A Comprehensive Monograph on Daptomycin: Chemistry, Pharmacology, and Clinical Application

I. Introduction: Daptomycin, a Paradigm-Shifting Antibiotic for Gram-Positive Infections

Preamble: A First-in-Class Agent for a Modern Challenge

Daptomycin represents the first clinically approved member of the cyclic lipopeptide class of antibiotics, a novel structural and mechanistic category that has become a cornerstone in the management of severe Gram-positive bacterial infections.[1] In an era defined by the escalating threat of antimicrobial resistance, daptomycin provides a critical therapeutic option, demonstrating potent, rapid, concentration-dependent bactericidal activity against a broad spectrum of challenging pathogens. Its clinical utility is most pronounced against organisms that have developed resistance to other classes of antibiotics, including methicillin-resistant

Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), making it an indispensable tool in modern infectious disease medicine.[4]

Synopsis of a Unique Profile

The therapeutic value of daptomycin is rooted in its unique, calcium-dependent mechanism of action, which is fundamentally different from that of any previously approved antibiotic.[5] It selectively targets the bacterial cell membrane, leading to a multifaceted disruption of cellular function that culminates in rapid cell death.[8] This report will provide an exhaustive analysis of daptomycin, beginning with its foundational chemistry and intricate mechanism of action. It will then transition to its complex pharmacological profile and the pivotal clinical trial evidence that established its efficacy for its primary indications: complicated skin and skin structure infections (cSSSI) and

Staphylococcus aureus bacteremia (SAB), including right-sided infective endocarditis.[4] The discussion will also address the drug's significant limitations, most notably its inactivation by pulmonary surfactant, which precludes its use in pneumonia, and its characteristic safety profile, dominated by a risk of myopathy.[8] Finally, the report will delve into the critical and evolving challenge of bacterial resistance, exploring the sophisticated molecular strategies that pathogens employ to evade this last-line agent.[10]

Report Roadmap

This monograph is structured to guide the reader from the fundamental science underpinning daptomycin to its practical application and the challenges that define its use in the clinical setting. The report will proceed from its discovery and chemical properties, through a detailed exploration of its mechanism of action and pharmacology, to a comprehensive review of its clinical efficacy, safety profile, and the mechanisms of bacterial resistance. The final sections will provide a detailed guide to prescribing and administration, culminating in a synthesis of daptomycin's established role in contemporary medicine.

II. Foundational Profile: Discovery, Chemistry, and Structure

2.1 A Serendipitous Discovery and a Challenging Development

Origins in Nature

The story of daptomycin begins, as with many landmark antibiotics, with its discovery as a natural product.[5] In the early 1980s, researchers at Eli Lilly and Company isolated a family of lipopeptide compounds, designated A21978C, from the fermentation broth of a soil microbe,

Streptomyces roseosporus. The soil sample containing this actinomycete was originally collected from the slopes of Mount Ararat in Turkey.[4] From this family of compounds, the specific molecule with an N-terminal decanoyl fatty acid side chain was selected for clinical development due to its superior in vivo efficacy and favorable toxicity profile in animal models; this molecule was named daptomycin.[12]

The Initial Setback

Eli Lilly advanced daptomycin into clinical trials in the late 1980s and early 1990s. However, the development program was voluntarily suspended following concerning safety signals in a Phase 1 study.[12] In this trial, healthy volunteers receiving higher doses of daptomycin administered twice daily (e.g., 8 mg/kg per day in two divided doses) developed unacceptable skeletal muscle toxicity. This was characterized by symptoms of myopathy accompanied by significant elevations in serum creatine phosphokinase (CPK), a key marker of muscle damage.[12] Believing the therapeutic window between efficacy and safety was too narrow, Eli Lilly shelved the compound.[12]

The Revival by Cubist Pharmaceuticals

The trajectory of daptomycin changed dramatically in 1997 when Cubist Pharmaceuticals licensed the compound from Eli Lilly.[4] The revival of the program was predicated on a pivotal re-evaluation of the drug's pharmacokinetic and pharmacodynamic (PK/PD) properties. The initial development had proceeded under the assumption of time-dependent killing, favoring more frequent dosing to keep drug concentrations above the minimum inhibitory concentration (MIC). However, subsequent analysis revealed that daptomycin exhibits rapid,

concentration-dependent bactericidal activity, where the peak concentration (Cmax​) and the total drug exposure over 24 hours relative to the MIC (AUC/MIC ratio) are the primary drivers of efficacy.[6]

This understanding led to a fundamental shift in dosing strategy. A once-daily dosing regimen was proposed, which achieves a high peak concentration to maximize bactericidal effect. Crucially, this regimen also provides a prolonged period of low drug concentration (a trough) before the next dose. The initial observation of myopathy was found to be dependent not only on the total dose but also on the frequency of administration.[4] The prolonged trough period of a once-daily regimen allows for muscle tissue to recover, thereby uncoupling the drug's efficacy from its primary toxicity. This critical insight into daptomycin's PK/PD profile was the single most important factor that transformed it from a failed compound into a viable and valuable therapeutic agent.

Regulatory Milestones

Following successful new clinical trials based on the once-daily dosing strategy, daptomycin, under the brand name Cubicin, received its initial U.S. Food and Drug Administration (FDA) approval (NDA #021572) on September 12, 2003. The first indication was for the treatment of complicated skin and skin structure infections (cSSSI).[16] The approval was later expanded to include

Staphylococcus aureus bacteremia (SAB), including cases with right-sided infective endocarditis (RIE).[12] The European Medicines Agency (EMA) granted marketing authorization on January 19, 2006.[19] Recognizing its importance in treating multi-drug resistant organisms, the World Health Organization (WHO) classifies daptomycin as a critically important antimicrobial for human medicine.[9]

2.2 Chemical Identity and Physicochemical Properties

Structural Architecture

Daptomycin is a structurally unique, semi-synthetic cyclic lipopeptide, also classified as a depsipeptide due to the presence of an ester bond within its cyclic core.[5] Its complex architecture is key to its mechanism of action and includes several distinct features:

• Peptide Core: The molecule is composed of a 13-amino-acid peptide chain. This chain is notable for containing several non-proteinogenic and D-enantiomer amino acids, including D-asparagine, D-alanine, D-serine, L-ornithine, the unusual amino acid L-kynurenine, and L-3-methyl-glutamic acid.[4] The presence of these non-standard residues contributes to its stability against degradation by proteases.
• Cyclic Structure: Ten of the amino acids, from the threonine at position 4 to the C-terminal L-kynurenine, form a macrocyclic ring. This ring is closed not by a typical peptide bond but by an ester linkage between the carboxyl group of the C-terminal kynurenine and the hydroxyl group on the side chain of threonine.[4]
• Lipophilic Tail: A three-amino-acid exocyclic tail extends from the ring. The N-terminus of this tail, a tryptophan residue, is covalently acylated with a ten-carbon (n-decanoyl) fatty acid.[4] This lipophilic tail is essential for the molecule's ability to insert into the bacterial cell membrane and is a defining feature of the lipopeptide class.[5]

Biosynthesis

The intricate structure of daptomycin is not assembled by standard ribosomal protein synthesis. Instead, it is constructed by a large, multi-modular enzymatic complex known as a nonribosomal peptide synthetase (NRPS), which is encoded by a cluster of genes including dptA, dptBC, and dptD.[9] This machinery sequentially adds the amino acid building blocks, with a final cyclization step catalyzed by a thioesterase domain to release the completed lipopeptide.[9]

Physicochemical Data

Daptomycin is supplied commercially as a sterile, preservative-free, pale yellow to light brown lyophilized powder or cake for intravenous use.[21] It has a high aqueous solubility of over 1 g/mL.[22] Key identifying and physical properties are summarized in Table 2.1.

Property	Value	Source(s)
DrugBank ID	DB00080	4
CAS Number	103060-53-3	4
Generic Name	Daptomycin	4
Brand Names	Cubicin®, Cubicin RF®, Dapzura®	1
Alternate Names	LY146032	7
Molecular Formula	C72​H101​N17​O26​	5
Molecular Weight	1620.67 g/mol	14
IUPAC Name	(3S)-3-amino]-4-oxobutanoyl]amino]-4--24-(3-aminopropyl)-15,21-bis(carboxymethyl)-6-(1-carboxypropan-2-yl)-9-(hydroxymethyl)-18,31-dimethyl-2,5,8,11,14,17,20,23,26,29-decaoxo-1-oxa-4,7,10,13,16,19,22,25,28-nonaazacyclohentriacont-31-yl]oxy]-4-oxobutanoic acid	14
Appearance	Pale yellow to light brown lyophilized powder/cake; Off-white to light yellow powder	21
Solubility	High aqueous solubility (>1 g/mL); Soluble in DMSO (to 100 mM), methanol	14

III. Mechanism of Action: A Multifaceted Assault on the Bacterial Cell Envelope

The bactericidal activity of daptomycin stems from a novel and complex mechanism that targets the bacterial cell envelope. The understanding of this mechanism has evolved from a simple model of membrane disruption to a more sophisticated view involving the specific inhibition of cell wall synthesis, which then leads to catastrophic membrane failure.

3.1 The Essential Role of Calcium and Membrane Binding

Calcium-Dependent Activation

Daptomycin's antibacterial activity is absolutely dependent on the presence of physiological concentrations of calcium ions (Ca2+).[10] In its free state at physiological pH, the daptomycin molecule is a trianion. It binds to

Ca2+ in a 1:1 stoichiometric ratio, a process thought to involve the aspartate and methylglutamate residues that form a DXDG motif.[4] This binding neutralizes some of the negative charge, converting the molecule to a monoanion and inducing a critical conformational change that is a prerequisite for membrane interaction.[4]

Micelle Formation and Membrane Insertion

The calcium-activated daptomycin complexes have been shown to self-assemble into small micelles in solution.[26] This aggregation is believed to facilitate the delivery of the antibiotic to the bacterial surface and promote the insertion of its decanoic acid lipid tail into the hydrophobic core of the bacterial cell membrane.[9]

Targeting Anionic Phospholipids

The specificity of daptomycin for Gram-positive bacteria is determined by its selective affinity for the anionic phospholipids that are abundant in their cell membranes, particularly phosphatidylglycerol (PG) and cardiolipin (CL).[4] The presence of PG is crucial for daptomycin's ability to bind, insert, and oligomerize within the membrane.[25] In contrast, the membranes of Gram-negative bacteria and mammalian cells are composed primarily of neutral phospholipids like phosphatidylethanolamine and phosphatidylcholine, respectively. This difference in membrane composition explains both daptomycin's narrow Gram-positive spectrum and its relative lack of toxicity toward host cells.[26]

3.2 The Dual-Pronged Bactericidal Effect: A Paradigm Shift in Understanding

The Classic Model: Membrane Depolarization and Ion Efflux

The initial and most dramatic observable effect of daptomycin on bacteria led to the first proposed mechanism of action. Upon insertion into the membrane, daptomycin molecules are thought to oligomerize, forming aggregates or pore-like structures.[9] This aggregation disrupts the structural integrity of the membrane, creating channels that allow for the rapid and uncontrolled efflux of intracellular potassium ions (

K+).[4] The massive loss of positive charge from the cell interior causes a rapid and profound depolarization of the membrane potential.[10] This collapse of the electrochemical gradient is catastrophic for the bacterium, as it immediately halts all gradient-dependent cellular processes, including nutrient transport, ATP synthesis, and the biosynthesis of DNA, RNA, and proteins, leading swiftly to cell death.[4]

The Modern Model: Inhibition of Cell Wall Synthesis

While the depolarization model accurately describes a key event, more recent research using advanced techniques has revealed a more precise and primary target. Studies employing fluorescence-labeled daptomycin have demonstrated that the antibiotic does not distribute randomly throughout the membrane but instead preferentially localizes at the bacterial division septum—the precise location of active cell wall synthesis.[28]

Further investigation revealed that daptomycin's true molecular target at this site is a tripartite complex formed by the antibiotic, the essential peptidoglycan precursor Lipid II, and the membrane phospholipid PG.[6] By binding to and sequestering these critical building blocks, daptomycin effectively blocks their incorporation into the growing peptidoglycan layer. This action directly inhibits cell wall synthesis and cell division, leading to the mislocalization and dispersion of the cell's biosynthetic machinery.[4]

3.3 Synthesis: Reconciling the Models and Clinical Implications

The modern understanding of daptomycin's mechanism does not invalidate the classic model but rather places it in its proper context. The inhibition of cell wall synthesis at the septum is now considered the primary bactericidal event. The structural weakening and destabilization of the cell envelope caused by this blockade is what ultimately leads to the secondary, albeit dramatic, consequences of ion leakage and membrane depolarization.[28] This refined model provides a more complete explanation for the drug's rapid bactericidal activity and its specific localization. Furthermore, it offers a clearer framework for understanding the molecular basis of bacterial resistance, as many resistance mutations are found in genes that regulate cell wall stress responses or phospholipid metabolism—pathways directly linked to the drug's primary site of action.

Inactivation by Pulmonary Surfactant

A critical clinical implication arising directly from daptomycin's mechanism is its ineffectiveness in treating pneumonia. The drug's lipophilic tail, essential for its membrane-inserting activity, causes it to bind avidly to the components of pulmonary surfactant in the lung alveoli.[8] This binding sequesters the drug and prevents it from reaching the necessary concentrations to exert its antibacterial effect on pathogens like

Streptococcus pneumoniae, even if the organism is susceptible in vitro.[4] This limitation is a direct consequence of the physicochemical properties that define its mode of action.

Potential Immunomodulatory Effects

Emerging evidence suggests that daptomycin may possess activities beyond direct bacterial killing. As a lipopeptide, it has the potential to interact with the host immune system. Preliminary studies indicate that daptomycin may have immunomodulatory effects, notably the downregulation of Toll-like receptors (TLRs) 1, 2, and 6 on immune cells.[10] These receptors are responsible for recognizing molecular patterns from Gram-positive bacteria. This contrasts with other antibiotics like linezolid and vancomycin, which have been shown to upregulate these same TLRs.[10] While the clinical significance of these findings is not yet fully established, they suggest a potential additional mechanism by which daptomycin may modulate the host response to infection.

IV. Pharmacological Profile: Pharmacokinetics and Pharmacodynamics

The clinical use of daptomycin is guided by a well-defined pharmacological profile. Its pharmacokinetics are predictable but require careful consideration in specific patient populations, while its pharmacodynamics clearly dictate the optimal dosing strategy for efficacy.

4.1 Absorption, Distribution, Metabolism, and Excretion (ADME)

• Administration and Absorption: Daptomycin is administered exclusively by the intravenous (IV) route, which ensures 100% bioavailability and a rapid onset of action. Following once-daily dosing, steady-state plasma concentrations are typically achieved by the third day of therapy.[6]
• Distribution: The drug exhibits a relatively small volume of distribution (Vd), approximately 0.1 L/kg in healthy adult subjects, indicating that it is primarily confined to the plasma and extracellular fluid compartments.[6] Daptomycin is highly bound to plasma proteins, primarily albumin, with protein binding ranging from 90% to 93% in individuals with normal renal function.[6]
• Metabolism: Daptomycin undergoes minimal to no metabolism in the body. In vitro studies using human liver microsomes have shown that it is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system.[6] This lack of hepatic metabolism results in a very low potential for clinically significant drug-drug interactions mediated by the CYP450 pathway.
• Excretion: The primary route of elimination for daptomycin is renal excretion. Approximately 78% of an administered dose is recovered as unchanged drug in the urine, with a minor fraction (around 5.7%) eliminated in the feces.[6] The elimination half-life ( t1/2​) in healthy adults with normal renal function is approximately 8 to 9 hours.[6]

4.2 Pharmacodynamics (PD): The Driver of Efficacy

• Concentration-Dependent Killing: Daptomycin's bactericidal activity is strongly concentration-dependent.[14] This means that higher drug concentrations achieve a more rapid and extensive killing of susceptible bacteria. This property is the foundation of the once-daily, high-dose regimen that is essential for its clinical success.
• The Key PK/PD Index: AUC/MIC: The pharmacodynamic parameter that best correlates with the clinical and microbiological efficacy of daptomycin is the ratio of the 24-hour area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC).[6] Achieving a target AUC/MIC ratio is crucial for optimizing treatment outcomes and suppressing the emergence of resistance.

4.3 Pharmacokinetics in Special Populations

The predictable pharmacokinetic profile of daptomycin can be significantly altered in certain patient populations, necessitating careful dose adjustments and monitoring.

• Renal Impairment: This is the most critical factor influencing daptomycin pharmacokinetics. Because the drug is primarily cleared by the kidneys, any degree of renal dysfunction reduces its clearance and increases systemic exposure. In patients with severe renal impairment (Creatinine Clearance [CrCl] < 30 mL/min), the elimination half-life can be dramatically prolonged to as long as 28 hours.[6] This substantial accumulation mandates a change in the dosing interval from every 24 hours to every 48 hours to prevent the buildup of drug to potentially toxic levels.[6] In this population, protein binding is also slightly decreased, ranging from 84% to 88%.[6]
• Hepatic Impairment: Daptomycin's pharmacokinetics are not significantly altered in patients with mild to moderate hepatic impairment (Child-Pugh Class B). Therefore, no dosage adjustment is required in this group. The drug has not been formally studied in patients with severe hepatic impairment (Child-Pugh Class C).[6]
• Pediatric Patients: Compared to adults, pediatric patients exhibit increased clearance and a shorter elimination half-life for daptomycin.[6] To achieve therapeutic exposures comparable to those in adults, children require higher weight-based (mg/kg) doses, with specific dosing regimens stratified by age.[32]
• Geriatric Patients: While age itself is not an independent factor for dose adjustment, elderly patients are at a higher risk of daptomycin toxicity, primarily due to the natural age-related decline in renal function.[6] Dosing in this population should be guided by the patient's calculated creatinine clearance, not by age alone.[33]
• Obesity: The Vd of daptomycin increases with body weight. To ensure appropriate dosing in obese patients, some guidelines recommend using an adjusted body weight for dose calculations to avoid potential under-dosing if ideal body weight is used or over-dosing if total body weight is used.[35]

Parameter	Value in Healthy Adults	Source(s)
Volume of Distribution (Vd)	~0.1 L/kg	6
Protein Binding	90–93%	6
Elimination Half-life (t1/2​)	8–9 hours	6
Total Body Clearance	8–9 mL/hr/kg	29
Primary Elimination Route	Renal (78% unchanged in urine)	6
Primary PK/PD Index	AUC/MIC	6

V. Clinical Applications and Therapeutic Efficacy

Daptomycin has secured a well-defined place in the therapeutic armamentarium for severe Gram-positive infections, supported by a robust body of evidence from randomized controlled trials and clinical experience. Its use is guided by specific regulatory approvals and clear limitations based on its pharmacological properties and trial data.

5.1 Regulatory Status and Labeled Indications

Daptomycin is approved by major regulatory agencies, including the U.S. FDA and the EMA, for the following indications:

• Complicated Skin and Skin Structure Infections (cSSSI): Daptomycin is indicated for the treatment of cSSSI caused by susceptible isolates of Gram-positive bacteria, including Staphylococcus aureus (both methicillin-susceptible and -resistant), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). This indication applies to both adult and pediatric patients aged 1 to 17 years.[4]
• Staphylococcus aureus Bloodstream Infections (Bacteremia) (SAB): Daptomycin is indicated for the treatment of S. aureus bacteremia in adult patients, including those with concurrent right-sided infective endocarditis (RIE), caused by both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) isolates.[6] The indication has also been extended to pediatric patients (1 to 17 years of age) with S. aureus bacteremia.[38]

Important Limitations of Use

The prescribing information for daptomycin carries several critical limitations that restrict its use in certain clinical scenarios:

• Pneumonia: Daptomycin is explicitly not indicated for the treatment of pneumonia. Due to its avid binding to and inactivation by pulmonary surfactant, it cannot achieve therapeutic concentrations in the lungs.[8]
• Left-Sided Infective Endocarditis: Daptomycin is not indicated for the treatment of left-sided infective endocarditis caused by S. aureus. Clinical trial data for this condition were limited, and the outcomes observed in these patients were poor.[9]
• Pediatric Patients Younger Than 1 Year: The use of daptomycin is not recommended in infants under one year of age. This is due to the risk of potential adverse effects on the muscular, neuromuscular, and/or nervous systems, which were observed in neonatal animal studies.[4]
• Other Infections: Daptomycin has not been formally studied in patients with prosthetic valve endocarditis or meningitis.[9]

5.2 Evidence from Clinical Trials: Complicated Skin and Skin Structure Infections (cSSSI)

The efficacy of daptomycin for cSSSI was established in two large, randomized, multinational, evaluator-blinded trials involving 1092 patients.[39] These pivotal studies compared daptomycin (4 mg/kg IV once daily) to standard-of-care therapy, which consisted of a penicillinase-resistant penicillin (e.g., nafcillin, oxacillin) or vancomycin.[39]

• Efficacy Outcomes: Among the 902 clinically evaluable patients, daptomycin demonstrated non-inferiority to the comparator antibiotics. The clinical success rates at the test-of-cure visit were 83.4% for the daptomycin group and 84.2% for the comparator group, with a 95% confidence interval that confirmed equivalence.[39]
• Duration of Therapy: A key finding from these trials was that patients treated successfully with daptomycin required a significantly shorter duration of IV therapy. 63% of daptomycin-treated patients achieved clinical success within 4 to 7 days, compared to only 33% of patients in the comparator arm (P<.0001). This suggests a potential for earlier transition to oral therapy or hospital discharge.[39]
• Special Populations: The efficacy and safety of daptomycin have also been confirmed in specific populations. A phase IIIb trial in elderly patients (≥65 years) demonstrated numerically higher clinical success rates for daptomycin compared to standard therapy (89.0% vs. 83.3%), with a particularly notable difference in patients with S. aureus infections (89.7% vs. 69.2%).[40] In pediatric patients (1 to 17 years), a multicenter trial found that once-daily, age-stratified daptomycin was comparable in safety and efficacy to standard therapy (clindamycin or vancomycin) for cSSSI, including those caused by MRSA.[42]
• Meta-Analysis: A meta-analysis of randomized controlled trials further supports these findings, concluding that the efficacy of daptomycin is not inferior to other first-line drugs for cSSSI and noting a trend toward superior efficacy when compared specifically with vancomycin for the treatment of S. aureus infections.[30]

Trial Identifier/Reference	Phase	Design	Patient Population	Daptomycin Regimen	Comparator	Key Efficacy Outcome (Clinical Success)
Arbeit et al., 2004 39	III	Randomized, Evaluator-Blinded, Multicenter	Adults with cSSSI	4 mg/kg IV q24h	Penicillinase-resistant penicillin or vancomycin	83.4% (Daptomycin) vs. 84.2% (Comparator); Non-inferior
Lagace-Wiens et al., 2013 41	IIIb	Randomized, Open-Label, Multicenter	Elderly (≥65 years) with cSSSI	4 mg/kg IV q24h	Semi-synthetic penicillin or vancomycin	89.0% (Daptomycin) vs. 83.3% (Comparator); Numerically higher
Bradley et al., 2017 42	IV	Randomized, Evaluator-Blinded, Multicenter	Pediatrics (1-17 years) with cSSSI	Age-stratified (5-10 mg/kg) IV q24h	Clindamycin or vancomycin	91% (Daptomycin) vs. 91% (Comparator); Similar

5.3 Evidence from Clinical Trials: Staphylococcus aureus Bacteremia (SAB) and Right-Sided Endocarditis (RIE)

The approval of daptomycin for SAB and RIE was based on a pivotal Phase 3, multicenter, randomized, open-label trial (NCT00093067) that compared daptomycin (6 mg/kg IV once daily) with standard therapy.[9] Standard therapy consisted of either a semi-synthetic penicillin (for MSSA) or vancomycin (for MRSA), with both arms receiving initial low-dose gentamicin for the first 4 days.[9] The study demonstrated that daptomycin was non-inferior to standard therapy for the treatment of

S. aureus bacteremia and right-sided endocarditis.[9]

Subsequent research has explored the role of higher doses and combination therapies, particularly for challenging MRSA infections.

• Higher-Dose and Combination Therapy: Studies have investigated daptomycin doses of 10 mg/kg/day and its use in combination with other agents like fosfomycin or beta-lactams, with the goals of improving clinical outcomes and preventing the emergence of resistance in high-inoculum infections.[44]
• Adjunctive Therapy in MSSA Bacteremia: The utility of daptomycin as an add-on therapy is not universal. The DASH trial (NCT02972983) was a randomized, controlled trial that evaluated whether adding daptomycin to a standard beta-lactam antibiotic shortened the duration of bacteremia in patients with MSSA. The results showed no significant difference in the duration of bacteremia between the daptomycin and placebo groups.[46] This important finding suggests that for infections caused by highly susceptible organisms like MSSA, where the primary beta-lactam therapy is already highly effective, adjunctive daptomycin does not provide additional benefit and should not be routinely considered.[46] This underscores the principle that daptomycin's greatest value lies in situations where standard therapy is compromised by resistance (e.g., MRSA) or is otherwise suboptimal.
• Pediatric SAB: A dedicated study in pediatric patients (1 to 17 years) with SAB (NCT01728376) was conducted to evaluate the safety and efficacy of age-stratified daptomycin regimens, confirming the safety of exposures that are comparable to those achieved in adults treated for the same indication.[31]

Trial Identifier/Reference	Phase	Design	Patient Population	Daptomycin Regimen	Comparator	Key Efficacy Outcome
Fowler et al., 2006 (NCT00093067) 9	III	Randomized, Open-Label, Multicenter	Adults with SAB, including RIE	6 mg/kg IV q24h	Semi-synthetic penicillin or vancomycin (both with initial gentamicin)	Non-inferior to standard therapy for treatment success
Cheng et al., 2020 (DASH Trial) 46	N/A	Randomized, Placebo-Controlled	Adults with MSSA bacteremia on beta-lactam therapy	Adjunctive daptomycin	Adjunctive placebo	No difference in duration of bacteremia

5.4 Spectrum of Activity and Susceptibility

Daptomycin's antibacterial activity is confined exclusively to Gram-positive bacteria.[6] It has no activity against Gram-negative organisms or fungi. Its spectrum includes the most clinically important Gram-positive pathogens, particularly those that pose a significant therapeutic challenge due to multi-drug resistance.

• Key Susceptible Pathogens:
• Staphylococcus aureus: Excellent activity against both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains, as well as vancomycin-intermediate S. aureus (VISA).[4]
• Enterococcus species: Active against both E. faecalis and E. faecium, including vancomycin-resistant (VRE) isolates.[4]
• Streptococcus species: Active against S. pyogenes, S. agalactiae, and viridans group streptococci.[32]
• Corynebacterium species.[9]
• In Vitro Potency: Daptomycin demonstrates excellent in vitro potency, with MIC90 values (the concentration required to inhibit 90% of isolates) typically ≤0.5 mg/L for staphylococci and ≤2.0 mg/L for enterococci.[48]

VI. The Challenge of Antimicrobial Resistance

While daptomycin remains a highly effective agent, the emergence of bacterial resistance is an ongoing and serious concern that threatens its long-term utility. Understanding the clinical context and molecular mechanisms of resistance is crucial for preserving its efficacy through antimicrobial stewardship and the development of novel therapeutic strategies.

6.1 Clinical Emergence and Risk Factors

Daptomycin resistance in clinical isolates of S. aureus and Enterococcus species, while still relatively uncommon, is being reported with increasing frequency.[9] The development of resistance is often associated with specific clinical scenarios, including:

• Prolonged Treatment Courses: Extended exposure to the antibiotic provides greater selective pressure for the emergence of resistant subpopulations.[10]
• High-Inoculum Infections: Infections with a large bacterial burden, such as infective endocarditis, deep-seated abscesses, or osteomyelitis, increase the statistical probability that a resistant mutant will arise.[10]
• Sub-optimal Dosing: Inadequate dosing that fails to achieve target PK/PD parameters can lead to treatment failure and the selection of resistant strains.[10]
• Prior Vancomycin Exposure: A notable phenomenon is the link between vancomycin non-susceptibility and daptomycin resistance. Strains of S. aureus with reduced susceptibility to vancomycin (VISA phenotype) have a higher propensity to develop daptomycin resistance during therapy, and resistance can even emerge in these strains without any prior exposure to daptomycin.[5]

6.2 Molecular Mechanisms of Resistance in Staphylococcus aureus

Resistance to daptomycin in S. aureus is a complex, multifactorial process involving adaptive mutations in several genetic loci. The predominant theme underlying these changes is the development of an electrostatic "repulsion" strategy, where the bacterial cell surface becomes more positively charged, thereby repelling the anionic calcium-daptomycin complex and preventing it from reaching its membrane target.[6]

• Alteration of Cell Surface Charge:
• mprF (Multiple Peptide Resistance Factor): Mutations in the mprF gene are one of the most common genetic events associated with daptomycin resistance. The MprF enzyme is responsible for synthesizing lysyl-phosphatidylglycerol (L-PG)—a positively charged phospholipid—and translocating it to the outer leaflet of the cell membrane. Gain-of-function mutations in mprF enhance this activity, leading to an accumulation of L-PG and a net increase in the positive charge of the cell surface, which repels the antibiotic.[25]
• dlt Operon: Overexpression of the dltABCD operon also contributes to a more positive surface charge. These genes mediate the incorporation of positively charged D-alanine residues into cell wall teichoic acids, further enhancing electrostatic repulsion.[25]
• Changes in Cell Wall and Membrane Homeostasis:
• Two-Component Systems (TCS): Mutations in key regulatory systems that govern cell envelope stress responses, such as yycFG (also known as WalKR) and vraSR, are frequently implicated in resistance. Activation of these systems can lead to a variety of adaptive changes, most notably a thickening of the cell wall, a phenotype that is also characteristic of VISA strains.[25]
• Phospholipid Metabolism: Mutations can also occur in genes that directly control the composition of the cell membrane. Changes in genes like pgsA (phosphatidylglycerol synthase) and cls2 (cardiolipin synthase) can alter the relative amounts of key phospholipids, potentially reducing the availability of PG, daptomycin's primary binding partner.[25]

6.3 Molecular Mechanisms of Resistance in Enterococcus Species and Other Pathogens

Enterococci employ distinct and sophisticated strategies to resist daptomycin, highlighting a remarkable evolutionary adaptation.

• Target "Diversion" in E. faecalis: In contrast to the repulsion strategy of S. aureus, the primary mechanism of resistance in E. faecalis is a process of "diversion." This involves a strategic reorganization of the cell membrane, where cardiolipin-rich microdomains, which are high-affinity binding sites for daptomycin, are redistributed away from the division septum. This effectively lures the antibiotic away from its critical site of action at the septum, preventing it from inhibiting cell wall synthesis.[25] This entire process is orchestrated by the LiaFSR three-component regulatory system. Activating mutations in this system, particularly in the negative regulator LiaF, trigger the phospholipid redistribution and confer resistance.[25]
• Repulsion in E. faecium: Interestingly, the resistance mechanism in E. faecium appears to be more similar to that of S. aureus. While also mediated by the LiaFSR system, the primary outcome is an increase in cell surface charge leading to electrostatic repulsion, rather than the diversion strategy seen in E. faecalis.[25]
• Target Elimination in Corynebacterium striatum: An alarming mechanism of high-level daptomycin resistance (HLDR) has been identified in Corynebacterium striatum. In this pathogen, a single loss-of-function mutation in the pgsA2 gene, which encodes phosphatidylglycerol synthase, can lead to the complete elimination of PG from the cell membrane. By removing the drug's primary target, the bacterium achieves profound levels of resistance, demonstrating the potential for some pathogens to evolve highly effective resistance through a single genetic event.[50]

Pathogen	Primary Resistance Strategy	Key Genes/Systems Implicated	Key Phenotypic Changes
Staphylococcus aureus	Electrostatic Repulsion	mprF, dlt operon, yycFG (WalKR), vraSR, pgsA, cls2	Increased positive surface charge, cell wall thickening, altered membrane fluidity
Enterococcus faecalis	Target Diversion	liaFSR, gdpD, cls	Redistribution of cardiolipin microdomains away from the septum, thickened cell wall
Enterococcus faecium	Electrostatic Repulsion	liaFSR, yycFG, cls	Increased positive surface charge, thickened cell wall, decreased PG content
Corynebacterium striatum	Target Elimination	pgsA2 (loss-of-function)	Complete removal of phosphatidylglycerol (PG) from the cell membrane

VII. Safety, Tolerability, and Risk Management

Daptomycin is generally well-tolerated, but its use is associated with a distinct profile of potential adverse events, including several rare but serious toxicities that require vigilant monitoring and specific risk management strategies.

7.1 Comprehensive Adverse Event Profile

• Common Adverse Reactions: In clinical trials, the most frequently reported adverse reactions (occurring in ≥2% of patients) included gastrointestinal disturbances (diarrhea, abdominal pain), central nervous system effects (headache, dizziness, insomnia), dermatological reactions (rash, pruritus), and general systemic symptoms (fever, edema).[1] Injection site reactions are also common.[1]
• Laboratory Abnormalities: The most common laboratory abnormalities observed with daptomycin therapy are elevations in creatine phosphokinase (CPK) and abnormal liver function tests (elevated transaminases).[18]

7.2 In-Depth Analysis of Clinically Significant Toxicities

Myopathy and Rhabdomyolysis

Skeletal muscle toxicity is the most well-known and clinically significant adverse effect of daptomycin.

• Clinical Presentation: Patients may present with muscle pain (myalgia) or weakness, particularly affecting the forearms and lower legs.[1] In more severe cases, this can progress to rhabdomyolysis, a condition involving the breakdown of muscle tissue that releases damaging proteins into the blood, potentially leading to acute kidney injury. The hallmark laboratory finding is a marked elevation in serum CPK levels.[8]
• Risk Factors: The risk of myopathy is strongly associated with drug exposure. Dosing more frequently than the recommended once-daily interval is a primary risk factor.[4] Co-administration with other drugs known to cause myopathy, particularly HMG-CoA reductase inhibitors (statins), may lead to an additive or synergistic risk.[6] Patients with renal impairment are also at increased risk due to drug accumulation.[6]
• Monitoring and Management: A clear risk management strategy is essential. Baseline and weekly monitoring of CPK levels is mandatory for all patients receiving daptomycin.[4] In patients with pre-existing renal impairment, CPK and renal function should be monitored more frequently.[34] It is strongly recommended to consider temporarily suspending statin therapy during the course of daptomycin treatment.[4] Daptomycin should be discontinued in patients who develop signs and symptoms of myopathy in conjunction with a CPK level greater than 5 times the upper limit of normal (ULN) (or >1,000 U/L), or in asymptomatic patients with a CPK level greater than 10 times the ULN (or >2,000 U/L).[6]

Eosinophilic Pneumonia

This is a rare but potentially life-threatening hypersensitivity reaction associated with daptomycin use.

• Clinical Presentation: It typically develops 2 to 4 weeks after the initiation of therapy and presents with symptoms such as new or worsening fever, cough, shortness of breath (dyspnea), and the appearance of new infiltrates on chest imaging.[1]
• Management: The condition requires the immediate discontinuation of daptomycin. Treatment with systemic corticosteroids is often necessary to resolve the inflammation. The reaction may recur upon re-exposure to the drug.[6]

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving daptomycin. Clinicians should monitor for new or worsening symptoms such as pain, burning, numbness, or tingling in the hands or feet. If neuropathy is suspected, discontinuation of daptomycin should be considered.[1]

Other Serious Reactions

Other rare but serious adverse reactions have been reported, including:

• Anaphylaxis/Hypersensitivity Reactions: Life-threatening allergic reactions can occur and require immediate discontinuation of the drug and appropriate emergency treatment.[32]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A severe skin reaction that can involve internal organs. Requires discontinuation of daptomycin and institution of appropriate therapy.[4]
• Tubulointerstitial Nephritis (TIN): An inflammatory kidney condition that can lead to acute renal failure. Requires drug discontinuation.[4]
• Clostridioides difficile-Associated Diarrhea (CDAD): As with other broad-spectrum antibiotics, daptomycin use can disrupt normal gut flora and lead to CDAD, which can range from mild diarrhea to fatal colitis.[4]

7.3 Clinically Significant Drug Interactions

Daptomycin has a low potential for metabolic drug interactions due to its lack of involvement with the CYP450 system. However, several clinically important interactions exist.

• HMG-CoA Reductase Inhibitors (Statins): This is the most significant interaction. The co-administration of daptomycin and any statin (e.g., atorvastatin, simvastatin, rosuvastatin) results in a pharmacodynamic interaction that increases the risk of myopathy and rhabdomyolysis.[6] The standard of care is to consider temporarily suspending statin therapy for the duration of daptomycin treatment.[4]
• Cholera Vaccine: This is a serious interaction. As a systemic antibiotic, daptomycin can be active against the live attenuated bacterial strain in the oral cholera vaccine, potentially rendering the vaccine ineffective. Co-administration should be avoided; cholera vaccine should not be given within 14 days of receiving systemic antibiotics.[29]
• Laboratory Test Interference: Clinically relevant plasma concentrations of daptomycin have been shown to cause a spurious prolongation of the prothrombin time (PT) and elevation of the International Normalized Ratio (INR). This interference occurs when certain types of recombinant thromboplastin reagents are used in the laboratory assay. Clinicians should be aware of this potential for falsely elevated coagulation parameters.[4]

VIII. Dosing, Administration, and Practical Considerations

Safe and effective use of daptomycin requires strict adherence to established dosing regimens, mandatory adjustments for renal impairment, and careful attention to the specific procedures for formulation and administration, which differ between patient populations and product types.

8.1 Dosing Regimens for Approved Indications

Dosing for daptomycin is based on the patient's weight, age, indication, and renal function.

Adult Dosing

• Complicated Skin and Skin Structure Infections (cSSSI): The recommended dose is 4 mg/kg administered intravenously once every 24 hours for a duration of 7 to 14 days.[29]
• Staphylococcus aureus Bacteremia (SAB) / Right-Sided Infective Endocarditis (RIE): The recommended dose is 6 mg/kg administered intravenously once every 24 hours for a duration of 2 to 6 weeks.[29]

Pediatric Dosing (Age-Stratified)

Pediatric patients require higher mg/kg doses than adults to achieve comparable systemic exposures due to their increased drug clearance. Dosing is stratified by age:

• cSSSI:
• Ages 12 to 17 years: 5 mg/kg IV once every 24 hours
• Ages 7 to 11 years: 7 mg/kg IV once every 24 hours
• Ages 2 to 6 years: 9 mg/kg IV once every 24 hours
• Ages 1 to <2 years: 10 mg/kg IV once every 24 hours (Duration for all age groups is up to 14 days) 29
• SAB:
• Ages 12 to 17 years: 7 mg/kg IV once every 24 hours
• Ages 7 to 11 years: 9 mg/kg IV once every 24 hours
• Ages 1 to 6 years: 12 mg/kg IV once every 24 hours (Duration for all age groups is up to 42 days) 29

Off-Label Higher Dosing

In clinical practice, particularly for severe infections caused by organisms with elevated MICs, such as VRE bacteremia, clinicians may use higher, off-label doses of daptomycin (e.g., 8-12 mg/kg/day). This practice should be guided by infectious disease specialists and may require more intensive safety monitoring.[35]

8.2 Mandatory Dose Adjustments for Renal Impairment

This is a critical safety consideration. Failure to adjust the dose in patients with renal impairment will lead to drug accumulation and an increased risk of toxicity.

• Creatinine Clearance (CrCl) < 30 mL/min: For adult patients with a CrCl less than 30 mL/min, the dosing interval must be extended to every 48 hours. The mg/kg dose for the specific indication remains the same (e.g., 4 mg/kg IV q48h for cSSSI; 6 mg/kg IV q48h for SAB).[18]
• Hemodialysis (HD) and Continuous Ambulatory Peritoneal Dialysis (CAPD): The every-48-hour dosing interval also applies to patients on dialysis. For patients undergoing intermittent hemodialysis, the dose should be administered after the completion of the dialysis session on hemodialysis days.[29]
• Pediatric Renal Impairment: A specific dosage regimen for pediatric patients with renal impairment has not been established. Use in this population requires extreme caution and consultation with a pediatric infectious disease specialist.[29]

8.3 Formulation, Reconstitution, and Administration

Daptomycin is available as a lyophilized powder for reconstitution in single-dose vials and as a premixed frozen solution for infusion.[22] Careful attention must be paid to the specific product formulation being used.

• Reconstitution of Lyophilized Powder:
• Cubicin® and Generics: Reconstitute the 500 mg vial with 10 mL of 0.9% Sodium Chloride Injection to yield a 50 mg/mL solution.[33]
• Cubicin RF®: Reconstitute the 500 mg vial with 10 mL of Sterile Water for Injection or Bacteriostatic Water for Injection. Do not use 0.9% Sodium Chloride for reconstitution of Cubicin RF, as this will result in a hyperosmotic solution.[33]
• Administration: The method of administration differs significantly between adult and pediatric patients.
• Adults: The reconstituted and diluted dose can be administered either as a 30-minute IV infusion or as a 2-minute IV push (direct injection).[32]
• Pediatric Patients: Daptomycin must be administered by IV infusion ONLY. It should NEVER be given as an IV push to pediatric patients. The infusion duration is age-dependent: 30 minutes for children aged 7 to 17 years, and 60 minutes for children aged 1 to 6 years.[29]
• Stability: Once reconstituted in the vial, the solution is stable for 12 hours at room temperature and for up to 48 hours if refrigerated. The final diluted solution in an IV bag is also stable for 12 hours at room temperature and 48 hours under refrigeration.[29]

Population	Indication	Dose (Normal Renal Function)	Dose (CrCl < 30 mL/min, including Dialysis)	Administration Notes
Adults (≥18y)	cSSSI	4 mg/kg IV q24h	4 mg/kg IV q48h	30-min infusion or 2-min IV push.
	SAB/RIE	6 mg/kg IV q24h	6 mg/kg IV q48h	Dose after hemodialysis on HD days.
Pediatrics (12-17y)	cSSSI	5 mg/kg IV q24h	Regimen not established	30-min infusion ONLY. NO IV PUSH.
	SAB	7 mg/kg IV q24h	Regimen not established
Pediatrics (7-11y)	cSSSI	7 mg/kg IV q24h	Regimen not established	30-min infusion ONLY. NO IV PUSH.
	SAB	9 mg/kg IV q24h	Regimen not established
Pediatrics (2-6y)	cSSSI	9 mg/kg IV q24h	Regimen not established	60-min infusion ONLY. NO IV PUSH.
	SAB	12 mg/kg IV q24h	Regimen not established
Pediatrics (1-<2y)	cSSSI	10 mg/kg IV q24h	Regimen not established	60-min infusion ONLY. NO IV PUSH.
	SAB	N/A	N/A

IX. Synthesis and Concluding Remarks

Daptomycin's Established Role

Daptomycin has firmly established itself as a cornerstone therapy in the treatment of severe infections caused by resistant Gram-positive pathogens. Its development represents a landmark achievement in antibiotic research, providing a first-in-class agent with a unique, calcium-dependent mechanism of action that confers rapid bactericidal activity against formidable foes like MRSA and VRE. Its proven efficacy in complicated skin and skin structure infections and S. aureus bacteremia, including right-sided endocarditis, makes it an invaluable asset in the hospital setting.

Balancing Efficacy and Risk

The clinical utility of daptomycin is defined by a crucial balance between its potent efficacy and a well-characterized profile of limitations and risks. Its power against a specific spectrum of pathogens is offset by its complete lack of efficacy in pneumonia due to inactivation by pulmonary surfactant—a direct consequence of the lipophilic properties essential to its mechanism. The primary safety concern, skeletal muscle toxicity, is a predictable and exposure-dependent risk that can be effectively managed through a clear and non-negotiable strategy: once-daily dosing, mandatory dose adjustment for renal impairment, and routine weekly monitoring of CPK levels. This manageable risk profile allows its potent benefits to be realized safely in appropriately selected and monitored patients.

The Ongoing Battle with Resistance

The specter of antimicrobial resistance remains the greatest long-term challenge to daptomycin's utility. While still relatively uncommon, the emergence of resistant strains of S. aureus and Enterococcus is a serious threat that underscores the imperative for judicious use. The complex and sophisticated adaptive mechanisms that bacteria employ—from electrostatic repulsion in S. aureus to target diversion in E. faecalis and even complete target elimination in C. striatum—highlight a dynamic evolutionary arms race. This necessitates vigilant antimicrobial stewardship, including the use of daptomycin only when proven or strongly suspected to be necessary, adherence to optimal dosing regimens to achieve bactericidal targets, and continued surveillance for emerging resistance.

Future Perspectives

The future of daptomycin will likely involve refining its use to maximize its longevity and efficacy. This includes further investigation into the role of therapeutic drug monitoring (TDM), particularly in critically ill patients, those with renal impairment, or those on renal replacement therapy, to optimize exposure and minimize toxicity.[3] Continued research into novel combination therapies aimed at overcoming resistance or achieving synergy is also a critical path forward. Ultimately, preserving the power of this vital antibiotic depends on a collective commitment to stewardship, ensuring that daptomycin remains an effective last-line defense against the most challenging Gram-positive infections for years to come.

X. Comprehensive Reference List

[1]

Works cited

1. Daptomycin Injection: MedlinePlus Drug Information, accessed August 1, 2025, https://medlineplus.gov/druginfo/meds/a608045.html
2. medlineplus.gov, accessed August 1, 2025, https://medlineplus.gov/druginfo/meds/a608045.html#:~:text=Daptomycin%20injection%20is%20used%20to,It%20works%20by%20killing%20bacteria.
3. Daptomycin: Physicochemical, Analytical, and Pharmacological Properties - PubMed, accessed August 1, 2025, https://pubmed.ncbi.nlm.nih.gov/26020161/
4. Daptomycin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00080
5. CAS 103060-53-3 Daptomycin - BOC Sciences, accessed August 1, 2025, https://www.bocsci.com/product/daptomycin-cas-103060-53-3-53270.html
6. Daptomycin - StatPearls - NCBI Bookshelf, accessed August 1, 2025, https://www.ncbi.nlm.nih.gov/books/NBK470407/
7. Definition of daptomycin - NCI Drug Dictionary, accessed August 1, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/daptomycin
8. Daptomycin - Infectious Diseases - Merck Manual Professional Edition, accessed August 1, 2025, https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/daptomycin
9. Daptomycin - Wikipedia, accessed August 1, 2025, https://en.wikipedia.org/wiki/Daptomycin
10. Daptomycin | Journal of Antimicrobial Chemotherapy - Oxford Academic, accessed August 1, 2025, https://academic.oup.com/jac/article/73/1/1/4558667
11. Daptomycin | 103060-53-3 - ChemicalBook, accessed August 1, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8855073.htm
12. Daptomycin: From the Mountain to the Clinic, with Essential Help from Francis Tally, MD - Oxford Academic, accessed August 1, 2025, https://academic.oup.com/cid/article/50/Supplement_1/S10/364812
13. Daptomycin: From the Mountain to the Clinic, with Essential Help from Francis Tally, MD, accessed August 1, 2025, https://academic.oup.com/cid/article-pdf/50/Supplement_1/S10/20908761/50-Supplement_1-S10.pdf
14. Daptomycin, Lipopeptide antibiotic (CAS 103060-53-3) (ab141204) | Abcam, accessed August 1, 2025, https://www.abcam.com/en-us/products/biochemicals/daptomycin-lipopeptide-antibiotic-ab141204
15. Development of daptomycin for Gram-positive infections - ResearchGate, accessed August 1, 2025, https://www.researchgate.net/publication/12304038_Development_of_daptomycin_for_Gram-positive_infections
16. Generic Cubicin Availability - Drugs.com, accessed August 1, 2025, https://www.drugs.com/availability/generic-cubicin.html
17. Drug Approval Package: Cubicin (Daptomycin) NDA #021572 - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-572_Cubicin.cfm
18. DAPTOMYCIN FOR INJECTION - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208385s005lbl.pdf
19. Human medicines European public assessment report (EPAR): Cubicin, daptomycin, Date of authorisation: 19/01/2006, Revision: 40, Status, accessed August 1, 2025, https://efim.org/node/142679
20. go.drugbank.com, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00080#:~:text=Chemically%2C%20daptomycin%20comprises%2013%20amino,covalently%20bonded%20to%20decanoic%20acid.
21. Daptomycin | CAS 103060-53-3 | SCBT - Santa Cruz Biotechnology, accessed August 1, 2025, https://www.scbt.com/p/daptomycin-103060-53-3
22. Attachment: Product Information Daptomycin - Therapeutic Goods Administration (TGA), accessed August 1, 2025, https://www.tga.gov.au/sites/default/files/auspar-daptomycin-191120-pi.pdf
23. Daptomycin (LY146032, CAS Number: 103060-53-3) | Cayman Chemical, accessed August 1, 2025, https://www.caymanchem.com/product/15615/daptomycin
24. Daptomycin 103060-53-3 | TCI AMERICA - TCI Chemicals, accessed August 1, 2025, https://www.tcichemicals.com/US/en/p/D4229
25. Mechanisms of Drug Resistance: Daptomycin Resistance - PMC, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4966536/
26. Mechanism of Action and Resistance to Daptomycin in Staphylococcus aureus and Enterococci - PMC - PubMed Central, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5088507/
27. pmc.ncbi.nlm.nih.gov, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5088507/#:~:text=Proposed%20mechanisms%20for%20the%20action,to%20the%20inner%20membrane%20leaflet.
28. Mode of action of the reserve antibiotic daptomycin solved | German Center for Infection Research, accessed August 1, 2025, https://www.dzif.de/en/mode-action-reserve-antibiotic-daptomycin-solved
29. Cubicin (DSC) (daptomycin) dosing, indications, interactions, adverse effects, and more, accessed August 1, 2025, https://reference.medscape.com/drug/daptomycin-342576
30. The safety and efficacy of daptomycin versus other antibiotics for skin and soft-tissue infections: a meta-analysis of randomised controlled trials | BMJ Open, accessed August 1, 2025, https://bmjopen.bmj.com/content/4/6/e004744
31. Safety & Efficacy of Daptomycin Versus Standard of Care (SOC) in 1 - 17 Year Olds With Staphylococcus Aureus Bacteremia (MK-3009-005) | ClinicalTrials.gov, accessed August 1, 2025, https://www.clinicaltrials.gov/ct2/show/NCT01728376
32. CUBICIN (daptomycin) Label - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021572s059lbl.pdf
33. Daptomycin Monograph for Professionals - Drugs.com, accessed August 1, 2025, https://www.drugs.com/monograph/daptomycin.html
34. Daptomycin: Side Effects, Uses, Dosage, Interactions, Warnings, accessed August 1, 2025, https://www.rxlist.com/daptomycin/generic-drug.htm
35. Daptomycin Dosing and Use Guidelines | UC Davis Health, accessed August 1, 2025, https://health.ucdavis.edu/media-resources/antibiotic-stewardship/documents/pdfs/guidelines/daptomycin.pdf
36. Daptomycin - Scottish Antimicrobial Prescribing Group, accessed August 1, 2025, https://www.sapg.scot/media/7590/sapg-opat-gppg-daptomycin-feb-2023-final.pdf
37. Cubicin | European Medicines Agency (EMA), accessed August 1, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/cubicin
38. AusPAR: Daptomycin - Therapeutic Goods Administration (TGA), accessed August 1, 2025, https://www.tga.gov.au/sites/default/files/auspar-daptomycin-191120.docx
39. Safety and Efficacy of Daptomycin for the Treatment of Complicated ..., accessed August 1, 2025, https://academic.oup.com/cid/article/38/12/1673/303768
40. Daptomycin Completed Phase 3 Trials for Infections Treatment | DrugBank Online, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00080/clinical_trials?conditions=DBCOND0024541&phase=3&purpose=treatment&status=completed
41. Safety and efficacy of daptomycin as first-line treatment for complicated skin and soft tissue infections in elderly patients: an open-label, multicentre, randomized phase IIIb trial - PubMed, accessed August 1, 2025, https://pubmed.ncbi.nlm.nih.gov/23990341/
42. Daptomycin for Complicated Skin Infections: A Randomized Trial - PubMed, accessed August 1, 2025, https://pubmed.ncbi.nlm.nih.gov/28202770/
43. Daptomycin in the Treatment of Subjects With Infective Endocarditis or Bacteremia Due to S. Aureus | ClinicalTrials.gov, accessed August 1, 2025, https://www.clinicaltrials.gov/study/NCT00093067
44. Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia | ClinicalTrials.gov, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT00695903
45. Study Details | Efficacy of Daptomycin Plus Fosfomycin Versus Daptomycin for Treatment of MRSA Bacteremia | ClinicalTrials.gov, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT01898338
46. Adjunctive Daptomycin in the Treatment of Methicillin-susceptible Staphylococcus aureus Bacteremia: A Randomized, Controlled Trial | Clinical Infectious Diseases | Oxford Academic, accessed August 1, 2025, https://academic.oup.com/cid/article/72/9/e196/5871967
47. Study Details | Daptomycin as Adjunctive Therapy for Staphylococcus Aureus Bacteremia, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT02972983
48. Daptomycin (LY146032) | Bacterial Inhibitor | MedChemExpress, accessed August 1, 2025, https://www.medchemexpress.com/daptomycin.html
49. Daptomycin Resistance and Tolerance Due to Loss of Function in Staphylococcus aureus dsp1 and asp23 | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed August 1, 2025, https://journals.asm.org/doi/10.1128/aac.01542-18
50. Mechanism of High-Level Daptomycin Resistance in Corynebacterium striatum | mSphere, accessed August 1, 2025, https://journals.asm.org/doi/10.1128/mspheredirect.00371-18
51. Cucicin (daptomycin) injection label - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021572s038lbl.pdf
52. daptomycin in sodium chloride injection - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213645s001lbl.pdf
53. pmc.ncbi.nlm.nih.gov, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8239264/#:~:text=Concomitant%20use%20of%20daptomycin%20and%20statins%20has%20been%20considered%20as,was%20highest%20with%20pravastatin%20treatment.&text=There%20are%20also%20many%20cases%20of%20myotoxicity%20observed%20with%20rosuvastatin%20treatment.
54. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DAPTOMYCIN FOR INJECTION - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217415s003lbl.pdf
55. Pfizer Daptomycin Powder for Solution for Injection or Infusion 500 mg/vial, accessed August 1, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=15429
56. Blood Stream Infections Completed Phase 1 Trials for Daptomycin (DB00080) - DrugBank, accessed August 1, 2025, https://go.drugbank.com/indications/DBCOND0044705/clinical_trials/DB00080?phase=1&status=completed
57. Blood Stream Infections Completed Phase 2 Trials for Daptomycin (DB00080) - DrugBank, accessed August 1, 2025, https://go.drugbank.com/indications/DBCOND0044705/clinical_trials/DB00080?phase=2&status=completed
58. CNS Infection Unknown Status Phase 4 Trials for Daptomycin (DB00080) | DrugBank Online, accessed August 1, 2025, https://go.drugbank.com/indications/DBCOND0115192/clinical_trials/DB00080?phase=4&status=unknown_status
59. Daptomycin Completed Phase 1 Trials for Gram Positive Bacterial Infections Basic Science, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00080/clinical_trials?conditions=DBCOND0070817&phase=1&purpose=basic_science&status=completed
60. Daptomycin | C72H101N17O26 | CID 21585658 - PubChem, accessed August 1, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Daptomycin
61. Study Details | Safety and Efficacy of Daptomycin for the Treatment of Complicated Skin and Skin-structure Infections | ClinicalTrials.gov, accessed August 1, 2025, https://www.clinicaltrials.gov/study/NCT00463801?cond=%22Staphylococcal%20Skin%20Infections%22&viewType=Table&rank=2
62. Safety and Efficacy of Daptomycin for the Treatment of Complicated Skin and Skin-structure Infections | ClinicalTrials.gov, accessed August 1, 2025, https://www.clinicaltrials.gov/study/NCT00463801
63. Mechanisms of Drug Resistance: Daptomycin Resistance | Request PDF - ResearchGate, accessed August 1, 2025, https://www.researchgate.net/publication/283263978_Mechanisms_of_Drug_Resistance_Daptomycin_Resistance
64. Daptomycin (intravenous route) - Side effects & uses - Mayo Clinic, accessed August 1, 2025, https://www.mayoclinic.org/drugs-supplements/daptomycin-intravenous-route/description/drg-20063292
65. Development of Daptomycin Resistance In Vivo in Methicillin-Resistant Staphylococcus aureus | Journal of Clinical Microbiology - ASM Journals, accessed August 1, 2025, https://journals.asm.org/doi/10.1128/jcm.43.10.5285-5287.2005
66. Daptomycin - Australian Prescriber, accessed August 1, 2025, https://australianprescriber.tg.org.au/articles/daptomycin.html
67. Daptomycin - Janusinfo.se, accessed August 1, 2025, https://janusinfo.se/beslutsstod/lakemedelochmiljo/pharmaceuticalsandenvironment/databaseenven/daptomycin.5.30a7505616a041a09b063204.html
68. Cubicin 500 mg powder for solution for injection or infusion - Patient Information Leaflet (PIL) - (emc) | 8124, accessed August 1, 2025, https://www.medicines.org.uk/emc/product/8124/pil