin (MRSA)
Daptomycin – rifampicin (MSSA)
Daptomycin – cotrimoxazole
Daptomycin- ceftaroline (MRSA)
daptomycin -vancomycin (biofilm-forming MRSA)
Daptomycin – fosfomycin – temporary prevention of development of resistance ~7 days.
EnterococcusDaptomycin – ampicillin (even in DAP R strains, liaFSR+ )
Daptomycin- ceftaroline (VRE)
Daptomycin- gentamicin
daptomycin-ceftobiprole (VRE)
Daptomycin – ceftriaxone
Synergy has been seen with Ertapenem and cefepime as well.
Acinetobacter
baumannii 
Daptomycin – colistin

 The mechanism of synergy is not well understood. beta-lactams may modulate the surface charge of the bacteria to make to susceptible to DAP. It is also reported to be specific for those beta-lactams which use PBP1 and restricted to a specific genetic mutation in Enterococci (liaFSR). 

Antagonism

DAP – LinezolidMRSA
DAP- TigecyclineEnterococcus
Dap- RifampicinEnterococcus

 

Properties:

IV (Off-label – Intraperitoneal)
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 – 1L/kg, small, do not cross cell membrane (restricted to plasma, extracellular fluid).
Excretion – 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 ULN.

Should not be prescribed in children <1 year – 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 – patient developing signs and symptoms of peripheral neuropathy should stop DAP.

FDA drug categories – use in pregnancy

AAdequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).
BAnimal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women
CAnimal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks.
DThere is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks.
XStudies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in the use of the drug in pregnant women clearly outweigh potential benefits.

https://chemm.nlm.nih.gov/pregnancycategories.htm

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 effect:
Hypersensitivity reaction, angiooedema, rhabdomyolysis, eosinophilic pneumonia, DRESS syndrome.

(full list of adverse effects)

Indication:

Complicated skin and soft-tissue infections (cSSTI) – adult 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 – Adults.
Staphylococcus aureus bacteraemia associated with cSSTI – Children > 1-year-old.
[https://www.medicines.org.uk/emc/product/177/smpc]

 

Spectrum:

It is active on gram-positive bacteria only. No meaningful activity against gram-negative. 
It also has activity against biofilms of Staph aureus (with rifampicin) and Borrelia burgdorferi (with doxycycline/cefuroxime).

Staph aureus
(MSSA, MRSA, VRSA
SusceptibleMIC/resistance may be seen in VISA/hVISA
Coagulase-negative StaphylococcusSusceptible
Streptococcus –
Group A, B, C, G, Strep milleri
Susceptiblepenicillin is four times more potent
Strep pneumoniaeSusceptible
Viridans StreptococcusSusceptiblepenicillin is four times more potent
EnterococcusSusceptibleResistance increasing. 10% E faecium resistant,
VRE may have high MIC
Anaerobic gram-positive organismSusceptible
CorynebacteriumSusceptible
ListeriaHigh MIC
LactobacillusHigh MIC
Pediococcus, LeuconostocSusceptible
ActinomycesHigh MIC
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