Daptomycin

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

Mechanism of action:

The Daptomycin (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 phospholipid phosphatidylglycerol (PG). After attachment, DAP forms oligomers and moves to encroach 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. The mechanisms involved are –

• generating a positive charge on the cell membrane to repulse daptomycin
• cell envelop stress response – decrease in PG content of cell membrane, thickening of the 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-

Mutation in the mprF gene	generating positively charged cell membrane phosphatidylglycerol (PG) through lysinylation (L-PG) and translocating the L-PG from the inner to the outer side of the cell membrane. This result in a positive charged outer side of the cell membrane, which repulses the calcium-DAP complex (Bayer 2013).
Activation of liaFSR regulatory system	This 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 operon	positively charged amino acid D-alanine is incorporated into teichoic acids in the cell wall, causing positive surface charge and repulsion of DAP.
Altered PG/cardiolipin metabolism	cls genes mutation- decreases the level of cardiolipin in the cell membrane pgsA gene mutation – encode 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 homeostasis	This 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 membrane	e.g. altered staphyloxanthin (carotenoid pigment) in Staph aureus may alter the fluidity resulting in resistance.
Loss of an 81 kDa membrane protein	which 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.
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 are restricted to a specific genetic mutation in Enterococci (liaFSR).

Following combinations were reported beneficial –

Strep mitis	Daptomycin -gentamicin
Staph aureus	Daptomycin-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.
Enterococcus	Daptomycin – 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

Antagonism (in-vitro) has been reported with the following combination (Hindler 2015, Luther 2015)

DAP – Linezolid	MRSA
DAP- Tigecycline	Enterococcus
Dap- Rifampicin	Enterococcus

PK/PD

• 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 – 1L/kg, small, does 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 UNL.

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 – 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.

Indication:

• Complicated skin and soft-tissue infections (cSSTI) – 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 – 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	Susceptible	MIC/resistance may be seen in VISA/hVISA
Coagulase-negative Staphylococcus	Susceptible
Streptococcus – Group A, B, C, G, Strep milleri	Susceptible	penicillin is four times more potent
Strep pneumoniae	Susceptible
Viridans Streptococcus	Susceptible	penicillin is four times more potent
Enterococcus	Susceptible	Resistance increasing. 10% E faecium resistant, VRE may have high MIC
Anaerobic gram-positive organism	Susceptible
Corynebacterium	Susceptible
Listeria	High MIC
Lactobacillus	High MIC
Pediococcus, Leuconostoc	Susceptible
Actinomyces	High MIC