Daptomycin
Daptomycin is a bactericidal cyclic lipopeptide antibiotic naturally produced by the soil bacterium Streptomyces roseosporus.[1] It is primarily used to treat serious Gram-positive bacterial infections, including complicated skin and skin structure infections caused by susceptible isolates of Staphylococcus aureus (including methicillin-resistant strains) and Streptococcus pyogenes, as well as Staphylococcus aureus bloodstream infections (bacteremia), including those associated with right-sided infective endocarditis. Approved for use in adults and pediatric patients aged one year and older, daptomycin is administered intravenously and represents a key option for infections resistant to other antibiotics like vancomycin.[1] Daptomycin's mechanism of action involves calcium-dependent insertion into the Gram-positive bacterial cell membrane, where it oligomerizes to form pores that cause rapid depolarization and disruption of the membrane potential.[1] This leads to the cessation of protein, DNA, and RNA synthesis, ultimately resulting in bacterial cell death without lysing the cell.[2] Unlike many other antibiotics, daptomycin is ineffective against Gram-negative bacteria due to its outer membrane barrier and is also unsuitable for treating pneumonia because pulmonary surfactant inactivates it.[1] Discovered in the early 1980s during a screening program by Eli Lilly and Company, daptomycin underwent initial clinical trials in the 1990s but faced challenges with efficacy at the tested doses, leading to its temporary shelving.[2] Revived by Cubist Pharmaceuticals with higher dosing regimens, it received FDA approval on September 12, 2003, under the brand name Cubicin, filling a critical gap in treating multidrug-resistant Gram-positive infections. Since then, it has become a cornerstone in antimicrobial stewardship, though monitoring for adverse effects such as creatine kinase elevation and myopathy is essential due to its potential for muscle toxicity.[1]Medical uses
Indications
Daptomycin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated skin and skin structure infections (cSSSI) in adult and pediatric patients aged 1 to 17 years, caused by susceptible Gram-positive organisms including Staphylococcus aureus (methicillin-susceptible and methicillin-resistant strains, or MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).[3] It is also indicated for Staphylococcus aureus bloodstream infections (bacteremia) in adults, including cases associated with right-sided infective endocarditis, and in pediatric patients aged 1 to 17 years, caused by methicillin-susceptible and methicillin-resistant strains.[3] Off-label applications of daptomycin include the management of left-sided infective endocarditis due to S. aureus, where it serves as an alternative despite lack of formal approval.[4] It is commonly employed off-label for osteomyelitis or septic arthritis caused by MRSA, prosthetic joint infections involving Staphylococcus or Enterococcus species, and persistent MRSA bacteremia in scenarios where standard therapies such as vancomycin have failed.[1] These uses leverage daptomycin's activity against multidrug-resistant Gram-positive pathogens, though clinical outcomes vary and often require combination regimens or higher doses.[5] Daptomycin's indications are restricted to Gram-positive infections due to its mechanism of action, which disrupts bacterial cell membrane function in these organisms; it shows no activity against Gram-negative bacteria or anaerobes.[1] Notably, it is not recommended for pneumonia, as the drug is inactivated by pulmonary surfactant, rendering it ineffective in the lung environment.[3] The agent is approved for use in adults and pediatric patients starting from 1 year of age, with considerations for age- and weight-based adjustments to ensure appropriate therapy.[3]Administration
Daptomycin is administered exclusively by intravenous infusion, typically over 30 minutes in adults, to minimize infusion-related reactions.[3] For pediatric patients aged 7 to 17 years, infusion should last 30 minutes, while those aged 1 to 6 years require a 60-minute infusion; rapid injection over 2 minutes is not recommended for children.[3] The drug must be diluted in 0.9% sodium chloride injection and is incompatible with dextrose-containing solutions, which can cause precipitation.[3] It should not be administered via elastomeric infusion pumps due to potential leaching of harmful substances.[3] In adults, dosing is based on actual body weight and varies by indication: 4 mg/kg once daily for complicated skin and skin structure infections (cSSSI), administered for 7 to 14 days, and 6 mg/kg once daily for Staphylococcus aureus bloodstream infections (bacteremia), including right-sided endocarditis, for 2 to 6 weeks.[3] Higher doses of 8 to 10 mg/kg once daily are recommended for off-label uses such as osteomyelitis, particularly in cases involving methicillin-resistant S. aureus or to mitigate resistance development, though these exceed FDA-approved regimens and require careful monitoring.[6] For obese patients, actual body weight is used for dosing calculations, as supported by pharmacokinetic data showing adequate exposure without adjustment to ideal body weight.[3] Pediatric dosing for cSSSI in patients aged 1 to 17 years is weight- and age-stratified: 5 mg/kg once daily for those 12 to 17 years, 7 mg/kg for 7 to 11 years, 9 mg/kg for 2 to 6 years, and 10 mg/kg for 1 to less than 2 years, up to a maximum of 14 days; use is not recommended in infants under 1 year due to risks of developmental toxicity.[3] For S. aureus bacteremia in pediatric patients aged 1 to 17 years, dosing is 7 mg/kg once daily for 12 to 17 years, 9 mg/kg for 7 to 11 years, and 12 mg/kg for 1 to 6 years, up to 42 days.[3] No dose adjustment is needed for hepatic impairment, but renal impairment requires modification: in adults with creatinine clearance less than 30 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis, the dose is administered every 48 hours, with timing post-hemodialysis on dialysis days.[3] Therapeutic monitoring includes baseline and weekly serum creatine phosphokinase (CPK) measurements to detect potential myopathy, with more frequent testing in patients with renal impairment, concomitant statin use, or symptoms of muscle pain or weakness.[3] For preparation, the lyophilized powder (available as 350 mg or 500 mg vials) is reconstituted with sterile or bacteriostatic water for injection to a concentration of 50 mg/mL, gently swirled without vigorous shaking, then further diluted in 0.9% sodium chloride to 50 mL for adults or adjusted volumes for pediatrics.[3] Reconstituted solutions are stable for up to 12 hours at room temperature or 48 hours under refrigeration (2°C to 8°C), and unused portions must be discarded.[3] Unopened vials should be stored refrigerated but can tolerate brief excursions to room temperature.[3]Pharmacology
Structure and properties
Daptomycin is a first-in-class cyclic lipopeptide antibiotic composed of a 13-amino acid depsipeptide core, featuring a decanoyl (10-carbon) fatty acid chain attached to the N-terminal tryptophan residue. The structure includes a 10-membered macrocyclic ring formed by a lactone ester linkage between the C-terminal kynurenine and the hydroxyl group of threonine at position 4, with a three-amino acid exocyclic tail extending from the ring. It incorporates several non-standard amino acids, including L-kynurenine (unique to daptomycin among known natural products), L-3-methylglutamic acid, and multiple D-amino acids such as D-asparagine, D-alanine, and D-serine, which contribute to its rigidity and biological activity.[7][8][9] The molecular formula of daptomycin is C72H101N17O26, with a molecular weight of 1620.67 Da. It is supplied as a sterile, lyophilized pale yellow to light brown powder for intravenous use, which exhibits poor intrinsic water solubility (approximately 0.017 mg/mL). Reconstitution is achieved with 0.9% sodium chloride to form a 50 mg/mL solution, as the drug shows improved solubility in saline.[2][9] Physicochemical properties include stability as a dry powder at room temperature, with reconstituted solutions maintaining chemical and physical integrity for up to 12 hours at 25°C or 48 hours at 2–8°C when protected from light. The pH of freshly reconstituted solutions is adjusted to 4.0–5.0 using sodium hydroxide. Daptomycin's activity is calcium-dependent, requiring divalent cations for oligomerization and membrane insertion, and it is notably sensitive to pulmonary surfactants, which bind and inactivate the molecule, precluding its use via inhalation routes.[10][11]Mechanism of action
Daptomycin is a calcium-dependent lipopeptide antibiotic that exerts its bactericidal activity against Gram-positive bacteria by binding to specific phospholipids in the bacterial cytoplasmic membrane. In the presence of calcium ions, daptomycin preferentially interacts with phosphatidylglycerol (PG) and cardiolipin, which are abundant in the membranes of Gram-positive organisms. This binding facilitates the oligomerization of daptomycin molecules, typically forming complexes of 4 to 7 monomers that insert into the lipid bilayer, leading to the formation of pores or membrane disruptions.[12][13][14] The insertion of these oligomers causes rapid depolarization of the membrane potential, primarily through the influx of ions such as sodium, which disrupts the electrochemical gradient across the membrane. This depolarization triggers the efflux of potassium ions (K⁺) and other intracellular components, including magnesium (Mg²⁺) and adenosine triphosphate (ATP). The resulting ATP depletion halts energy-dependent processes, leading to secondary inhibition of DNA, RNA, and protein synthesis, ultimately causing cell death. Daptomycin's activity is concentration-dependent and manifests rapidly, often within minutes of exposure.[15][16][17] Daptomycin's selectivity for Gram-positive bacteria stems from its inability to penetrate the outer membrane of Gram-negative bacteria, allowing direct access to the cytoplasmic membrane only in organisms lacking this barrier. Additionally, its activity is inactivated in the pulmonary environment due to binding with pulmonary surfactant, which sequesters the drug and prevents effective interaction with bacterial membranes. Unlike beta-lactams or glycopeptides, which target cell wall synthesis, daptomycin's membrane-directed mechanism results in no cross-resistance with these classes.[18][19][20]Pharmacokinetics
Daptomycin is administered intravenously and exhibits 100% bioavailability via this route.[10] Following a 30-minute infusion, peak plasma concentrations are typically achieved at the end of the infusion, approximately 1 hour after the start of administration.[21] The volume of distribution at steady state is approximately 0.1 L/kg in healthy adults.[10] Daptomycin is highly bound to plasma proteins, with binding ranging from 90% to 93% primarily to albumin, though this decreases slightly to 84% to 88% in patients with severe renal impairment.[10] It demonstrates good penetration into skin and soft tissues but limited penetration into cerebrospinal fluid and bone.[1][5] Metabolism of daptomycin is minimal, with only minor oxidative metabolites identified in urine and no significant metabolites in plasma; it does not involve cytochrome P450 enzymes.[10] Excretion occurs primarily via the kidneys, with approximately 52% of the dose recovered unchanged in urine (total drug-related material ~78%) and approximately 6% via biliary/fecal elimination.[10] The elimination half-life is 7 to 9 hours in individuals with normal renal function but prolongs to around 30 hours in those with severe renal impairment or on hemodialysis.[10] Pharmacokinetics are linear and dose-proportional for doses up to 12 mg/kg administered once daily.[10] As an intravenous agent, daptomycin is not affected by food intake.[10]Microbiology and spectrum of activity
Bacterial spectrum
Daptomycin exhibits bactericidal activity against a broad range of aerobic Gram-positive bacteria, with particular clinical utility in treating infections caused by multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Among staphylococci, daptomycin is active against Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates) and coagulase-negative staphylococci. It also demonstrates efficacy against various streptococcal species, including beta-hemolytic groups A (Streptococcus pyogenes), B (S. agalactiae), C, and G streptococci, as well as S. pneumoniae and S. bovis.[22][23] Daptomycin targets enterococci, encompassing both Enterococcus faecalis and Enterococcus faecium (including vancomycin-resistant strains). It further shows activity against Corynebacterium species, while its potency against Listeria monocytogenes is variable. The antibiotic is inactive against all Gram-negative bacteria, atypical pathogens (e.g., Legionella species), mycobacteria, and anaerobic bacteria. This selectivity stems from its mechanism of action, which depends on insertion into the Gram-positive cytoplasmic membrane.[1]In vitro activity
Daptomycin exhibits potent in vitro activity against a range of Gram-positive bacteria, particularly when tested under standardized conditions that account for its calcium dependency. Susceptibility testing is performed using broth microdilution methods with supplementation of 50 mg/L calcium ions (Ca²⁺), as recommended by CLSI guidelines, to ensure accurate minimum inhibitory concentration (MIC) determinations.[24][25] Against Staphylococcus aureus, including methicillin-resistant strains (MRSA), daptomycin demonstrates high potency with MIC₉₀ values typically ranging from 0.5 to 1 mg/L. The CLSI susceptible breakpoint for staphylococci is ≤1 mg/L, aligning with the MIC distributions observed in clinical isolates. For enterococci, MIC₉₀ values are 1 to 4 mg/L for Enterococcus faecalis and 2 to 8 mg/L for vancomycin-resistant enterococci (VRE), primarily E. faecium; CLSI breakpoints define susceptibility as ≤2 mg/L for non-E. faecium enterococci and susceptible-dose dependent as ≤4 mg/L for E. faecium. Streptococci, including beta-hemolytic species, show even greater susceptibility, with MIC₉₀ values of ≤0.25 mg/L and a CLSI breakpoint of ≤1 mg/L.[18][26][24]| Organism Group | Typical MIC₉₀ (mg/L) | CLSI Susceptible Breakpoint (mg/L) |
|---|---|---|
| S. aureus (incl. MRSA) | 0.5–1 | ≤1 |
| E. faecalis | 1–4 | ≤2 (non-E. faecium) |
| VRE (E. faecium) | 2–8 | ≤4 (dose-dependent) |
| Streptococci | ≤0.25 | ≤1 |