High-Dose Daptomycin and Clinical Applications

Abstract

Objective:

To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d).

Data Sources:

A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms daptomycin, high dose, and dosing. Review article references and society guidelines were reviewed.

Study Selection and Data Extraction:

Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included.

Data Synthesis:

Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant Staphylococcus aureus (when vancomycin minimum inhibitory concentration is >1 mg/L) and Enterococcus. High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg).

Relevance to Patient Care and Clinical Practice:

This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards.

Conclusions:

The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

Introduction

Daptomycin, the first approved cyclic lipopeptide, exhibits bactericidal activity against gram-positive bacteria.¹ Unlike vancomycin and linezolid, daptomycin is bactericidal against virtually all multidrug-resistant gram-positive organisms.² Daptomycin inserts into gram-positive membranes through an affinity for the anionic phospholipid composition of gram-positive membranes.^3,4 Insertion disrupts cell division and peptidoglycan synthesis. Membrane pores form, causing ion leak and fatal structural changes.^5,6 Current Food and Drug Administration labeling indicates daptomycin for complicated skin and skin structure infections and Staphylococcus aureus bacteremia, including those with right-sided endocarditis, but the uses extend across many severe gram-positive infections.⁷

Early experimental data combined with case reports of daptomycin 2 mg/kg treatment failure from the 1990s suggested dose-related, concentration-dependent daptomycin efficacy.^8-10 Daptomycin’s high protein binding (90%-94%) was indicted as the cause of this reduced efficacy, and studies began investigating higher doses (eg, 6 mg/kg/d) to increase free drug concentrations and improve bactericidal activity.^9-11 The first case report describing what is now considered high-dose daptomycin (≥8 mg/kg/d) was published in 2006.¹² The report demonstrated daptomycin 12 mg/kg/d for 41 days successfully treating device-related infective endocarditis (IE).¹² Since then, daptomycin ≥8 mg/kg/d has been widely studied. This review aims to assess the efficacy and safety of high-dose daptomycin (≥8 mg/kg/d).

Rationale for High-Dose Daptomycin

Support for high-dose daptomycin first derives from the pharmacokinetic/pharmacodynamic (PK/PD) parameters established as daptomycin efficacy predictors: the maximum concentration to minimum inhibitory concentration ratio (C_max/MIC) and area-under-the-curve to MIC ratio (AUC/MIC).^13-15 Murine modeling suggests that daptomycin C_max/MIC ratios should range from 70 to 250, and 24-hour AUC/MIC ratios from 500 to 1000 (free drug AUC/MIC 50-100) to achieve 99% bacterial cure rates of S aureus and Streptococcus pneumoniae.¹⁴ Concordantly in humans, an AUC/MIC of less than 666 has been associated with higher mortality in severe gram-positive infections.¹⁶ Achieving these PK/PD targets is linearly dose dependent, with 8 mg/kg more likely to achieve target exposures than 6 mg/kg in animals and humans.^14,16

As MIC is organism specific, optimizing AUC/MIC with high-dose daptomycin relates linearly to higher dose requirements among specific organisms. This relationship is illustrated by Avery et al,¹⁷ who reported that the probability of achieving target AUC/MIC exceeded 90% with daptomycin monotherapy for enterococcal isolates with MICs from 1 to 2 mg/L only when daptomycin doses exceed 8 mg/kg. These MICs are substantially higher than those for S aureus, which nearly always has MICs of <1 mg/L.¹⁸ The Clinical and Laboratory Standards Institute recently revised Enterococcus faecium breakpoints, implementing dose-dependent (use of 8-12 mg/kg required) susceptibility for MICs ≤4 mg/L. Enterococcus faecalis susceptibility was defined as ≤2 mg/L and intermediate susceptibility as 4 mg/L.¹⁹ In keeping with these revisions, the European Committee on Antimicrobial Susceptibility Testing cautions against using high-dose daptomycin (10-12 mg/kg) to treat enterococcal infections with MICs ≥4 mg/L.²⁰ Together, the clear dose relationship to PK efficacy parameters supports dose escalation to enhance daptomycin efficacy.

The rationale for the first clinical application of 12 mg/kg/d of daptomycin was the penetration of biofilms in S aureus IE.¹² Biofilm occurs when bacteria congregate, typically in concentrated infections such as IE or osteomyelitis, to produce a polymeric gelatinous matrix that prevents antimicrobials from reaching the embedded organisms.²¹ High bacterial concentrations may also promote the inoculum effect, where high local bacterial load increases the MIC of an organism beyond susceptibility tests.^22,23 Gram-positive pathogens, staphylococci, enterococci, and streptococci, can all produce biofilms varying in composition.^24,25

Recently, Jahanbakhsh et al²⁶ showed that daptomycin exhibits dose-dependent killing in the CDC (Centers for Disease Control) biofilm reactor model simulating human antibiotic exposure. Daptomycin 10 mg/kg exhibited enhanced S aureus bactericidal activity over 6 mg/kg, including a nonsusceptible strain, in an in vitro endocardial vegetation model.²⁷ The 10-mg/kg dose also prevents the increase in daptomycin MIC of S aureus that occurs with 6 mg/kg dosing in endocardial vegetations.²⁸ These in vitro models provide valuable PK/PD data but lack generalizability to the long treatment durations commonly seen clinically with daptomycin. For example, a study evaluating time from initial therapy to 96 hours observed a spike in bacterial regrowth of a methicillin-susceptible S aureus strain treated with daptomycin 10 mg/kg from 72 to 96 hours, although this occurred in only 1 of 6 isolates.²⁸ However, a study of high-inoculum infection resembling bacterial burden similar to deep-seated clinical infections (9 log₁₀ CFU/g) demonstrated that doses of 10 mg/kg result in greater bacterial burden reduction than 6 to 8 mg/kg.²⁹

Translating the in vitro dosing to in vivo models in a mouse tissue cage model of methicillin-resistant S aureus (MRSA) foreign-body infections, daptomycin dosed at the human equivalent (determined by comparable AUC/MIC) of 10 mg/kg lowered bacterial counts more than the 6-mg/kg dose.³⁰ Likewise, in a rabbit aortic valve endocarditis model, 10-mg/kg modeled dosing was more effective than 6 mg/kg at eradicating S aureus.³¹ Both doses eliminated infected vegetations of the susceptible strain; however, the 10-mg/kg dose lowered the high inoculum (7.3 log₁₀ CFU/g) of the daptomycin-resistant endocardial vegetations by 1.9 additional log₁₀ CFU/g units compared with 6 mg/kg (4.4 vs 6.3 log₁₀ CFU/g).³¹ Although these data are encouraging, the modeled nature of these vegetations fails to capture mature biofilm formation and higher inoculum typical at the time of daptomycin initiation. No high- versus low-dose comparisons exist in mature biofilm models; however, daptomycin is one of the only antimicrobials to reduce biofilm mass and bacterial viability beyond the surface of mature S aureus biofilms.³²

Dose-related PK/PD target attainment, activity in biofilm-associated infections, and high inoculum killing provide the rationale for high-dose daptomycin. The heterogeneity of bacterial strains and models between studies as well as dosing differences between the experiments limit deriving a specific dose from the experimental data but strongly support clinical investigation of high-dose daptomycin. Institutional concerns such as medication cost can also complicate the rationale for daptomycin. Several economic analyses of daptomycin versus vancomycin plus gentamicin or daptomycin versus vancomycin for the treatment of MRSA infections have demonstrated similar or possibly improved cost-effectiveness with daptomycin.^33,34 Moreover, these studies were published prior to the introduction of daptomycin generic in 2016, which would likely further improve cost justifications of daptomycin in present times. Together, these components form the preclinical rationale for high-dose daptomycin.

Data Sources and Selection

This review was a narrative review in which we performed a search of the PubMed/MEDLINE database from January 2000 to December 2020. Articles were identified by the search terms daptomycin AND high dose AND disease state-specific terms, including one of the following as independent searchers: endocarditis, bacteremia, hemodialysis, osteomyelitis, meningitis, renal replacement therapy, obesity, and burns. Reviewed articles were in English and included clinical trials, observational studies, retrospective studies, review articles, editorials, abstracts, meta-analyses, and systematic reviews. Studies were included if they reported using high-dose daptomycin (≥8 mg/kg/d) and clinical outcomes. References from society guidelines were reviewed whenever possible. Selected experimental evidence was chosen to accompany clinical studies when appropriate.

Endocarditis

IE occurs when bacteria adhere to and infect the cardiac endothelium.³⁵ S aureus accounts for 31% to 40% of all native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE). Viridians group streptococci and enterococci are less frequent pathogens, at 17% and 11%, respectively.^36,37 The American Heart Association endocarditis guidelines suggest daptomycin ≥8 mg/kg/d for infections caused by resistant organisms, specifically left-sided MRSA IE and resistant enterococcal IE (10-12 mg/kg/d).³⁸ Evidence for high-dose daptomycin in IE is more robust than in other disease states. However, no prospective trials have investigated high-dose daptomycin, limiting evidence to retrospective and observational data. Specific outcomes and safety details of key high-dose daptomycin studies are present in Table 1.

Table 1.

Clinical Studies With High-Dose Daptomycin Doses.

Reference	Study design	Population	Daptomycin regimens	Results and conclusions	Safety
Huang et al, 2020109	Retrospective, single center	n = 10; Severe burn injury (>50% BSA), Chinese, 20-50 years, 7 days postburn	6 mg/kg/d (n = 3) vs 12 mg/kg/d (n = 7). The higher dose was given after 6 mg/kg/d did not reach desired serum concentrations.	Two of 3 MRSA infections in the high-dose group converted to negative cultures, whereas 0 of 2 in the standard-dose group became negative. High-dose daptomycin produced higher concentrations than standard doses through 7 hours after the dose	No significant difference in CPK levels between high doses and standard doses (1 patient showed transient CPK increase after high doses). Albumin was increased with high-dose daptomycin on day 7 compared with baseline
Peghin et al, 201947	Prospective, single center	n = 43; NVE and PVE from enterococcal spp	Daptomycin-based regimen (high-dose ± another agent, n = 16) vs daptomycin-sparing regimen (no daptomycin, n = 27). Mean daptomycin dose: 10.25 mg/kg/d	No difference in mortality rates and/or treatment failure in either group. Shorter antibiotic therapy length was found in the daptomycin-based group (45 vs 56 days; P = 0.02)	No rhabdomyolysis or eosinophilic pneumonia occurred in patients receiving high-dose daptomycin
Russo et al, 201939	Prospective, single center	n = 327 (224 NVE and 103 PVE); Monomicrobial gram-positive endocarditis	Daptomycin-containing regimen (n = 84) vs nondaptomycin regimen (n = 140); daptomycin doses ranged from 4 to ≥8 mg/kg/d	Daptomycin 4-6 mg/kg/d was associated with higher mortality and treatment failure compared with ≥8 mg/kg/d dosing (NVE mortality: 26.1% vs 1.2%; PVE mortality: 6.5% vs 0%). Standard daptomycin doses of 4-6 mg/kg/d were associated with 30-day mortality in daptomycin-treated patients (OR = 2.2; P = 0.02)	No patient receiving daptomycin had an adverse event warranting a change in therapy
Chuang et al, 201863	Prospective, 2-center Taiwanese observational cohort	n = 108; VRE BSI treated with daptomycin or linezolid	Daptomycin <9 mg/kg (58%) vs daptomycin ≥9 mg/kg (14%) vs linezolid (28%)	Daptomycin ≥9 mg/kg cleared bacteremia faster than <9 mg/kg (−0.04 vs −0.56 Δ log10 copies/mL/d). Slower bacterial clearance predicted mortality (aOR = 1.4; P = 0.045	None reported
Britt et al, 201760	Retrospective, national cohort of Veterans Affairs hospitals	n = 911; BSI with VRE and treated with daptomycin	Daptomycin 6 mg/kg/d (78%), 8 mg/kg/d (16%), or ≥10 mg/kg/d (7%)	Doses ≥10 mg/kg/d were associated with greater survival than both 6 (aHR: 2.58; P = 0.004) and 8 mg/kg/d (aHR: 2.52; P = 0.008). Doses ≥10 mg/kg/d were associated with a lower 30-day mortality risk. Doses of 8 and 10 mg/kg/d were both associated with enhanced microbiological clearance rates than 6 mg/kg/d	CPK elevation occurred in 1.2% of those measured, and no patient in the ≥10-mg/kg/d group experienced CPK elevation. Concurrent statin use was not associated with elevated CPK (1.3% vs 0.7%; P = 0.504)
Claeys et al, 201657	Retrospective, multicenter, propensity matched	n = 262; MRSA BSI treated with daptomycin or vancomycin	Daptomycin 8.2 mg/kg/d (IQR = 6.4-10) vs vancomycin trough target (15-20 mg/L)	All-cause 30-day mortality was lower with daptomycin (6.1% vs 15.3%; P = 0.01). Change in therapy occurred less frequently with daptomycin (15.3% vs 28.2%; P = 0.05)	Adverse drug reactions were reported in 11.5% of patients in both groups. Three patients receiving daptomycin had CPK elevations >2000 U/L, and 2 (1.5%) reported myopathy
Guleri et al, 201542	Retrospective, multicenter, data from EU-CORE	n = 610; At least 1 dose of daptomycin for serious gram-positive IE	Daptomycin doses ≥8 to ≤10 mg/kg/d (n = 109, 17.9%) and doses >10 mg/kg/d (n = 7, 1.1%)	Daptomycin doses ≥8 mg/kg/d had a trend toward higher clinical success rates than doses <8 mg/kg/d (92.2% vs 78.3%)	Blood CPK elevations were reported in 11 of 610 patients (1.8%); myalgia and rhabdomyolysis each occurred in 1 patient
Ceron et al, 201448	Retrospective, single center	n = 32; Patients ≥18 years old with monomicrobial enterococcal IE	Daptomycin 6 to 10 mg/kg/d (n = 6) vs ampicillin/ceftriaxone (n = 21) vs ampicillin or vancomycin ± gentamicin (n = 5); median daptomycin dose: 8.5 mg/kg/d	Daptomycin-treated patients had a longer duration of bacteremia (6 days vs 1 day vs 1 day; P < 0.01). Daptomycin-treated patients needed more frequent therapy changes (66.7% vs 0% vs 20%; P < 0.01	No differences in adverse events related to antibiotic therapy (0% vs 0% vs 20%)
Carugati et al, 201340	Prospective observational, multicenter	n = 441; Left-sided IE caused by S aureus, Enterococcus faecalis, or coagulase-negative staphylococci	Daptomycin (n = 49) vs other standard of care antibiotics (n = 392); median daptomycin dose: 9.2 mg/kg/d (7.7-10.0)	Daptomycin was associated with faster clearance of MRSA bacteremia (1 vs 5 days; P < 0.01). Daptomycin was used as second-line in 68% of daptomycin-treated patients	Doses ≥8 mg/kg/d were not associated with a difference in adverse events
Murray et al, 201346	Matched retrospective, multicenter	n = 170; MRSA bacteremia (etiologies: IE = 40; bone/joint = 58; SSTI = 56) treated with daptomycin or vancomycin for >72 hours. Patients who received vancomycin for >72 hours prior to daptomycin initiation were excluded	Daptomycin (n = 85) vs vancomycin (n = 85); median daptomycin dose: 8.4 mg/kg/d (IQR = 6.3-9.9)	Daptomycin was associated with lower rates of clinical failure (20% vs 48.2%; P < 0.001), 30-day mortality (3.5% vs 12.9%; P = 0.047), persistent bacteremia (18.8% vs 42.4%; P = 0.001), and duration of bacteremia (3 vs 5 days; P = 0.003)	One patient treated with daptomycin 12 mg/kg/d experienced significant CPK elevation (67-7221 U/L) on day 17 of daptomycin. No musculoskeletal symptoms were observed. Nonsignificant CPK elevations were observed in 30.6% of daptomycin-treated patients (median increase: 92 U/L) after a median of 11 treatment days
Kullar et al, 201159	Retrospective, multicenter	n = 250; Bacteremia, 163; IE, 59. Patients ≥18 years old receiving high-dose daptomycin for >72 hours for S aureus and/or enterococcal infections at any site (complicated bacteremia, 163; IE, 59)	Median daptomycin dose: 8.9 mg/kg/d;89.6% of patients received high-dose daptomycin as salvage therapy	Clinical success occurred in 83.6% of patients with MRSA and VRE; clinical failure occurred in 9 (6%) patients with bacteremia and 5 (8%) patients with IE; 13 patients developed daptomycin nonsusceptibility, usually after prior extensive vancomycin exposure	Three (1.2%) patients experienced an adverse event associated with daptomycin. Of 152 patients with baseline CPK ≤200 U/L, 16 (n = 10.5%) had CPK elevations >200 U/L; 24 patients were taking concomitant statin therapy, and none developed myopathies

Abbreviations: aHR, adjusted hazard ratio; aOR, adjusted odds ratio; BSA, body surface area; BSI, blood stream infection; CPK, creatinine phosphokinase; EU-CORE, European Cubicin Outcomes Registry and Experience; IE, infective endocarditis; IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; SSTI, skin and soft tissue infection; VRE, vancomycin-resistant Enterococcus.

To date, 2 prospective studies have evaluated high-dose daptomycin in exclusively IE cohorts.^39,40 The recent prospective observational study included 327 definitive gram-positive IE cases (70% NVE, 30% PVE, >95% left-sided IE) at a single center in Italy over 8 years.³⁹ Patients were grouped according to daptomycin-containing regimens (DCRs) and regimens without daptomycin, resulting in combination therapy with 40% of NVE and all the PVE cases. DCRs of all doses were associated with lower 30-day mortality for NVE and PVE in multivariate analyses. Daptomycin 4 to 6 mg/kg was associated with higher odds of 30-day mortality only among NVE cases (odds ratio [OR] = 2.2; 95% CI = 1.91-4.56; P = 0.02). Notably, 69% of DCR-treated PVE patients received daptomycin ≥8 mg/kg/d, and none experienced treatment failure or 30-day mortality. No patient treated with any dose of daptomycin experienced adverse events that required therapy change.³⁹ These results provided the first prospective clinical data exclusively in IE, showing an association between mortality and 4- to 6-mg/kg dosing (rather than ≥8 mg/kg).

Carugati et al⁴⁰ evaluated prospectively collected data from the multicenter International Collaboration on Endocarditis (ICE) Plus and ICE Daptomycin Substudy. All patients exhibited left-sided IE, and NVE accounted for 80% of cases. A median daptomycin dose of 9.2 mg/kg/d was compared with standard-of-care antibiotics, primarily vancomycin, and showed no mortality difference. High-dose daptomycin achieved comparable clinical outcomes despite more comorbidities (ie, diabetes), and nearly 50% was used as second-line therapy. A nonsignificant reduction in time to clearance of bacteremia occurred with daptomycin compared with the primarily vancomycin-treated cohort (1.5 vs 3 days; P = 0.10). However, no differences in clinical and microbiological outcomes or adverse events occurred between daptomycin ≥8 and <8 mg/kg/d. The small number of daptomycin-treated cases (n = 28) prevented robust outcomes and safety conclusions and limited the detection of group differences.

Much of the support for high-dose daptomycin in IE comes from lower-quality evidence of large international data sets from the European Cubicin Outcomes Registry and Experience (EU-CORE), in which inferential statistics are not used for data analysis. Seaton et al⁴¹ described the effectiveness of high-dose daptomycin among 6075 patients and 597 IE cases from the EU-CORE, specifically comparing ≤6, >6 to <8, and ≥8 mg/kg/d. Clinical success rates rose with ≥8 mg/kg/d (94%) compared with >6 to <8 mg/kg/d (85%) and ≤6 mg/kg/d (81%).⁴¹ Guleri et al⁴² specifically analyzed the IE cases from the EU-CORE cohort, reporting an increase in success rates from 4 to ≥8 mg/kg. Doses ≥8 mg/kg achieved a 92% success rate compared with 81% success with doses ≥6 to <8 mg/kg. The difference was consistent among both right- and left-sided IE.⁴² The combination of EU-CORE and USA-CORE registry data accumulated 798 IE cases demonstrating similar numerical trends in clinical success rate favoring high-dose daptomycin, ≥8 mg/kg/d (84.4%) compared with >6 to <8 mg/kg/d (70.9%) and ≤6 mg/kg/d (74.2%).⁴³ Additionally, creatinine phosphokinase (CPK) elevations were rare in the entire cohort of 11 557 patients (1.9%) and not associated with daptomycin dosing.⁴³

These registries included all patients receiving at least 1 dose of daptomycin with a median duration of roughly 14 days for standard and high doses.^41-43 Appropriate therapy for IE would last between 4 and 6 weeks,³⁸ limiting safety and efficacy assessment of full-course therapy. Another relevant limitation to these registries is the ambiguity in clinical success definitions because registry data include both cured (more definitive) and improved (more ambiguous) IE cases as clinical successes. Moreover, the inability to make causal inferences from these descriptive noncomparative data limits application beyond hypothesis generation.

Despite preclinical work displaying enhanced efficacy with high-dose daptomycin in MRSA, scant clinical support has been generated. Early case reports describe high success rates (80%) with high-dose daptomycin (median 8.3 mg/kg/d) in device-related IE from Staphylococcus epidermidis and S aureus.⁴⁴ In a prospective observational cohort, more rapid clearance of MRSA bacteremia in IE was associated with a median daptomycin dose of 9.6 mg/ kg/d (interquartile range [IQR] = 8.4-10.5 mg/kg/d) compared with vancomycin (1 vs 5 days; P < 0.01).⁴⁰ A clinical trial of daptomycin 6 mg/kg reported that the clearance of MRSA bacteremia was considerably slower (8 days)⁴⁵ than reported by Carugati et al⁴⁰ (1 day). The higher median dose (9.4 vs 6 mg/kg/d) may have enhanced the clearance of bacteremia. High-dose daptomycin has produced success rates of 60% compared with 35% with vancomycin in the early management of MRSA IE,⁴⁶ supporting further investigation of high doses as initial therapy in MRSA IE.

In a prospective single-center study of 43 enterococcal IE cases (91% E faecalis), Peghin et al⁴⁷ reported that daptomycin (average 10 mg/kg, range 8-12 mg/kg) achieved success in 15/16 (94%) patients compared with 21/27 (78%) patients not receiving daptomycin and was associated with 10-day reduction in treatment duration. Notably, 70% of daptomycin treated patients received combination therapy with ampicillin or gentamicin.⁴⁷ In contrast, a single-center retrospective study by Ceron et al⁴⁸ observed extended bacteremia and worse clinical response with daptomycin (average 8.5 mg/kg) compared with ampicillin or vancomycin plus gentamicin in enterococcal infections, with MIC of 1 to 2 mg/L. However, only 6 of 32 patients received daptomycin, and daptomycin was not used in combination, limiting robust comparison.⁴⁸ In vitro modeling of enterococcal IE vegetations supports the superiority of daptomycin 10 to 12 mg/kg/d over lower doses in E faecalis and E faecium isolates,⁴⁹ which could explain differing results observed in these studies because doses of ≥10 mg/kg/d⁴⁷ may outperform 8.5 mg/kg/d⁴⁸ in enterococcal IE. Differences in combination therapy may contribute to differences in outcomes. Sakoulas et al⁵⁰ reported that adding ampicillin to 4 mg/kg daptomycin to treat vancomycin-resistant Enterococcus (VRE) in vitro resulted in bactericidal activity exceeding 10 mg/kg. They also noted rapid VRE blood clearance in endocarditis when changing a patient from daptomycin 6 mg/kg every 48 hours (renal adjustment) plus linezolid to daptomycin 12 mg/kg every 48 hours plus ampicillin 1 g every 6 hours.⁵⁰

In summary, these data support high-dose daptomycin as a reasonable option in the management of gram-positive IE. The lack of dose-to-dose comparison studies and randomized controlled trials limits definitive dose justifications; however, the consistency of high clinical success rates and lack of increased adverse events combined with PK/PD principles and support from preclinical endocarditis models provide a sound rationale for high doses. High doses may be especially beneficial in MRSA IE by hastening bacterial clearance. Enterococcal IE often presents with higher MICs, but daptomycin 10 to 12 mg/kg appears clinically effective with MICs ≤2 mg/L. Combination therapy appears encouraging for enterococcal IE, but more evidence is needed at different daptomycin doses.

Bacteremia

Bloodstream infections frequently arise secondary to foreign devices or conditions where local flora enters circulation through barrier degradation or insertion (eg, diabetic ulcers, catheters). This pathophysiology causes consistent overlap with other infections such as endocarditis and prosthetic joint injections, often linking efficacy studies between the conditions, but antimicrobial efficacy in eliminating the bacterial seeding location will vary between bacteremia etiology (eg, skin penetration vs indwelling device). Coagulase-negative Staphylococcus, S aureus, and enterococcal species are the most prevalent gram-positive pathogens causing bacteremia.⁵¹ The rapid bactericidal actions and broad spectrum of activity has made high-dose daptomycin attractive in treating bacteremia associated with various underlying infections.^35,52

Early studies suggested standard-dose (6 mg/kg/d) daptomycin as an effective option for treating bacteremia. In a retrospective cohort of 126 bacteremic patients from CORE registry data, Sakoulas et al⁵³ observed no outcome differences between daptomycin ≥6 or <6 mg/kg in catheter-related and non–catheter-related bacteremia. A randomized controlled trial of daptomycin 6 mg/kg/d monotherapy in MRSA bacteremia demonstrated comparability to standard vancomycin therapy, prompting the question of improving effectiveness with higher doses.⁴⁵ In the study, some S aureus isolates developed reduced daptomycin susceptibility (MIC 2-4 mg/L), leading to clinical failure after 12 days of daptomycin 6 mg/kg, and numerically higher microbiological failure with daptomycin was observed (15.8% vs 9.6%; P = 0.17).⁴⁵ Applying in vitro PD rationale for high daptomycin to this clinical trial, Rose et al²⁸ showed that daptomycin 10 mg/kg may prevent the MRSA MIC increases seen with 6 mg/kg. Concordantly, guidelines support daptomycin 8 to 10 mg/kg/d for MRSA bacteremia on PD rationale and recommend 10 mg/kg/d when vancomycin treatment failure occurs.⁵⁴

Several retrospective cohorts evaluating high-dose daptomycin have demonstrated efficacy over vancomycin in MRSA bacteremia with elevated vancomycin MICs (>1-2 mg/L). Murray et al⁴⁶ conducted a matched, multicenter, retrospective cohort study evaluating early high-dose daptomycin (median 8.4 mg/kg/d) in MRSA bacteremia with vancomycin MICs >1 mg/L (daptomycin was initiated within 72 hours of the first dose of any anti-MRSA agent).⁴⁶ High-dose daptomycin was associated with lower 30-day mortality (3.5% vs 12.9%; P = 0.047), reduced persistent bacteremia (18.8% vs 42.4%; P = 0.001), and shorter duration of bacteremia (3 vs 5 days; P = 0.003) than vancomycin.⁴⁶ Combination therapy was used sparingly (15% of daptomycin cases), improving generalizability to high-dose monotherapy. One patient experienced a significant but asymptomatic CPK elevation (67-7221 U/L after 17 days of 12 mg/kg daptomycin) warranting daptomycin discontinuation.⁴⁶

In another matched retrospective cohort of MRSA bacteremia, Moore et al⁵⁵ demonstrated an association between daptomycin 7 mg/kg/d and lower 60-day mortality than vancomycin when vancomycin MICs were >1 mg/L (9% vs 20%; P = 0.046). The lower dose and later daptomycin initiation (5 days⁴⁶ vs 2 days⁵⁵) limit study comparison, although there were comparable reductions (~10%) in mortality with daptomycin 8.9 mg/kg/d⁴⁶ and 7 mg/kg/d.⁵⁵ Notably, these studies used automated testing systems⁴⁶ or Etest⁵⁵ for MIC determination, which have shown discordance and frequent MIC overestimation compared with the gold standard of broth microdilution.⁵⁶ A larger propensity-matched cohort using broth microdilution for susceptibility testing associated daptomycin 8.2 mg/kg/d (IQR = 6.4-10 mg/kg/d) with lower 30-day mortality (6.1% vs 15.3%; P = 0.01), with 95% of MICs as 0.5 or 1 mg/L.⁵⁷ Similar to others, only 2.3% of patients exhibited significant CPK elevations with high-dose daptomycin. The overall incidence of drug-related adverse events was the same between high-dose daptomycin and vancomycin (11.5%).⁵⁷

Aggregating data from these studies of daptomycin >6 mg/kg/d in MRSA bacteremia carries limitations, mainly because of differing definitions of the composite end point of clinical failure, which resulted in different drivers of the benefits observed with daptomycin. For example, Murray et al⁴⁶ showed persistent bacteremia as the driver of clinical failure. In contrast, Claeys et al⁵⁷ identified a change in therapy as a primary driver of clinical failure, and persistent bacteremia was no different between high-dose daptomycin and vancomycin. The lack of change in therapy as a component of the definition of clinical failure definition by Murray et al⁴⁶ underscores the variability in outcome definitions. These discrepancies may have benefited daptomycin (a change in therapy away from vancomycin would be relatively common in the setting of these studies with elevated vancomycin MICs). Nevertheless, both these composites were driven by mortality improvements with daptomycin in the absence of increased adverse events.^46,57 Additionally, when lower doses of daptomycin (6 mg/kg/d) were used in the setting of vancomycin MICs of 1.5 and 2 mg/L, clinical failure and bacteremia clearance rates did not differ between daptomycin or vancomycin groups,⁵⁸ suggesting that there may be benefits with the higher doses.

When used primarily as salvage therapy (90%), a descriptive multicenter retrospective cohort found that daptomycin 8.9 mg/kg/d for a median of 10 days achieved an 84% success rate in predominantly MRSA infections (75% complicated bacteremia or endocarditis).⁵⁹ Considerable practice variability was reflected by 44% of patients receiving combination therapy with daptomycin, most commonly gentamicin, linezolid, and rifampin.⁵⁹ Adverse events attributed to daptomycin occurred in 3 cases (1.2%), with only 1 patient requiring a dose decrease (11.4-8 mg/kg/d) for an asymptomatic CPK of 5700 U/L. Daptomycin dosing was not associated with change in CPK levels, and the highest observed CPKs fell within a normal range (60.5 U/L; IQR = 35-193 U/L).⁵⁹ The evidence lacks comparative studies between standard- and high-dose daptomycin in MRSA bacteremia, likely because of the guideline recommendations based on PD data influencing clinical practice. Therefore, high-dose daptomycin in MRSA bacteremia derives its support from retrospective cohorts comparing it to vancomycin. Although there are limitations to these data, they reflect high rates of successful treatment and suggest improved efficacy without compromising safety.

Enterococcal bacteremia may also benefit from high-dose daptomycin, and unlike MRSA bacteremia, some data directly compare standard-dose with high-dose daptomycin. Britt et al⁶⁰ assessed a retrospective cohort of 911 Veterans Affairs patients receiving daptomycin 6, 8, or 10 mg/kg/d for VRE bloodstream infections. Patients receiving daptomycin ≥10 mg/kg/d had lower 30-day mortality (risk ratio = 0.83; P = 0.015). VRE was cleared comparably with 8 and ≥ 10 mg/kg/d but faster than 6 mg/kg/d.⁶⁰ In vitro data support this dose-dependent bactericidal daptomycin activity in VRE isolates at 10 and 12 mg/kg/d.⁴⁹ Interestingly, Britt et al⁶⁰ had a higher proportion of E faecalis isolates in the 10 mg/kg/d group (22% vs 11% in other groups). Higher doses of daptomycin (12 mg/kg/d in vitro) can suppress resistance in E faecalis,⁴⁹ possibly contributing to the observed benefit.⁶⁰ Additionally, the Veterans Affairs population represents an almost entirely male cohort with significant comorbidity burden, limiting extrapolation.⁶⁰

A 2-center prospective observational Taiwanese cohort of 112 VRE E faecium infections showed lower mortality with higher daptomycin doses, regardless of the daptomycin MIC (evaluated at MIC ≤2 and MIC =4).⁶¹ Daptomycin ≥9 mg/kg/d (median 10 mg/kg) was associated with lower 14-day mortality (OR = 0.09; 95% CI = 0.02-0.44) than >7 to <9 mg/kg/d and >6 to ≤7 mg/kg/d. There was no association between dosing and CPK elevations, with only 1 of 25 patients in the ≥9-mg/kg/d group exhibiting CPK elevation.⁶¹ Similarly and by the same group, another prospective observational study of high-dose daptomycin in VRE bacteremia demonstrated lower 14-day mortality with ≥9 mg/kg/d than daptomycin 6 to 9 mg/kg/d (adjusted OR = 0.26; P = 0.01).⁶² Additionally, the Taiwanese group linked enhanced bacterial clearance to daptomycin ≥9 mg/kg/d compared with 6 to 9 mg/kg/d in VRE bacteremia. Slower bacterial clearance was predictive of higher mortality (OR = 3.21; P = 0.045).⁶³ The prospective nature and head-to-head comparisons of standard- and high-dose daptomycin in these studies exceed the quality of evidence present in MRSA bacteremia. However, the restriction to 1 study group at the same institution may imply confounding practice patterns unaccounted for in statistical analyses.

In summary, high-dose daptomycin appears to be useful for MRSA bacteremia, especially with vancomycin MICs >1 mg/L. Conclusions remain limited by the reliance on retrospective observational data and the lack of comparison between standard- and high-dose daptomycin. Specific dosing recommendations are better tailored to microbiological bacteremia sources because more robust data support dose-dependent benefit in enterococcal bacteremia. Specifically, daptomycin doses of ≥9 mg/kg/d demonstrated faster microbiological clearance and an association with lower mortality. The lack of observed significant increases in adverse events with high-dose daptomycin further adds to the rationale.

Osteomyelitis and Prosthetic Joint Infections

Osteomyelitis and prosthetic joint infections pose challenges that may prompt consideration of high-dose daptomycin—namely, the presence of biofilm associated with prosthetic devices.^64-66 Additionally, clinical failure and recurrence are associated with vancomycin use in MRSA osteomyelitis.^67-70 A single dose of daptomycin 8 mg/kg achieves bone concentrations above the susceptibility breakpoint of S aureus isolates assayed by a diode array–high-performance liquid chromatography method.⁷¹ Notably, daptomycin ≥6 mg/kg/d for osteomyelitis or foreign body prosthetic infections has increased over the years: 25.3% in 2009 to 60.4% in 2012.⁷²

A descriptive clinical trial of 75 patients with prosthetic joint infections planned to undergo 2-stage revision arthroplasty compared clinical and microbiological outcomes between daptomycin 8 mg/kg/d, daptomycin 6 mg/kg/d, and a comparator group (92% vancomycin).⁷³ The primary outcome was CPK elevations >500 U/L, and it lacked the power to demonstrate comparative efficacy. Clinical success rates were numerically higher in daptomycin groups—58% for 6 mg/kg/d daptomycin and 61% for 8 mg/kg/d—compared with the comparator 38%. CPK elevations were similar between 6 and 8 mg/kg/d (16% vs 21.7%). The numerical improvements with daptomycin in this trial are mirrored in several other reports. A systematic review of patients receiving daptomycin for osteomyelitis and prosthetic joint infections found higher cure rates with 10 mg/kg/d (85%) and 6 to 8 mg/kg/d (85%) compared with 4 to 6 mg/kg/d (71%).⁷⁴ Gallagher et al⁷⁵ retrospectively assessed daptomycin in non–hardware-associated osteomyelitis, and success occurred more frequently with ≥6 mg/kg/d (91%) compared with <6 mg/kg/d (76%).⁷⁵ One prospective descriptive report of 16 osteoarticular infections treated with high-dose daptomycin (median 8.15 mg/kg) used a daptomycin-rifampin combination and demonstrated clinical success in 14 of 15 evaluable patients. No patient experienced CPK elevations or daptomycin-associated adverse events while on the combination therapy.⁷⁶

The use of daptomycin at doses of 6 to 10 mg/kg/d for infections involving native bone or prosthetic joints is increasing. The evidence provides preliminary support of high-dose daptomycin in osteoarticular infections by describing comparable safety and efficacy. Doses of ≥8 mg/kg/d are reasonable in osteomyelitis, although presently, not conclusively more effective than standard 6-mg/kg/d dosing.

Meningitis/Central Nervous System Infection

Limited evidence exists for high-dose daptomycin in central nervous system (CNS) infections, but growing clinical experience shows heterogeneous results. Studies report low cerebrospinal fluid (CSF) levels after high-dose daptomycin. A prospective study of 7 days of daptomycin 10 mg/ kg/d in 9 patients with meningitis showed maximum concentrations ranging from 0.08 to 0.39 mg/L representing only 0.45% penetration and levels inadequate for clinical efficacy.⁷⁷ Similarly, daptomycin 9 mg/kg/d demonstrated 3-hour postinfusion CSF concentration of 0.86 mg/L (4% penetration) in a VRE meningitis case.⁷⁸ Six hours after a single dose of daptomycin 10 mg/kg, the CSF concentration was 0.461 mg/L (0.8% penetration).⁷⁹ An adjusted penetration of 11.5% was determined after accounting for protein binding differences between the CSF and serum, but the low available free fraction of daptomycin remains problematic despite the percentage considering that the daptomycin-susceptible MICs for most S aureus and S pneumoniae range from 0.1 to 1 mg/L.⁷⁹

Despite the low CSF penetration, a case report describing 3 device-related cases of meningitis caused by VRE faecium showed successful treatment with 3 to 4 weeks of daptomycin from 6, 9, and 12 mg/kg/d, plus gentamicin or linezolid.⁷⁸ The isolate treated with 12 mg/kg/d exhibited a daptomycin MIC of 2 mg/L, and gentamicin was administered in combination for the first 10 days. Two days after initiation, mental status improved, and all follow-up cultures were negative. The patient experienced a non-significant CPK elevation to 783 U/L after 10 days, and the dose was decreased to 10 mg/kg and continued for 11 days, during which CPK normalized. The daptomycin 9 mg/kg/d treated case also combined gentamicin to treat a VRE isolate with a daptomycin MIC of 3 mg/L. Daptomycin was initiated after 10 days of vancomycin, ceftriaxone, and piperacillin-tazobactam, after which all follow-up cultures were negative. After 15 days of high-dose daptomycin, the dose was lowered to 6 mg/kg every 48 hours because of renal injury attributed to gentamicin and continued for 15 more days, at which the patient’s clinical status returned to baseline.

In summary, data for daptomycin in CNS infections are limited to isolated experiences, and daptomycin appears limited by low CNS penetration. The failure of concentration studies to reach CSF levels of 1 mg/L severely limits high-dose daptomycin in meningitis. Studies examining increases in CSF to serum ratios with higher daptomycin doses such as 12 mg/kg/d are essential to determine if higher doses can overcome the low penetration to produce therapeutic CNS concentrations.

Special Populations

Intermittent Hemodialysis

Timing, filter types, and the high removal rate of daptomycin (15%-50% depending on filter type) complicate daptomycin dosing in intermittent hemodialysis (iHD).^80,81 Prescribing information recommends dosing daptomycin every 48 hours after iHD⁷; however, dosing 3 times weekly during or after iHD is frequently used for patients with end-stage renal disease (ESRD) because there is no viable alternative method of administration.

Salama et al⁸² prospectively evaluated 9 ESRD patients on long-term iHD and recommended increasing daptomycin doses by 12% to 20% or 35% when using low- or high-permeability dialyzers, respectively, when daptomycin is administered during the last 30 minutes of iHD. Therefore, a patient prescribed 8 mg/kg of daptomycin would receive 9 mg/kg for low-permeability dialyzers or 11 mg/kg for high-permeability dialyzers to compensate for drug removal. Findings from 12 iHD patients by Patel et al⁸³ further complicate dosing, suggesting increasing daptomycin doses by 50% to address the 72-hour interdialytic period after the week’s third HD session. Considering recommendations from both Salama et al⁸² and Patel et al,⁸³ a patient prescribed daptomycin 8 mg/kg for persistent MRSA bacteremia undergoing iHD with a high-permeability dialyzer on Mondays, Wednesdays, and Fridays would require daptomycin 11 mg/kg on Mondays and Wednesdays and 16.5 mg/kg on Fridays during the last 30 minutes of iHD.

A significant dosing limitation remains a lack of evidence for the importance of partitioned AUC values over 24 to 48 hours and 48 to 72 hours during interdialytic periods. When increasing the interdialytic dose by 50% in Patel et al,⁸³ the initial 24-hour AUC achieves exposures comparable to 12 mg/kg in normal renal function, but 24-hour AUCs fall below those expected by 6-mg/kg dosing in the 24- to 48-hour and 48- to 72-hour periods. Notably, when 6 mg/kg was increased by 50% to 9 mg/kg, exposures were comparable between 9 mg/kg in iHD and 6 mg/kg in non-iHD patients over the 24- to 78-hour periods. Mimicking daily dosing exposures in iHD is unlikely feasibly, and the dose increase strategies provide a practical way to optimize exposure in a challenging setting.

More frequent monitoring of CPK than the once weekly recommended for patients with normal renal function may improve safety for patients with renal dysfunction requiring iHD, especially when receiving high-dose daptomycin.⁷ A single-center retrospective cohort showed that CPK elevations did not occur in 38 patients on iHD receiving ~6.4 mg/kg of daptomycin.⁸⁴ When a similar study of 164 patients with renal dysfunction (62% on iHD) compared daptomycin ≥9 mg/kg with <9 mg/kg (~80% were dosed every other day), doses ≥9 mg/kg were associated with more CPK elevations (10.8% vs 1.6%; P = 0.024) in the entire cohort.⁸⁵ However, only 2 of 4 CPK elevations in the high-dose group were in patients receiving iHD, and only 1 was symptomatic.⁸⁵ Another cohort of 50 renally impaired patients, 30 on iHD, predominantly with MRSA and VRE bacteremia, showed no symptomatic CPK elevations with high-dose daptomycin (median 8.46 mg/kg) and only 1 asymptomatic elevation.⁸⁶ A pooled sample analysis by Butterfield et al⁸⁷ proposed monitoring more frequently than once weekly for patients with ESRD because of the potential for elevated minimum concentrations associated with adverse effects; however, the ideal frequency of CPK monitoring with high-dose daptomycin remains undefined.

Continuous Renal Replacement Therapy

The diversity in modes of continuous renal replacement therapy (CRRT) warrants careful application of high-dose daptomycin. In a prospective open-label study of critically ill patients, daptomycin 8 mg/kg every 48 hours during continuous venovenous hemodialysis (CVVHD) showed an increased volume of distribution and a higher free fraction compared with healthy volunteers.⁸⁸ Daptomycin 8 mg/kg/48-hours and 4 mg/kg/24-hours achieved similar AUCs; however, 8 mg/kg/48-hours displayed favorable PK measures, such as higher peaks and lower trough concentrations.⁸⁸ Continuous venovenous hemodiafiltration (CVVHDF) presents challenges to daptomycin dosing not seen with CVVHD. CVVHDF clears daptomycin more rapidly than CVVHD, resulting in lower peaks and AUCs, with daily dosing compared to 48-hour dosing in CVVHD.⁸⁹ Daptomycin 6 to 8 mg/kg/d during CVVHD achieved an AUC comparable to that in patients with normal renal function.⁸⁹

Xu et al⁹⁰ compared high-dose daptomycin (8, 10, and 12 mg/kg) and dosing intervals in CVVHD and CVVHDF. In CVVHD, daptomycin 12 mg/kg/24-hours demonstrated clearance and AUC similar to normal renal function, whereas 48-hour dosing intervals led to lower AUCs, especially during the second day. In CVVHDF, elevated troughs occurred at doses ≥10 mg/kg and were consistently higher than CVVHD across all doses and most pronounced at higher doses (eg, 12 mg/kg/24-hours: steady-state trough: 22.5 vs 44.3 mg/L). The AUCs were below the efficacy boundary for both CRRT modes with all 48-hour dosing between hours 24 and 48.⁹⁰ Notably, all doses in CVVHD resulted in troughs below the cutoff of 24.3 mg/L associated with CPK elevations.⁹¹

The safety thresholds were modeled after 12-mg/kg/d dosing in patients with normal renal function.⁹⁰ This resulted in CVVHD 12 mg/kg/24-hour dosing and 10 mg/kg/24-hour dosing being comparable to 10 and 8 mg/kg/d in non-CRRT patients, respectively, based on PK data evaluating daptomycin doses from 6 to 12 mg/kg in healthy patients.⁹² Therefore, doses of 10 to 12 mg/kg/24-hour may be optimal in CVVHD to achieve concentrations reflective of high-dose daptomycin when indicated. CVVHDF doses of 8 mg/kg achieved AUCs similar to 10 mg/kg in healthy volunteers. This 8 mg/kg dose was the maximum that did not cross safety thresholds in CVVHDF and may be optimal for achieving sufficient high-dose daptomycin concentrations in CVVHDF.⁹⁰

In contrast, Xie et al⁹³ aggregated daptomycin studies with dosing (6-8 mg/kg every 24-48 hours) in CRRT (72% on CVVHDF in the final analysis) and suggested that 6 mg/kg/24-hours with a CRRT clearance of 30 to 35 mL/h/kg optimized safety and efficacy. The 8-mg/kg/24-hour dose was more likely to achieve a trough >24.3 mg/L compared with 6 mg/kg (31% vs 14%), although not by a significant amount, and the likelihood of association with clinical muscle toxicity is low given that the boundary is based on a small study of 6 patients⁹¹; others have not repeated the association between troughs >24.3 mg/L and toxicity.^94,95 Furthermore, a high proportion of CVVHDF may have caused higher troughs. The safety concerns in this study should be interpreted in light of the risk-benefit underexposure. The study did not evaluate 10- to 12-mg/kg dosing or make recommendations based on CRRT mode, contrasting the study by Xu et al.⁹⁰ Additionally, 8 mg/kg/24-hour dosing had a low cumulative fraction of response against organisms with MICs >0.5 mg/L, posing a substantial limitation in treating enterococcal infections with MICs typically around 1 to 4 mg/L.⁹⁶

In summary, CVVHDF appears to impart higher risks and lower PK predictors of efficacy than CVVHD with high-dose daptomycin. Daptomycin 10 to 12 mg/kg/24-hours is supported by PK evaluations in CVVHD comparable to high-dose daptomycin exposure. Similar doses in CVVHDF may increase predictors of daptomycin-associated adverse effects. However, initial daptomycin doses up to 8 mg/kg/24-hours are reasonable to obtain high-dose daptomycin exposure in CVVHDF safely.

Obesity

The body weight dosing of daptomycin warrants caution in obesity because using ‘total body weight (TBW) assumes that PK parameters change linearly with increasing body weight. Studies have evaluated total, lean, and adjusted body weights with differing conclusions.^91,97-100 Risk-benefit assessments become crucial when choosing a dosing regimen in obese patients. Clinicians must consider increases in daptomycin volume of distribution of up to 37% during acute infections and potential suboptimal efficacy from using body weights yielding lower doses.⁸¹ Highlighting the concern, a retrospective cohort of hospitalized obese patients receiving daptomycin (average dose 6 mg/kg/d) dosed by TBW showed that obesity promotes CPK elevations >1000 U/L in 8.4% of patients,¹⁰¹ much greater than the rate of CPK elevations observed in a large international cohort of about 2%.⁴³ Indeed, PK analysis suggests a near 2-fold elevation in AUC, peak, and trough concentrations in obesity compared with average weight with 6 mg/kg.¹⁰² These concerns may prompt clinicians to favor an adjusted body weight or fixed dosing strategy but must be weighed with clinical evidence and the fact that these data come in the context of standard daptomycin doses.

Evidence demonstrating clear consequences of exposure concerns has not been reported, nor has a specific dosing strategy in obese patients been deemed optimal. Some data support no difference in outcomes, including a retrospective analysis of 101 patients that showed no difference in clinical failure (defined as development of resistant isolates or recurrent infection) or 90-day mortality when daptomycin was dosed by actual body weight versus adjusted body weight with a 0.4 correction factor.⁹⁹ Another retrospective analysis reported a clinical cure rate of 56.3% in 16 patients with S aureus bacteremia and a mean body mass index (BMI) of 37.6 kg/m² when given a fixed dose of 750 mg daptomycin.¹⁰³ Altogether, it may be prudent to use adjusted body weight or choose a dose on the lower end of the high-dose spectrum (eg, 8 instead of 10 mg/kg/d) if using actual body weight to mitigate risk for CPK elevations as no kinetic data have evaluated these high doses in obesity. Notably, studies demonstrating robust benefits with high-dose daptomycin that use TBW dosing generally lack obese patients.^61-63 However, Britt et al⁶⁰ showed clinical benefit without safety concerns between high- and standard-dose daptomycin in a borderline obese cohort (average BMI ~27 kg/m², with 30% >30 kg/m²). Kinetic assessments must be interpreted in the context of these clinical data.

Burns

Thermal burns induce physiological changes and alter PK, especially for highly protein-bound and renally cleared drugs such as daptomycin.^104,105 Mohr et al¹⁰⁶ conducted a single-center open-label comparison of PK data of daptomycin in burn patients 7 to 27 days after injury to healthy volunteers. Daptomycin AUC decreased, and the volume of distribution increased, consistent with changes observed in other antimicrobials. Given the high protein binding of daptomycin, an increased free fraction could be expected because severe burns lead to hypoalbuminemia. Indeed, daptomycin was 86.5% protein bound in burn patients¹⁰⁶ compared with 91.7% in healthy individuals.¹⁰⁷ However, the AUC was 47% lower in patients with burns following a single 6-mg/kg dose, indicating the influence of additional factors, including the possibility of continued wound protein loss causing the leaching of daptomycin out of circulation.^106,108

A 10- to 12-mg/kg/d dose may be prudent to achieve efficacy in burn patients; however, as burn wounds heal, daptomycin dosing may require reductions as clearance normalizes. Recently, Huang et al¹⁰⁹ retrospectively compared 10 patients receiving high-dose daptomycin 12 mg/kg/d with 6 mg/kg/d. High-dose daptomycin had significantly higher peak concentrations than 6 mg/kg/d and a doubled AUC, with no difference in adverse events. Notably, 6 mg/kg showed AUC and peak steady-state concentrations lower than suggested efficacy standards in S aureus bacteremia/IE.¹¹⁰ High-dose daptomycin should be considered for burn patients, given the increased total clearance and failure of standard doses to achieve adequate efficacy limits. The present evidence does not reflect true high-dose daptomycin because these high doses are used to achieve concentrations comparable to standard doses. Indeed, the steady-state AUCs achieved from 12 mg/kg/24-hours in this study reached exposure similar to 6 mg/kg/d in healthy volunteers (642 former¹⁰⁹ vs 632 latter⁹²). Whether doses >12 mg/kg would be beneficial in an MRSA bacteremia secondary to thermal burns to achieve the comparable 8- to 10-mg/kg dose remains undescribed.

Conclusion and Relevance to Clinical Practice

The clinical use of high-dose daptomycin is increasing because of its favorable adverse effect profile, less-intensive monitoring than vancomycin, and convenient once-daily dosing frequency for most patients. Additionally, high-dose daptomycin appears useful as early and salvage therapy for S aureus isolates with elevated MICs to vancomycin while daptomycin sensitivity is preserved. High-dose daptomycin effectively treats endocarditis and bacteremia caused by resistant MRSA and Enterococcus species, and the in vitro evidence supports daptomycin efficacy in high-inoculum and biofilm-associated infections. Table 2 presents a summary of recommendations for dosing daptomycin in the discussed populations. Conventional wisdom suggests that adverse effects increase with higher daptomycin doses, but data rarely report a higher incidence of daptomycin-related adverse effects with escalating doses. Individualizing high-dose daptomycin therapy based on risk-benefit assessments, indication and organism, patient characteristics, and the method of drug clearance is highly encouraged. Evidence for osteomyelitis, CNS infections, and morbidly obese patients is minimal, lacking data beyond isolated case reports of high-dose daptomycin often combined with other antimicrobials. Future studies should seek to describe PK patterns and compare clinical outcomes between high-dose daptomycin and other therapies commonly used for severe gram-positive infections, such as glycopeptides (vancomycin, dalbavancin, and oritavancin), linezolid, and ceftaroline.

Table 2.

High-Dose Daptomycin Considerations.

Indication	Optimized daptomycin dose	Details
Endocarditis
Staphylococcal	≥9 mg/kg/d	MRSA clearance may be increased by dosing of ≥9 mg/kg
Enterococcal	10-12 mg/kg/d	Higher MICs and in vitro and case series data provide justification for using the highest daptomycin doses in these infections; however, alternative therapy should be considered when MIC is ≥4 mg/L
Bacteremia
Staphylococcal	≥8 mg/kg/d	Additive benefit may exist when using higher doses early during therapy when vancomycin MIC is >1 mg/L
Enterococcal	10-12 mg/kg/d	Higher doses have improved both survival and bacterial clearance compared with traditional dosing
Osteomyelitis	6-10 mg/kg/d	No differences between doses within the range of 6-10 mg/kg have been shown
Meningitis	8-10 mg/kg/d	No data directly support a specific dose, and most studies suggest poor CNS penetration. Use should err on the side of higher doses because some small reports have obtained success with doses of 8-10 mg/kg in meningitis
Special populations
Obesity	The indication should drive the dosing decision. Adjusted body weight may be used in place of total body weight with concerns for toxicity	Given the limited evidence for any specific practice, exercise caution with any adjustment yielding a lower dose, especially in the setting of indications for high-dose daptomycin. Isolated clinical evidence suggests benefits with high doses over standard doses in overweight and obese populations without compromising safety
Intermittent hemodialysis	Doses of 8 mg/kg may warrant conversion to doses as high as 16 mg/kg (50% increase) during 72-hour interdialytic periods when dosed in patients with high-permeability dialyzers but may not warrant increases in 48-hour interdialytic periods	Consider twice-weekly CPK monitoring. Daptomycin exposures are likely to be suboptimal over 24- to 72-hour periods between dialyses, which should be interpreted in the context of organisms’ MICs
CRRT
CVVHD	8-12 mg/kg/d	Daptomycin 12 mg/kg/24-hours achieves similar PK parameters similar to normal renal function
CVVHDF	8 mg/kg/d	Frequent monitoring of trough concentrations is likely necessary with doses >10 mg/kg/d
Burns	10-12 mg/kg/d	High doses may only achieve drug exposures similar to standard doses because of elevated daptomycin clearance

Abbreviations: CNS, central nervous system; CPK, creatinine phosphokinase; CRRT, continuous renal replacement therapy; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; PK, pharmacokinetic.