daptomycin: prescribing information – dosing, contraindications, interactions, side effects

Cubicin is indicated for the treatment of the following infections (see sections 4.4 and 5.1).
- Adult and paediatric (1 to 17 years of age) patients with complicated skin and soft-tissue infections (cSSTI).
- Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.
- Adult and paediatric (1 to 17 years of age) patients with Staphylococcus aureus bacteraemia (SAB). In adults, use in bacteraemia should be associated with RIE or with cSSTI, while in paediatric patients, use in bacteraemia should be associated with cSSTI.
Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-administered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clinical studies in patients employed infusion of daptomycin over at least 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes.
This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see sections 4.8 and 5.2).

Posology
Adults
- cSSTI without concurrent SAB: Cubicin 4 mg/kg is administered once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
- cSSTI with concurrent SAB: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.
- Known or suspected RIE due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy should be in accordance with available official recommendations.
Cubicin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.
Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during treatment (see section 4.4).
Renal impairment
Daptomycin is eliminated primarily by the kidney.
Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in adult patients with any degree of renal impairment (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairment (see sections 4.4 and 5.2). The dosage regimen for Cubicin in paediatric patients with renal impairment has not been established.
Dose adjustments in adult patients with renal impairment by indication and creatinine clearance Indication for use Creatinine clearance Dose recommendation Comments cSSTI without SAB

 30 ml/min

4 mg/kg once daily
See section 5.1

< 30 ml/min

4 mg/kg every 48 hours
(1, 2)
RIE or cSSTI associated with
SAB
 30 ml/min
6 mg/kg once daily
See section 5.1
< 30 ml/min

6 mg/kg every 48 hours
(1, 2) cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia (1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).
(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for adult patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days (see section 5.2).
Hepatic impairment
No dose adjustment is necessary when administering Cubicin to patients with mild or moderate

hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.
Elderly patients
The recommended doses should be used in elderly patients except those with severe renal impairment (see above and section 4.4).
Paediatric population (1 to 17 years of age)
The recommended dosage regimens for paediatric patients based on age and indication are shown below.
Age Group
Indication cSSTI without SAB cSSTI associated with SAB
Dosage Regimen
Duration of
Therapy
Dosage Regimen
Duration of
Therapy
12 to 17 years
5 mg/kg once every
24 hours infused over
30 minutes
Up to 14 days
7 mg/kg once every
24 hours infused over
30 minutes
(1)
7 to 11 years
7 mg/kg once every
24 hours infused over
30 minutes
9 mg/kg once every
24 hours infused over
30 minutes
2 to 6 years
9 mg/kg once every
24 hours infused over
60 minutes
12 mg/kg once every
24 hours infused over
60 minutes
1 to < 2 years
10 mg/kg once every
24 hours infused over
60 minutes
12 mg/kg once every
24 hours infused over
60 minutes cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;
(1) Minimum duration of Cubicin for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient. The duration of Cubicin may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient. In the paediatric SAB study, the mean duration of IV Cubicin was 12 days, with a range of 1 to 44 days. The duration of therapy should be in accordance with available official recommendations.
Cubicin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.
Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during treatment (see section 4.4).
Paediatric patients below the age of one year should not be given Cubicin due to the risk of potential effects on muscular, neuromuscular and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see section 5.3).
Method of administration
In adults, Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.
In paediatric patients aged 7 to 17 years, Cubicin is given by intravenous infusion over a 30-minute period (see section 6.6). In paediatric patients aged 1 to 6 years, Cubicin is given by intravenous infusion over a 60-minute period (see section 6.6).
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile
In clinical studies, 2,011 adult subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. In paediatric studies, 372 patients received Cubicin, of whom 61 received a single dose and 311 received a therapeutic regimen for cSSTI or SAB (daily doses ranged from 4 mg/kg to 12 mg/kg). Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.
The most frequently reported adverse reactions (frequency common (≥ 1/100 to < 1/10)) are:
Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.
Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia (occasionally presenting as organising pneumonia), drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.
Tabulated list of adverse reactions
The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common ( 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data):
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1
Adverse reactions from clinical studies and post-marketing reports
System organ class
Frequency
Adverse reactions
Infections and infestations
Common:
Fungal infections, urinary tract infection, candida infection
Uncommon:
Fungaemia
Not known*:
Clostridioides difficile-associated diarrhoea**
Blood and lymphatic system disorders
Common:
Anaemia
Uncommon:
Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased, leukocytosis Rare:
Not known*:
Prothrombin time (PT) prolonged
Thrombocytopaenia
Immune system disorders
Not known*:
Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to angioedema, pulmonary eosinophilia, sensation of oropharyngeal swelling, anaphylaxis**, infusion reactions including the following symptoms:
tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste Metabolism and nutrition disorders Uncommon:
Decreased appetite, hyperglycaemia, electrolyte imbalance
Psychiatric disorders
Common:
Anxiety, insomnia

System organ class
Frequency
Adverse reactions
Nervous system disorders
Common:
Dizziness, headache
Uncommon:
Paraesthesia, taste disorder, tremor, eye irritation
Not known*:
Peripheral neuropathy**
Ear and labyrinth disorders
Uncommon:
Vertigo
Cardiac disorders
Uncommon:
Supraventricular tachycardia, extrasystole
Vascular disorders
Common:
Hypertension, hypotension
Uncommon:
Flushes
Respiratory, thoracic and mediastinal disorders
Not known*:
Eosinophilic pneumonia1**, cough
Gastrointestinal disorders
Common:
Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension Uncommon:
Dyspepsia, glossitis
Hepatobiliary disorders
Common:
Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)) Rare:
Jaundice
Skin and subcutaneous tissue disorders
Common:
Rash, pruritus
Uncommon:
Urticaria
Not known*:
Acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS)**, vesiculobullous rash with or without mucous membrane involvement (SJS or TEN)** Musculoskeletal and connective tissue disorders Common:
Limb pain, serum creatine phosphokinase (CPK)2 increased
Uncommon:
Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase (LDH) increased, muscle cramps Not known*:
Rhabdomyolysis3 **
Renal and urinary disorders
Uncommon:

Renal impairment, including renal failure and renal insufficiency, serum creatinine increased Not known*:
Tubulointerstitial nephritis (TIN)**
Reproductive system and breast disorders
Uncommon:
Vaginitis
General disorders and administration site conditions
Common:
Infusion site reactions, pyrexia, asthenia
Uncommon:
Fatigue, pain
*
Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
**
See section 4.4.
While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).
In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of treatment.
When clinical information on the patients was available to make a judgement, approximately 50 % of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.
The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy adult volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

General
If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.
Anaphylaxis/hypersensitivity reactions
Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.
Pneumonia
It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia.
Cubicin is therefore not indicated for the treatment of pneumonia.
RIE due to Staphylococcus aureus
Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 adult patients (see “Clinical efficacy in adults” in section 5.1). The safety and efficacy of Cubicin in children and adolescents aged below 18 years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established.
The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.
Deep-seated infections
Patients with deep-seated infections should receive any required surgical interventions (e.g.
debridement, removal of prosthetic devices, valve replacement surgery) without delay.
Enterococcal infections
There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).
Non-susceptible micro-organisms
The use of antibacterials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Clostridioides difficile-associated diarrhoea
Clostridioides difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8).
If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated.
Drug/laboratory test interactions
False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see section 4.5).
Creatine phosphokinase and myopathy
Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular

pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Cubicin (see sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9 %) than in those that received comparators (0.5 %).
Therefore, it is recommended that:
- Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.
- CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).
- It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.
- Cubicin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.
- Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.
- Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.
Peripheral neuropathy
Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Cubicin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).
Paediatric population
Paediatric patients below the age of one year should not be given Cubicin due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see section 5.3).
Eosinophilic pneumonia
Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In most reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organising pneumonia. The majority of cases occurred after more than 2 weeks of treatment with Cubicin and improved when Cubicin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re- exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products).
Cubicin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and vesiculobullous rash with or without mucous membrane involvement (Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)), which could be life-threatening or fatal, have been reported with daptomycin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, Cubicin should be discontinued immediately and an alternative treatment should be considered. If the patient has

developed a severe cutaneous adverse reaction with the use of daptomycin, treatment with daptomycin must not be restarted in this patient at any time.
Tubulointerstitial nephritis
Tubulointerstitial nephritis (TIN) has been reported in post-marketing experience with daptomycin.
Patients who develop fever, rash, eosinophilia and/or new or worsening renal impairment while receiving Cubicin should undergo medical evaluation. If TIN is suspected, Cubicin should be discontinued promptly and appropriate therapy and/or measures should be taken.
Renal impairment
Renal impairment has been reported during treatment with Cubicin. Severe renal impairment may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).
An adjustment of Cubicin dose interval is needed for adult patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.
Caution is advised when administering Cubicin to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular monitoring of renal function is advised (see section 5.2).
In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see section 4.5).
The dosage regimen for Cubicin in paediatric patients with renal impairment has not been established.
Obesity
In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0-∞ daptomycin was significantly increased (mean 42 % higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid.
Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.
Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during co-administration by intravenous infusion over a 30-minute period using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated.
There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in adult patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.
Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.
During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported.
This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).

Pregnancy
No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs the possible risk.
Breast-feeding
In a single human case study, Cubicin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.
Fertility
No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.

In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15 % of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11 % of the administered dose is removed over 48 hours).
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code:
J01XX09
Mechanism of action
Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.
PK/PD relationship
Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human adult doses of 4 mg/kg and 6 mg/kg once daily.
Mechanisms of resistance
Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients with difficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.
The mechanism(s) of daptomycin resistance is (are) not fully understood.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S.
pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.
Susceptibility
The prevalence of resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly Susceptible Species
Staphylococcus aureus *
Staphylococcus haemolyticus
Coagulase negative staphylococci
Streptococcus agalactiae*
Streptococcus dysgalactiae subsp equisimilis*
Streptococcus pyogenes*
Group G streptococci
Clostridium perfringens
Peptostreptococcus spp
Inherently resistant organisms
Gram negative organisms
* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.
Clinical efficacy in adults
In two adult clinical trials in complicated skin and soft tissues infections, 36 % of patients treated with Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound infection (38 % of patients), while 21 % had major abscesses.

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy adult volunteers. Steady-state concentrations are achieved by the third daily dose.
Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy adult subjects following administration of daptomycin as a 30- minute intravenous infusion or as a 2-minute intravenous injection.
Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.
Distribution
The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood-brain barrier and the placental barrier following single and multiple doses.
Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy adult volunteers and adult patients treated with daptomycin, protein binding averaged about 90 % including subjects with renal impairment.
Biotransformation
In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.