Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data

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Review

Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data Eric Senneville a,∗ , Jocelyne Caillon b , Brigitte Calvet c , Franc¸ois Jehl d a

Infectious Diseases Department, Gustave Dron Hospital, University of Lille II, Tourcoing, France Laboratory of Bacteriology, University of Nantes, Nantes, France Department of Anesthesiology, General Hospital of Béziers, Béziers, France d Laboratory of Bacteriology, University of Strasbourg, Strasbourg, France b c

a r t i c l e

i n f o

Article history: Received 22 July 2015 Accepted 6 November 2015 Keywords: Daptomycin High-dose Resistance Tolerance

a b s t r a c t Daptomycin exhibits excellent antibacterial activity against a wide range of Gram-positive bacteria. The on-label standard daily doses for daptomycin are 4 mg/kg for skin infections and 6 mg/kg for bacteraemia or right-sided endocarditis. Daptomycin bactericidal activity is predominantly concentration-dependent and by considering the values of pharmacokinetic targets established by several authors as well as the peak and trough concentrations of daptomycin obtained at various daily dosages, it appears that these targets can easily be reached with a dose of 6 mg/kg but only for a minimum inhibitory concentration (MIC) at 0.1 mg/L, and that for increasing MICs (e.g. 0.5 mg/L or 1 mg/L) these targets may only be attained with higher dosages (i.e. ≥10 mg/kg). High-dose (HD) daptomycin therapy has also been proven to be effective for reducing the risk of selection of daptomycin-resistant strains. Given the concentration-dependent bactericidal activity of daptomycin, the absence of a dose-toxicity relationship and the need to prevent the selection of resistant strains, we propose to consider for staphylococcal (i) skin and soft-tissue infections, daily doses of daptomycin of 6 mg/kg (new standard dose) and (ii) endocarditis or bacteraemia including those associated with intravascular catheter and implant-related infections, ≥10 mg/kg (HD) when the MIC is unknown or >0.25 mg/L, and 6–10 mg/kg (intermediate doses) when the MIC is ≤0.25 mg/L. For severe and deep-seated enterococcal infections, we propose high (≥10 mg/kg) daily doses of daptomycin in combination with another active agent, especially a ␤-lactam. © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Daptomycin, the first licensed cyclic lipopeptide, has a broad antibacterial spectrum including almost all existing Gram-positive cocci. Daptomycin differs from the glycopeptide agents vancomycin and teicoplanin in that it exerts a highly bactericidal activity both against meticillin-susceptible and -resistant staphylococcal strains [1]. Moreover, the bactericidal activity of daptomycin is not altered in bacteria in stationary growth phase, which makes it a major agent for the treatment of Gram-positive cocci-related acute severe infections, such as bacteraemia and infective endocarditis, as well as chronic infections including those involving infected implants. The bactericidal activity of daptomycin is predominantly concentration-dependent, whereas tolerance relates

∗ Corresponding author. Tel.: +33 3 20 694 949; fax: +33 3 20 694 696. E-mail address: [email protected] (E. Senneville).

to trough levels, explaining why it is currently recommended to administer high daily doses of daptomycin once for severe or difficult-to-treat infections [2]. Indeed, both in vitro and experimental model studies have shown the superiority of high-dose (HD) vs. standard-dose (SD) daptomycin in terms of bactericidal activity, efficacy and emergence of bacterial resistance during treatment [2]. Surprisingly, the superiority of HD vs. SD daptomycin regimens has not been definitely established in clinical studies so far. One reason might be that ‘HD daptomycin’ has not yet been clearly defined (Table 1). The on-label standard daily doses for daptomycin are 4 mg/kg for skin infections and 6 mg/kg for bacteraemia or right-sided endocarditis. Most authors therefore consider that daily doses >6 mg/kg can be qualified as ‘HD’. As a result, in published studies ‘HD daptomycin’ treatment can refer to very different daily doses ranging from 6.1 mg/kg to >12 mg/kg [3–13]. However, daily doses as diverse as 6.1 mg/kg and >12 mg/kg should not be considered under the same denomination because daptomycin bactericidal activity is essentially concentration-dependent and

http://dx.doi.org/10.1016/j.ijantimicag.2015.11.005 0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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Table 1 Definitions of ‘high-dose’ (HD) daptomycin treatment in clinical studies. Reference

Type of infection

Daptomycin daily dose (mg/kg/day)

Relationship between daily dosing and outcome

[3] [4] [5]

cSSSI Gram-positive infections Staphylococcus aureus infections

10 ≥8 [18/94 patients (19%) >10] Mean, 8 (range, 7–9)

[6] [7]

≥8 Median, 8.9 (IQR 8.0–10.0) Median, 8.3 (range, 6.4–10.7)

No

[9]

Any Gram-positive infections Complicated Gram-positive infections Cardiac implantable electric device infections Severe Gram-positive infections

No No Yes [clinical success, 16/22 (73%) in the SD group vs. 29/31 (94%) in the HD group; P = 0.05] No No

No

[10] [11] [12] [13]

Bone and joint infections Enterococcal infections Infectious endocarditis Left-sided endocarditis

Median, 7.61 (range, 6.03–11.53) Median, 8.15 (range, 6.6–8.9) >6 Median, 9.8 (IQR 8.2–10.0) Median, 9.2

[8]

No No No No

cSSSI, complicated skin and skin-structure infection; SD, standard dose; IQR, interquartile range.

these different dosing regimens obviously cannot be compared as a whole. Therefore, this paper aims to review the current experimental and clinical data supporting the use of HD daptomycin and attempts to define what ‘HD’ daptomycin treatments might be.

2. Spectrum of antibacterial activity and mechanism of action Daptomycin is a semisynthetic antibiotic belonging to a new class of antibacterial agents, the cyclic lipopeptides, derived from Streptomyces roseosporus. It exhibits excellent antibacterial activity against a wide range of Gram-positive bacteria, including both susceptible and multidrug-resistant pathogens. Meticillinresistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant S. aureus (VRSA) [although some studies have established a correlation between increased vancomycin and daptomycin minimum inhibitory concentrations (MICs)], vancomycin-resistant enterococci (VRE) and streptococci, including Streptococcus pneumoniae, have been shown to be susceptible to daptomycin, as well as Corynebacterium spp. and Bacillus spp. Enterococcus faecium, including VRE strains, are susceptible to daptomycin with reported MIC90 values of 0.5–4 mg/L [14]. The US Food and Drug Administration (FDA) and the Clinical and Laboratory Standards Institute (CLSI) breakpoints were established at 4 mg/L for enterococci, four times higher than those relative to staphylococci (1 mg/L), emphasising the need for an optimised daptomycin dosage regimen. Daptomycin is also active against naturally vancomycin-resistant strains of Lactobacillus spp., Pediococcus spp. and Leuconostoc spp. The anti-anaerobic activity of daptomycin has been demonstrated against all tested strains of Clostridium perfringens, Clostridium difficile and Propionibacterium spp. Daptomycin has no antibacterial activity against Gram-negative bacteria [14–18]. Daptomycin has a unique mechanism of action which differs from that of other antibacterial agents. The hydrophilic tail of the molecule is inserted irreversibly into the cell membrane of the bacteria. The drug is then postulated to undergo a calcium-dependent polymerisation and to bind to the bacterial cell membrane, thus leading to efflux of potassium from the cell and subsequent membrane depolarisation. Cell death results from an impairment of potassium-dependent macromolecular synthesis without cell lysis. Thus, fewer pro-inflammatory bacterial fragments and toxins are released compared with other antibacterial agents [19,20].

3. In vitro and experimental data supporting the use of high-dose daptomycin 3.1. Logarithmic phase 3.1.1. Normal inoculum (105 –106 CFU/mL) In the presence of physiological levels of free calcium, the bactericidal activity of daptomycin is rapid and concentrationdependant, as described for aminoglycosides [21]. In their detailed review, Hair and Keam reported that the higher the concentration, the faster a 3-log kill is achieved: indeed, 99.9% kill was achieved in 0.5 h against meticillin-susceptible S. aureus (MSSA) and MRSA with daptomycin at 8–16 mg/L, in 3 h with 1–4 mg/L and in 6 h with 1 mg/L [18]. Similar results in favour of high concentrations were obtained with vancomycin-susceptible or -resistant enterococci: 99.9% kill was achieved in 6 h at 4–8 mg/L and in 12 h at 1 mg/L. Thus, targeting high in vivo concentrations through a higher than usual dosage regimen would be in accordance with this kind of dynamic bactericidal activity. 3.1.2. High inoculum (108 CFU/mL) Many in vitro studies reported that high bacterial inocula significantly increase daptomycin MICs. In addition, the mutant prevention concentration measured by broth dilution increases in parallel with bacterial density [13,22–25]. Argemi et al. studied the effect of inoculum size on daptomycin bactericidal activity against seven strains of Enterococcus faecalis by means of time–kill curves [26]. Daptomycin at 60 mg/L resulted in a 4-log decrease of a 106 CFU/mL inoculum in 4 h against all strains. At a higher inoculum (109 CFU/mL), a 60 mg/L concentration only resulted in a bacteriostatic effect (6/7 strains). At a 120 mg/L concentration, daptomycin was bactericidal against 8/9 strains in 1–4 h with a 3–5-log decrease. One should note that 60 mg/L is the peak concentration after a 4 mg/kg dose and 120 mg/L after a higher 8–10 mg/kg dose [26]. 3.2. Stationary phase Against stationary growth phase bacteria, daptomycin remains bactericidal but only at higher concentrations, especially with high inocula. Mascio et al. reported a 3-log decrease of a 1010 S. aureus inoculum in exponential growth phase at 10 mg/L and a 5-log decrease at 100 mg/L [27]. Against the same inoculum of bacteria in stationary growth phase, daptomycin at 10 mg/L was not bactericidal, whereas a 4-log

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Table 2 Peak and trough concentrations of daptomycin at various dosage regimens. No. of patients

7 24 – – 24 12 12 24 12 12 12 12 12 12

No. of doses Single

Multiple (duration in days)

S – – –

– M (7) – – M (7) – M (4) M (14) – M (4) – M (14) – M (14)

S – – S – S – S –

Cmin (mg/L)

Cmax (mg/L)

Reference

5 6.4 5.9 6.7 9.1 – – 15.3 – – – – – –

77.5 57.8 – – 98.6 95.7 93.9 133.0 106.2 123.3 129.7 139.3 164.8 181.7

[18] [16] [5] [5] [16] [17] [17] [16] [17] [17] [17] [17] [17] [17]

Cmin , trough serum concentration; Cmax , peak serum concentration.

decrease could be achieved in 24 h at 100 mg/L. Similar data were obtained by Argemi et al. with E. faecalis in stationary phase at 109 CFU/mL [26]. A 60 mg/L concentration was only bacteriostatic for 9/9 strains, whilst at 120 mg/L daptomycin was bactericidal with a 4-log reduction in 4 h (8/9 strains). Finally, the bactericidal activity of daptomycin at 120 mg/L was significantly higher compared with 60 mg/L against bacteria in stationary phase. 4. Pharmacokinetics and pharmacodynamics Initial pharmacokinetic studies dealt with approved daptomycin dosage regimens. Thereafter, studies performed at higher dosage regimens were conducted, first on healthy volunteers [28–31] and then in special populations, either for a single dose or at steady state. Because renal excretion is the primary route of elimination of daptomycin, it requires dosage adjustment in patients with reduced creatinine clearance (CLCr ) (i.e. every other day administration for CLCr < 30 mL/min). The pharmacokinetics of daptomycin are influenced by 90–94% protein binding [32–34], resulting in an 8–9 h half-life. This binding is reversible in vitro, suggesting the bioavailability of the bound fraction in vivo [14]. In most studies on increasing doses, daptomycin exhibits linear pharmacokinetic behaviour at dosage regimens ranging from 0.5 mg/kg to 8 mg/kg. Above these values, slightly non-linear pharmacokinetics is often described, up to 12 mg/kg at steady state [18,29]. Benvenuto et al. reported that daptomycin pharmacokinetics are linear up to 12 mg/kg [30]. This may be of importance

in a context where ‘HDs’ are considered to reach the higher concentrations needed in the above-described situations. Table 2 shows the peak and trough concentrations achieved at various dosage regimens. It appears from these data that the attainment of concentrations up to and above 120 mg/L that may be required in cases of a high inoculum, stationary phase or the two combined results from doses of ≥8–10 mg/kg. Daptomycin exhibits concentration-dependent antimicrobial activity [14–16,18]. The parameters that best correlate with in vivo activity are 24-h area under the concentration–time curve (AUC24 )/MIC ratio and the peak serum concentration (Cmax )/MIC ratio [35,36]. There is considerable variation in the range of the targeted AUC/MIC ratio required for optimal antibacterial activity. LaPlante and Rybak reported that the free AUC/MIC that generated maximum kill against MRSA was 189 [14]. Using a murine thigh model, Louie et al. showed that the free AUC/MIC ratios for static and maximum bactericidal activities, respectively, were 245 and 516 [36]. In a similar model, Safdar et al. demonstrated the need for a free AUC/MIC ratio for stasis and 2-log kill of 438 and 1061, respectively [35]. Taking into account daptomycin protein binding of 90%, the required total AUC varies according to MICs in order to reach the targeted values of pharmacokinetic/pharmacodynamic parameters. Benvenuto et al. reported total AUC ranging from 730 mg h/L to 1290 mg h/L with doses from 6 mg/kg to 12 mg/kg and from single dose to steady state [30] (Table 3). Considering target values of 190 according to LaPlante and Rybak [14], 438 according to Safdar et al. [35] and 516 according to Louie et al. [36], and the peak and trough concentrations of daptomycin obtained at various daily dosages, it appears

Table 3 Daptomycin AUCs and AUC/MIC ratios according to doses and MICs. Daptomycin dose (mg/kg)

Day 1 6 8 10 12 Day 4 6 8 10 12 Day 14 10 12

Total AUC0–24 (mg h/L)

Corresponding free AUC based on 90% protein binding

Free AUC/MIC based on MICs of: 0.1 mg/L

0.5 mg/L

1 mg/L

729 773 1013 1269

72.9 77.3 101.3 126.9

729 773 1013 1269

145.8 154.6 202.6 253.8

72.9 77.3 101.3 126.9

632 658 1038 1277

63.2 65.8 103.8 127.7

632 658 1038 1277

126.4 131.6 207.6 255.4

63.2 65.8 103.8 127.7

1082 1290

108.2 129

1082 1290

216.4 58

108.2 129

Adapted from Benvenuto et al. [30]. AUC, area under the concentration–time curve; MIC, minimum inhibitory concentration.

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that these targets can easily be reached with a dose of 6 mg/kg but only for an MIC at 0.1 mg/L. With increasing MICs (e.g. 0.5 mg/L or 1 mg/L), these targets may only be attained with higher dosages such as 10 mg/kg if considering the suggested 189 target value [14], or even 12 mg/kg if considering the 245 target value suggested by Safdar et al. [35]. Thus, it clearly appears from these data that elevated doses are needed to reach a bactericidal effect with the higher MICs. 5. In vitro experimental models and experimental animal infections Numerous experimental model studies have reported better bactericidal activity of daptomycin using higher doses. In an in vitro pharmacodynamic model simulating endocardial vegetations, Akins and Rybak demonstrated that a 10 mg/kg dose resulted in better daptomycin bactericidal activity with a more pronounced inoculum decrease in situ vs. a 6 mg/kg dose against MRSA, GISA and VRE strains [21]. Moreover, HDs also reduced the emergence of resistant mutants (Table 4). Very similar data were obtained by other authors who showed in their models of endocardial vegetations that daptomycin at 8 mg/kg demonstrated bactericidal activity in 24 h, whilst it required 36 h with a 6 mg/kg dosage regimen [37–41]. They also demonstrated that HDs prevent the emergence of resistant mutants. Vidaillac et al. further reported, in the same model, that HD daptomycin (10 mg/kg) and de-escalation simulation (10 mg/kg/day to 6 mg/kg/day) appeared to be the most efficient regimen against the MRSA, vancomycinintermediate S. aureus (VISA) and heterogeneous VISA (hVISA) strains tested, exhibiting the fastest bactericidal activity (4–8 h) compared with that of the standard regimen of 6 mg/kg/day and escalation therapy of 6 mg/kg to 10 mg/kg [41]. Some experimental models of animal infection have shown that HD daptomycin regimens improved cure rates as well as the prevention of resistant mutants emergence. Studying the relationship between various doses and efficacy in a rabbit endocarditis model, Chambers et al. showed that bacterial eradication in vegetations is achieved with higher doses of daptomycin [42]. In the same study, the reduced efficacy of daptomycin against a strain with an MIC of 2 mg/L was reversed by increasing the dose to 18 mg/kg. In a meticillin-resistant Staphylococcus epidermidis endocarditis model, García-de-la-Mària et al. reported a vegetation sterilisation rate of 73% with 10 mg/kg and only 33% with a standard dose [43]. In an experimental MRSA foreign-body infection, Garrigós et al. showed that daptomycin monotherapy was effective in reducing the bacterial count by 3.6 log at the infection site only by using a 10 mg/kg dose compared with a 2-log decrease with a lower dose [44]. No resistant mutants emerged with the higher dose (Table 5).

Table 4 Residual bacterial inoculum after 72 h in the in vitro infection models [21].

Therapy regimen group

Monotherapy Rifampicin Daptomycin 100 mg/kg/day Daptomycin 45 mg/kg/day Combination Linezolid + rifampicin Vancomycin + rifampicin Daptomycin 100 mg/kg/day + rifampicin Daptomycin 45 mg/kg/day + rifampicin

Bacterial count (mean log CFU/mL ± S.D.) (no. of samples) Day 8

Day 11

−2.59 + 0.91 (20) −3.14 + 0.74 (15)

−2.75 + 1.35 (19) −3.59 + 0.49 (15)

−2.54 + 1.21 (25)

−2.71 + 1.56 (22)

−2.38 + 1.17 (20) −2.69 + 1.19 (20)

−3.23 + 1.45 (19) −3.73 + 1.48 (20)

−4.57 + 0.69 (17)

−4.538 + 0.68 (17)

−4.67 + 0.99 (18)

−4.38 + 0.92 (18)

S.D., standard deviation.

6. High-dose daptomycin in association: efficacy and prevention of resistance Numerous studies have proven the need for HD daptomycin regimens even when associated with other antibiotics. In a model simulating endocardial vegetations, daptomycin combined with either gentamicin or rifampicin resulted in a more rapid bactericidal activity at 10 mg/kg compared with the standard dose [45]. In vitro studies with bacteria embedded in mature biofilms reported that HD daptomycin plus linezolid, rifampicin or clarithromycin was more effective than each agent alone [46,47]. In prosthetic joint infections, addition of rifampicin optimises the efficacy of daptomycin [48]. Indeed, resistant mutants have been selected with either a standard dose [49] or a higher dose of daptomycin used in monotherapy [48]. HD daptomycin associated with rifampicin has also been shown to have better efficacy in animal implant-related infections due to MRSA compared with standard doses [44,50]. In a model of endocardial vegetations, Steed et al. showed the importance of HD daptomycin associated with trimethoprim/sulfamethoxazole (SXT) against MRSA with diminished susceptibility to daptomycin [51]. Indeed, using SD daptomycin in this setting resulted in a decrease of the initial inoculum within 24 h, followed by a re-growth occurring after 24 h. However, this phenomenon was avoided when HD daptomycin combination therapy was used. Finally, several in vitro studies have shown that the combination of daptomycin with ␤lactam agents such as oxacillin and ceftaroline/ceftobiprole could result in a synergistic effect and also prevent the emergence of daptomycin-non-susceptible (DNS) isolates [52]. Similar results have been established both for E. faecalis and E. faecium infections in combination with a ␤-lactam (i.e. amoxicillin and ceftaroline) [53]. 7. Clinical data justifying the use of high doses

Residual inoculum (mean log CFU/mL ± S.D.)

Growth control Daptomycin 10 mg/kg/day Daptomycin 6 mg/kg/day Vancomycin 1 g q12 h

Table 5 Decreases in bacterial counts at Days 8 and 11 [44].

GISA-992

MRSA-494

VREF-590

10.57 ± 0.09

10.14 ± 0.17

9.85 ± 0.0

2.00 ± 0.0

2.00 ± 0.0

2.52 ± 0.43

3.41 ± 1.19

5.57 ± 1.07

9.99 ± 0.0

5.45 ± 0.07

9.02 ± 0.25

2.1 ± 0.08

S.D., standard deviation; GISA, glycopeptide-intermediate Staphylococcus aureus; MRSA, meticillin-resistant S. aureus; VREF, vancomycin-resistant Enterococcus faecium; q12 h, every 12 h.

The emergence of DNS Gram-positive bacteria, especially S. aureus, following daptomycin treatment has been reported [54]. This may be related to (i) maintenance of the infected foreign body, (ii) the absence or unsatisfactory drainage of an abscess, (iii) the immune status of the patient or (iv) an elevated MIC of the infecting bacteria when daptomycin therapy is initiated. In all these cases, suboptimal dosing may promote the selection of daptomycin-resistant bacteria, especially in Staphylococcus spp. Among the options that aim to limit the emergence of DNS strains described with SD daptomycin for some complex infections, HD daptomycin and/or combination with other antimicrobial agents

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are paramount [55,56]. Clinical studies on the efficacy of HD daptomycin do not provide useful data on the outcome of daptomycin MICs for the pathogens identified during treatment. It is therefore difficult to assess which parameters result in elevated MICs during daptomycin therapy, especially mono vs. combination and HD vs. SD therapy. Of note, most HD daptomycin studies have included patients treated for on-label daptomycin indications but also with off-label indications, such as left-sided endocarditis and bone and joint infections including prosthetic joint infections. Interestingly, the Infectious Diseases Society of America (IDSA) guidelines go beyond the recommended daily doses of daptomycin and propose daily dosages as high as 8–10 mg/kg in cases of complicated bacteraemia and 10 mg/kg in combination with gentamicin, rifampicin, linezolid, SXT or a ␤-lactam agent for persisting bacteraemia during treatment and/or failing vancomycin treatment [57]. In addition, the IDSA expert panel recommends the use of a daily dose of 8–10 mg/kg for the treatment of infectious endocarditis due to MRSA [57]. HD and SD daptomycin treatments have been compared both in terms of tolerance and efficacy in different settings. In the Cubicin Outcome Register and Experience (CORE), <6 mg/kg vs. ≥6 mg/kg daily doses have been compared in patients treated for osteoarticular infections mostly due to S. aureus in, respectively, 139 and 188 patients. No significant differences in terms of clinical efficacy (90% vs. 96%, respectively) were observed [58]. In the European CORE (EUCORE) study, similar results were found in patients treated for osteomyelitis with 6.2–8 mg/kg [success rate, 82% (23/28)] and 4–6.2 mg/kg and [success rate, 75% (130/174)] [59]. In the study by Lai et al., 67 patients, the majority of whom were treated in intensive care units for miscellaneous infections with daptomycin at a median daily dose of 7.61 mg/kg (range 6.03–11.5 mg/kg) for a median duration of 14 days, had an outcome unrelated to the daily dosage of daptomycin (i.e. ≥8 mg/kg or <8 mg/kg) [9]. Similar results were found in a single-centre retrospective study in which time to microbiological cure was assessed in 46 patients, including 28 (61%) neutropenic patients with bacteraemia due to Enterococcus spp. treated with either ≤6 mg/kg or >6 mg/kg daptomycin, with respect to the MICs (≤2 mg/L vs. >2 mg/L; ≤4 mg/L) [60]. Although the data for enterococci are scarce, HD daptomycin has been proposed for severe VRE infections as well as for deepseated enterococcal infections, including those associated with biofilms [61,62]. Bassetti et al. compared the efficacy and tolerance of daptomycin at a mean daily dose of 5 mg/kg (range 4–6 mg/kg) and 8 mg/kg (range 7–9 mg/kg) for the treatment of miscellaneous Gram-positive cocci infections [5]. The authors found a statistically significant better clinical outcome and microbiological eradication rate in patients treated with higher doses. No withdrawal of daptomycin therapy was reported in the study. In another study assessing the role of higher daptomycin doses, patients treated for left-sided endocarditis with a median daily dose of 9.2 mg/kg had more rapid sterilisation of blood cultures without any significant impact on mortality [13]. In a retrospective analysis (EUCORE study), 373 of 1127 patients had a primary complicated skin and soft-tissue infection (cSSTI), most commonly a surgical-site infection (48%), and 244 had bacteraemia, 55% of which were catheter-related [63]. S. aureus was the commonest pathogen in cSSTIs (43%) and coagulase-negative staphylococci in bacteraemia (36%). The most frequently prescribed daptomycin doses were 4 mg/kg and 6 mg/kg for cSSTIs and 6 mg/kg for bacteraemia. Clinical success rates were 81% and 77% for cSSTIs and bacteraemia, respectively. A trend towards higher clinical success was noted with higher daptomycin doses in bacteraemia (78% for 6 mg/kg vs. 90% for doses >6 mg/kg) [63]. Daptomycin was compared with vancomycin for the treatment of MRSA-related bacteraemia with strains exhibiting a vancomycin

5

MIC > 1 mg/L [64]. Daptomycin was used at a median daily dose of 8.4 mg/kg [interquartile range (IQR) 6.3–9.9 mg/kg] and serum vancomycin trough levels achieved a median value of 17.6 mg/L (IQR 14.9–21.2 mg/L). Early use of daptomycin was significantly associated with improved outcomes (80% vs. 51.8%; P < 0.001), including decreased 30-day mortality (3.5% vs. 12.9%; P = 0.047) and persistent bacteraemia (18.8% vs. 42.4%; P = 0.001), supporting an early switch from vancomycin to daptomycin in these settings. Daptomycin at a daily dose of 12 mg/kg has been used for the treatment of GISA-related endocarditis in combination with rifampicin [65] and in combination with fosfomycin for the treatment of an implanted cardiac device infected by a DNS MRSA strain [66]. In another study, daptomycin at a daily dose of 10 mg/kg combined with fosfomycin cured three patients with S. aureus endocarditis including MSSA and MRSA strains [67].

8. Safety of high-dose daptomycin therapy In a rat model, Kostrominova et al. demonstrated a concentration-dependent and time-dependent effect of daptomycin on the plasma membrane of primary cultures of differentiated, spontaneously contracting rat myotubes [68]. The suggested effect of daptomycin is a loss of sarcolemma integrity because of membrane disturbances, consistent with daptomycin’s mechanism of action. The authors hypothesised that daptomycin may compromise the repair process of muscle fibres, which may be linked to the minimal daptomycin-induced muscle toxicity (DIMT) observed when daptomycin is administered once daily, allowing longer intervals of time to repair muscle damage. The observed decrease in creatinine phosphokinase (CPK) blood levels after Day 8 of daptomycin therapy may reflect a reduction in the number of affected myofibre cells. It is hypothesised that regenerated myofibres may be less sensitive to chemical injury than mature muscle cells [69]. The CPK blood level is a reliable sensitive marker of DIMT and it is recommended to discontinue daptomycin therapy in patients with clinical signs and symptoms of muscle toxicity (weakness, myalgia, etc.) and/or a CPK level increase >1000 U/L [5× upper limit normal (ULN)] or >2000 U/L (10× ULN) in an asymptomatic patient (http://www.accessdata. fda.gov/drugsatfda docs/label/2010/021572s033lbl.pdf). Bhavnani et al. demonstrated that both AUC and minimum serum concentration (Cmin ) of daptomycin are significantly associated with CPK elevations. A Cmin ≥ 24.3 mg/L could lead to a >30-fold higher risk of CPK elevations [70]. These data combined with the predominant concentration-dependent bactericidal effect of daptomycin justify its once-daily administration. However, it is important to distinguish CPK elevation from rhabdomyolysis, which corresponds to the breakdown of muscle tissue that leads to the release of muscle fibre contents (especially myoglobin) into the blood and potentially to kidney damage [71]. Otherwise, various values from 5 or 10× to 50× ULN levels have been proposed as diagnostic criteria for rhabdomyolysis [72]. In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving HD daptomycin therapy, although this has recently been disputed [73]. The existence of a relationship between the daily dose and the occurrence of DIMT has been assessed in some studies that compared HD with SD daptomycin [5,9,13,74,75]. In the study by Lai et al., the incidence of CPK elevation was significantly higher in patients treated with daptomycin >8 mg/kg compared with ≤8 mg/kg (16.7% vs. 0%; P = 0.02) [9]. Figueroa et al. reported a series of 61 patients treated with a mean dose of 8 mg/kg daptomycin for a median of 25 days, among whom 3 patients treated with 8 mg/kg daptomycin had musculoskeletal symptoms with CPK elevations

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Table 6 Incidence of daptomycin-induced muscle toxicity according to the daily dosage of daptomycin. Reference

Median daily dose in mg/kg (range)

Daptomycin-induced muscle toxicity

Definition of ‘high-dose’: daily dose in mg/kg

Definition of ‘elevated CPK’

[5] [30] [74]

6 vs. 8 (7–9) 6–12 6 vs. 8

8 N/A 8

>ULN >ULN (104 U/L) >500 U/L

[13]

9.2 (7.7–10)

>6

>400 U/L (normal range <50 U/L)

[11]

8.2 (7.7–9.7)

0/22 vs. 1/31 (3.2%); 1 discontinuation 0 4/25 (16.0%) vs. 5/23 (21.7%) in patients treated with 6 mg/kg and 8 mg/kg, respectively 1/28 (3.6%): no difference between < and >8 mg/kg 7/220 (3.2%), all asymptomatic

>6

[77]

6.6 (4–9)

>6

[75] [8] [76]

8 (6.1–12) 8.3 (6.4–10.7) 8 (7–11)

≥8 >6 >6

>5× ULN >ULN 10× ULN (100 U/L)

[10] [3] [12] [7] [9]

8.15 (6.6–8.9) 10 9.8 (8.2–10.0) 8.9 (8.0–10.0) 7.61 (6.03–11.53)

>6 10 ≥8 ≥8 >6

[78] [4]

10 (8.33–12.5) 8

≥10 ≥8

>ULN (188 U/L) >ULN >ULN >ULN ≥3× ULN (160 U/L)a ; ≥5× ULN, or ≥5× ULNa if normal or not at baseline >ULN >ULN

[69] [6]

7.8 (6.5–10.8) 8

2/20 (10%) including 1/20 (5%) with rhabdomyolysis 7/74 (10%) >6 mg/kg vs. 12/196 (6%) <6 mg/kg 5/25 (20%), no discontinuation; non-obese 3/69 (4.4%), all with myalgia; 2/3 with morbid obesity 0 8.3% (4/48) 0 ≥8 4/67 (5.9%); 0/37 in patients with ≤8 mg/kg vs. 4/24 (16.7%) in patients with >8 mg/kg (P = 0.02) 0 6/94 (6.4%) AEs, including 2 (2.1%) discontinuations for AEs 10/104 (9.6%) 6/69 (8.6%), all asymptomatic

>5× ULN if muscle symptoms or 10× ULN if asymptomatic >ULN (150 U/L)

≥8 ≥8

>2.5× ULN (>1000 U/L) >ULN

CPK, creatinine phosphokinase; ULN, upper limit of normal; N/A, not applicable; AE, adverse event. a On two serial measurements.

>1000 U/L [76]. However, a review of the main clinical studies that addressed this question does not provide data in favour of a significantly higher risk of elevated CPK in patients treated with HD vs. SD daptomycin therapy (Table 6). Assessment of a correspondence between DIMT and the mean daily dose of daptomycin does not show any link between the two variables (Fig. 1). In summary, the available data do not support the existence of a higher risk of DIMT in patients treated with HD vs. SD daptomycin therapy. It must be noted, however, that the safety of HD daptomycin has only been retrospectively assessed in small sample size studies. In addition, the EUCORE registry has a questionable design as criteria for selection of the included patients are unclear. The lack of data on the relationship between high dose and safety of daptomycin leads us to be cautious on the use of HD daptomycin especially in patients with co-morbidities who required several weeks of treatment. Given the absence of well designed studies that address this important issue, the authors claim the need for prospective studies to compare the safety and effectiveness of HD vs. SD daptomycin therapy. In addition to the risk of muscle toxicity, some

25

20

15 Median daily dose (mg/kg) % of paents with DIMT*

10

5

0 1

5

9

13

17

21

Fig. 1. Proportion of patients with daptomycin-induced muscle toxicity (DIMT) and the mean daily dose of daptomycin (mg/kg) in 21 patients from the 18 clinical studies reported in Table 6. The 21 patients are reported in increasing order of percentage of median daily dose of daptomycin.

cases of eosinophilic pneumonia have been reported, which usually resolves quickly after treatment withdrawal [79]. Again, the relationship with the daily dose has not been established, but given the potential severity of this adverse effect this diagnosis should be considered in any patient who experiences pulmonary problems while on daptomycin treatment.

9. Conclusions The literature review shows that the term ‘HD’ is associated with the use of daily doses of daptomycin exceeding 6 mg/kg in every report and corresponding to the highest daily doses recommended by the authorities. Notably, a very wide range of daily doses are used under the term ‘HD’, ranging from 6.1 mg/kg to 12 mg/kg (i.e. by a factor of two). In addition, the value of the daily dose that defines HD daptomycin corresponds generally to a median or mean value with wide variations in the studied population. Available studies have established that it is possible to double the highest recommended daily doses of daptomycin (i.e. 6 mg/kg to >12 mg/kg) without modifying its profile for tolerance, although this is quite unfeasible for vancomycin. For an MIC > 1 mg/L it is necessary to obtain vancomycin trough concentrations of ca. 15–25 mg/L, which have been associated with an increased risk of nephrotoxicity [80,81]. It must be noted that the range of daily doses used in patients treated with SD daptomycin is relatively narrow (i.e. 4–6 mg/kg), whereas it may range from 6 mg/kg to >12 mg/kg in patients treated with HD daptomycin. Results provided in the published clinical studies do not definitely demonstrate that HD daptomycin is associated with a better patient outcome compared with SDs, probably due to the fact that no clinical study has compared daily doses of daptomycin with a broad intergroup range (e.g. 6 mg/L vs. 10 mg/L) so far. The absence of evidence of the superiority of HD vs. SD daptomycin therapy cannot therefore be drawn from these retrospective clinical studies.

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Although the selection of DNS strains is unlikely to be detected during infections of low-grade severity, the increase in MICs during treatment appears to be a major argument for using HD daptomycin. To combat against the selection of DNS strains, it is important, however, to keep in mind that the drainage of purulent collections and the removal of infected implants are paramount to rapidly and effectively decreasing the bacterial inoculum and suppressing bacteria embedded in a mature biofilm. The concentration-dependent bactericidal effect of daptomycin and the favourable safety profile at daily doses up to 12 mg/kg associated with the risk of emergence of DNS strains under SD treatment represent strong arguments for HD daptomycin treatment. Combinations with other antibiotic agents, especially ␤-lactams, SXT, linezolid, gentamicin, fosfomycin and ceftaroline, are other means to enhance the bactericidal effect of daptomycin and to prevent the emergence of DNS strains [82]. Given the concentration-dependent bactericidal effect of daptomycin, the absence of a dose-toxicity relationship and the need for preventing the selection of resistant strains, we propose to consider for staphylococcal (i) SSTIs, daily doses of daptomycin of 6 mg/kg (new SD) and (ii) for endocarditis, bacteraemia including those associated with intravascular catheter and implant-related infections, ≥10 mg/kg (HD) when the MIC is unknown or >0.25 mg/L, and 6–10 mg/kg (intermediate dose) when the MIC is ≤0.25 mg/L. For severe and deep-seated enterococcal infections, we propose high (≥10 mg/kg) daily doses of daptomycin in combination with another active agent, especially a ␤-lactam. To conclude, the available published studies on the efficacy and risk of selection of bacterial resistance during daptomycin therapy suggest that SDs may not be most appropriate for some potentially severe infections such as bacteraemia and foreign-body infections. In addition to the use of combined antibiotic regimens and the need for surgical intervention, administration of the most appropriate daily dose of daptomycin is important to consider in these situations. By taking into account the current available data regarding the antibiotic properties and safety of daptomycin, we propose precise definitions of the so-called HD daptomycin therapy for SSTIs, bacteraemia including endocarditis, and implant-related infections. Funding: None. Competing interests: All of the authors have received grants for meeting support from Novartis SA. Ethical approval: Not required.

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Please cite this article in press as: Senneville E, et al. Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2015.11.005