Version May 2024
INTRODUCTION — Daptomycin is a lipopeptide antimicrobial with activity against gram-positive organisms, including antimicrobial-resistant pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp [1,2].
Issues related to pharmacokinetic and pharmacodynamic considerations, challenges with susceptibility testing and emergence of resistance, dosing, monitoring, adverse effects, and drug interactions will be reviewed here.
Details regarding the management of specific clinical syndromes for which daptomycin may be used are discussed separately:
●(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)
●(See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)
●(See "Infection due to coagulase-negative staphylococci: Treatment".)
●(See "Nonvertebral osteomyelitis in adults: Treatment".)
●(See "Antimicrobial therapy of left-sided native valve endocarditis".)
●(See "Treatment of enterococcal infections".)
●(See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents".)
MECHANISM OF ACTION — Daptomycin, a cyclic lipopeptide, is a large anionic molecule; the primary mechanism of action is calcium-dependent depolarization of the gram-positive bacterial cell membrane. The lipophilic tail of the drug binds and inserts itself into the bacterial membrane and then generates an ion-conducting channel that disrupts the functional integrity of the gram-positive membrane, causing release of intracellular potassium, membrane depolarization, and subsequent cell death [3].
Daptomycin does not appear to require bacterial cell division or active metabolism for bactericidal activity and has been demonstrated to remain highly active against S. aureus in stationary growth phase [4].
SPECTRUM OF ACTIVITY — Daptomycin has in vitro bactericidal activity against gram-positive bacteria (including some anaerobes); it is not active against gram-negative bacteria.
The spectrum of activity includes: Staphylococcus spp (including S. aureus and coagulase-negative staphylococci), Enterococcus spp (both Enterococcus faecium and Enterococcus faecalis), Streptococcus pneumoniae (including penicillin-resistant strains), and other viridans-group Streptococcus, beta-hemolytic Streptococcus spp (namely Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae), Corynebacterium spp, Leuconostoc spp, Pediococcus spp, and gram-positive anaerobes (including Clostridium spp and Cutibacterium acnes) [3].
Some species of coagulase-negative staphylococci are reported to have reduced susceptibility to daptomycin (including Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus sciuri, and Staphylococcus warneri) [5,6].
Daptomycin has decreased activity against Listeria monocytogenes and Actinomyces spp. Daptomycin is not active against the rapid-growing Mycobacterium spp, Nocardia spp, or Rhodococcus spp.
SUSCEPTIBILITY TESTING — Daptomycin susceptibility breakpoints are summarized in the table (table 1).
Laboratory determination of daptomycin susceptibility is complicated by discrepancies between the Clinical Laboratory and Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [7,8].
The CLSI and EUCAST breakpoint for methicillin-resistant S. aureus (MRSA) is 1 mg/L. CLSI breakpoints for E. faecalis and E. faecium are 4 and 8 mg/L, respectively; EUCAST has determined that there is insufficient evidence to support setting clinical breakpoints for Enterococcus spp [9,10].
Daptomycin susceptibility testing requires fixed concentrations of divalent calcium ions (Ca2+). The International Organization for Standardization reference broth microdilution method in cation-adjusted Mueller-Hinton broth must be supplemented with Ca2+ (to a final concentration of 50 mg/L). It is not possible to perform agar dilution and disk diffusion accurately [3].
Use of commercial susceptibility testing methods (such as BD Phoenix, MicroScan, and Vitek2) or a gradient strip test (such as Etest) can overestimate the daptomycin minimum inhibitory concentration (MIC). In addition, commercial methods may be restricted in reporting susceptibility based on the platform’s package insert and will withhold results for important species, such as E. faecium.
There is considerable variability in the reproducibility of daptomycin MIC measurements. In general, if a daptomycin-nonsusceptible strain is identified, that isolate should undergo additional testing. In addition, to detect emergence of daptomycin resistance, diagnostic laboratories should strongly consider the need for repeat daptomycin susceptibility testing if an isolate (especially Enterococcus spp and MRSA) is isolated repeatedly while on therapy.
Daptomycin susceptibility breakpoints should not be reported for organisms isolated from the respiratory tract.
RESISTANCE — The mechanisms of daptomycin resistance are multifactorial and not fully understood. In general, the changes appear to be isolate-specific, with alterations to the cell membrane and cell wall via adaptions in metabolic function and stress response regulatory pathways. Emergence of resistance appears to occur more commonly in the setting of recalcitrant, deep-seated infections and infections associated with a high organism burden (such as endocarditis, catheter-related bacteremia, or an undrained abscess).
In S. aureus, there is an association between membrane remodeling and cross-resistance between daptomycin, vancomycin (a glycopeptide antimicrobial), and dalbavancin (a lipoglycopeptide antimicrobial) [11]. Daptomycin nonsusceptibility has also been observed in some vancomycin-intermediate S. aureus strains [12,13]. Vancomycin resistance in S. aureus strains, which is mediated by the vanA gene, does not affect daptomycin susceptibility. Not all S. aureus strains appear to respond to daptomycin exposure in the same way. There are seemingly conflicting observations whereby both too much and too little membrane order are prohibitive to optimal daptomycin binding [14].
In enterococci, the emergence of daptomycin nonsusceptibility is associated with diverse evolutionary pathways and mutations in the cell envelope stress response system and genes involved in phospholipid biosynthesis [15-17].
Mutations associated with daptomycin nonsusceptibility have been purported to be related to charge repulsion and membrane fluidity. Gain-of-function mutations in membrane biosynthesis genes, such as mprF, can contribute to daptomycin resistance [18,19]. This same mutation also confers a host immune evasion advantage by concurrently inhibiting cationic host defense peptides and impairing immune recognition by the innate immune system [20,21].
PHARMACOKINETICS — Daptomycin is a large molecule with a molecular mass of approximately 1.6 kDa, high protein binding (90 to 95 percent), and distribution primarily in the vascular space with a low volume of distribution of 0.1 L/kg [22]. The pharmacokinetics of daptomycin are linear up to doses of 12 mg/kg, administered intravenously for 14 days [23]. The drug is primarily excreted via the kidneys [24]. Daptomycin has an elimination half-life of approximately 8 to 9 hours in adults [22,24] compared with 6.7 hours in adolescents, 5.6 hours in children aged 7 to 11 years, and 5.3 hours in children <6 years of age [25].
The pharmacokinetics of daptomycin in children differ compared with that in adults; children have lower total body water and blood protein concentrations [26]; this is important given daptomycin’s high protein binding and low volume of distribution. Children between 2 and 11 years demonstrate age-dependent plasma clearance of daptomycin [25]. Therefore, higher daptomycin doses are required in these patients to achieve a similar systemic exposure associated with efficacy in adults [25].
Pharmacokinetic considerations by organ system include:
●Respiratory tract − Daptomycin is inactivated by alveolar surfactants and therefore should not be used for bronchioalveolar pneumonia [27]. Empiric use of daptomycin in the clinical setting of pulmonary infiltrates should be avoided.
●Urinary tract − Daptomycin is suitable for treatment of urinary tract infections caused by resistant gram-positive organisms; approximately 54 percent of the drug is excreted as microbiologically active drug in the urine [22,28]. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents".)
●Central nervous system − Daptomycin penetrates poorly into the cerebrospinal fluid (CSF), due to its high molecular mass and high protein binding. Meningeal inflammation does not appear to increase CSF penetration [29]. CSF concentrations have been reported to be as low as 0.45 percent [30] and 0.8 percent of plasma concentrations in patients with health care-associated meningitis [31].
●Skin and soft tissue − Daptomycin has good skin and soft tissue penetration with soft tissue concentrations of approximately 70 to 90 percent of those of the free drug in the plasma [32]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)
●Bone and joint − Daptomycin is considered to have poor bone penetration relative to its serum concentration (<10 percent); however, evidence to support its use is increasing by attainment of therapeutic bone concentrations above that of the minimum inhibitory concentration of gram-positive bacteria [33-35]. In one trial including more than 140 children with osteomyelitis randomly assigned to treatment with daptomycin or comparator antibiotics (vancomycin, nafcillin, or equivalent), noninferiority criteria for clinical improvement at day 5 were not met; however, clinical cure rates at the end of therapy were similar between the two groups (82 versus 87 percent) [36]. (See "Nonvertebral osteomyelitis in adults: Treatment".)
●Biofilm − Daptomycin has variable activity against biofilms associated with S. aureus and vancomycin-resistant enterococci; efficacy is enhanced with combination antimicrobial therapy and novel strategies such as daptomycin microencapsulation in polymeric platforms [37-45]. Activity against biofilm associated with Staphylococcus epidermidis in the context of foreign material has been observed [46-48].
PHARMACODYNAMICS
General principles — Daptomycin acts via concentration-dependent bacterial killing with a prolonged postantibiotic effect (4.8 to 10.8 hours) [49,50]. The area-under-the-curve/minimum inhibitory concentration ratio (AUC/MIC) is the best pharmacokinetic/pharmacodynamic index for predicting efficacy.
For S. aureus infection, a murine model noted total drug AUC/MIC ratios for bacteriostasis were 388 to 537, which correlate with free drug AUC/MIC values of 31 to 43 [49]. A subsequent in vitro study of methicillin-resistant S. aureus found free drug AUC/MIC ratios for bacteriostasis of 37.2 ± 16.5 [51]. Despite studies failing to consistently show a clear relationship between exposure and outcome across different infection syndromes, a total drug AUC/MIC >666 has been associated with lower mortality [52] and trough concentrations <3.2 mg/L (at steady state) have been associated with poor clinical outcomes [53].
For enterococcal bloodstream infection, a free drug AUC/MIC target of >27.4 predicted survival at 30 days [54]. Monte Carlo simulation demonstrates that, even with daptomycin doses of 12 mg/kg/day, >90 percent target attainment is only possible for isolates with MIC ≤2 mg/L (measured by Etest). Therefore, monotherapy would be unable to achieve adequate exposure against the entire wild-type population of enterococcal strains. Combination therapy has been proposed as an alternative way to reduce the free drug AUC/MIC targets that allow for a >90 percent target attainment, using 12 mg/kg/day for strains with MIC of 4 mg/L [55].
Therapeutic drug monitoring — Data supporting use of therapeutic drug monitoring (TDM) for daptomycin are limited [56]. Further study of TDM is warranted to help optimize dosing, prevent toxicity, and avoid emergence of resistance, particularly given unpredictable serum daptomycin levels and increasing use of high-dose therapy [52,53,57-60]. This need is especially important for use of daptomycin in the context of altered pharmacokinetics, such as renal impairment, hemodialysis, continuous renal replacement therapy, extremes of body weight, hypoalbuminemia, and critical illness. A major limitation to the clinical implementation of daptomycin TDM is lack of accessibility to timely bioanalytic assays [61].
CLINICAL USE
General principles — Daptomycin may be used for (1) targeted treatment against gram-positive infections for situations in which standard therapy is not possible due to bacterial resistance or intolerance to other antibiotic agents or (2) empiric treatment of serious infection in patients known to be colonized with a resistant gram-positive organism.
Daptomycin should never be used for treatment of bronchopneumonia, since pulmonary surfactant greatly reduces binding to the bacterial cell membrane and thereby preventing activity of the drug. However, daptomycin does have efficacy in hematogenous pulmonary infections, such as that arising from septic pulmonary emboli [62].
Issues related to dosing are discussed below. (See 'Dosing' below.)
Patients on daptomycin should be monitored clinically for development of muscle pain or weakness, and should undergo creatine phosphokinase (CPK) monitoring during drug administration. For patients on statin therapy, issues related to consideration of temporary statin discontinuation during daptomycin therapy are discussed below. (See 'Monitoring' below and 'Statins' below.)
Daptomycin is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in complicated skin and soft tissue infections and S. aureus bacteremia.
There has been increasing clinical experience with off-label use of daptomycin for a wider spectrum of infection syndromes. These include left-sided and prosthetic valve endocarditis, bone and joint infections (including infection involving prosthetic material), complicated urinary tract infections, and other deep-seated infections [63-70]. With the exception of uncomplicated urinary tract infections (where daptomycin achieves relatively high urinary concentrations, allowing lower doses to be used effectively) [71], pathogen susceptibility and daptomycin exposure at the site of infection must be considered carefully when selecting an off-label dose regimen. Increasing use of higher daptomycin doses (>6 mg/kg/day) has been reported for the treatment of osteomyelitis and prosthetic joint infections [66,67,72]. Furthermore, the pharmacokinetic alterations in critical illness (in patients without renal impairment) support higher dosing.
The Infectious Diseases Society of America 2011 guidelines suggest daily doses of daptomycin up to 10 mg/kg in cases of endocarditis or complicated bacteremia caused by methicillin-resistant S. aureus (MRSA) [73]. In addition, daptomycin may be used in the setting of vancomycin failure (clinical or microbiologic); the higher dose of 10 mg/kg has been used in this setting due to the association of concurrent emergence of nonsusceptibility to vancomycin and daptomycin. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)
Further expanded use of daptomycin includes the directed treatment of vancomycin-resistant enterococci (VRE) pathogens. Complicated infections caused by VRE represent a distinct clinical challenge, with limited effective antimicrobial options available and a propensity to affect vulnerable immunocompromised patients. Although an effective dosing regimen appropriate for Enterococcus spp has not been identified, with concerns regarding treatment failure and emergence of resistance, there are reports of clinical success, especially associated with the use of high dose daptomycin (up to 12 mg/kg/day) [74,75]. Until future clinical studies provide more guidance in relation to the clinical efficacy of optimized dosing regimens, close clinical monitoring should accompany the use of high-dose daptomycin when treating all enterococcal infections. (See "Treatment of enterococcal infections".)
There is increasing evidence to support the effectiveness and tolerability of high-dose daptomycin therapy (≥8 mg/kg). However, available data are limited to small, retrospective studies. In general, the frequency of CPK elevation among patients treated with high-dose daptomycin therapy has been reported at rates of 2.8 to 3.2 percent [74,76]. One retrospective cohort study including 60 patients treated with high-dose daptomycin (≥10 mg/kg/day) noted no increase in CPK elevation [77].
Dosing
Standard dosing — Daptomycin is approved by the FDA and the EMA for use in complicated skin and soft tissue infections (adult dose: 4 mg/kg intravenously [IV] every 24 hours) and S. aureus bacteremia (adult dose: 6 mg/kg IV every 24 hours) associated with either complicated skin and soft tissue infections or right-sided endocarditis. The same indications are approved for children 1 to 17 years of age, with the exception of right-sided endocarditis. Pediatric dosing is summarized in the table (table 2).
Renal impairment — Daptomycin dose adjustment is required in renal impairment:
●Creatinine clearance ≥30 mL/minute − For patients with creatinine clearance ≥30 mL/minute, daptomycin should be administered every 24 hours.
●Creatinine clearance <30 mL/minute – For patients with creatinine clearance <30 mL/minute, daptomycin should be administered every 48 hours.
●Hemodialysis – For patients on hemodialysis, daptomycin should be administered three times per week following dialysis. For the 72-hour interdialytic period that occurs during three-times weekly hemodialysis, a dose increase by 50 percent should be considered [78].
●Continuous ambulatory peritoneal dialysis – For patients on continuous ambulatory peritoneal dialysis, intravenous daptomycin should be administered every 48 hours [79].
●Continuous renal replacement therapy – A number of different dosing approaches have been suggested in the setting of continuous renal replacement therapy (CRRT), ranging from 8 mg/kg every 48 hours for continuous venovenous hemodialysis [80] to 8 mg/kg every 24 hours for continuous venovenous hemodiafiltration [81]. A subsequent study suggested that 6 mg/kg every 24 hours, with a CRRT dose of 30 to 35 mL/h/kg, provided the best balance of efficacy and toxicity when treating S. aureus [82]. (See "Drug removal in continuous kidney replacement therapy".)
Hepatic impairment — No adjustment is required for mild to moderate hepatic dysfunction.
Patients with obesity — Data are limited regarding the optimal approach to daptomycin dosing in patients with obesity. The FDA recommends standard weight-based dosing for all patients; however, dosing daptomycin using total body weight in patients with obesity has been associated with increased risk of adverse effects [83] (see 'Myopathy and rhabdomyolysis' below). Therefore, when using daptomycin for treatment of serious infections in patients with body mass index >30 mg/m2, we favor use of adjusted body weight to maintain adequate drug concentrations and to limit adverse effects and toxicity (calculator 1) [84].
Data on clinical outcomes for use of adjusted body weight are limited; retrospective data suggest such outcomes appear to be comparable among patients dosed via adjusted body weight versus total body weight [84]. Dosing based on ideal body weight has been associated with similar clinical and microbiologic outcomes compared with actual body weight [85].
Critical illness — Pharmacokinetic changes in critically ill patients may affect achievement of adequate daptomycin exposure [86,87]. Factors such as augmented renal clearance, increased unbound fraction of daptomycin, and increased volume of distribution may warrant higher daptomycin doses and use of therapeutic drug monitoring [87-89]. Critically ill patients with MRSA bacteremia treated with 6 to 8 mg/kg have been found to have inadequate daptomycin exposure [89]. Therefore, we favor higher daptomycin doses (up to 10 to 12 mg/kg) in critically ill patients [56,89-91].
Pregnancy and breastfeeding — Data on the use of daptomycin during pregnancy are limited. Case reports have described successful use during the second and third trimesters of pregnancy, without fetal adverse effects [92-94].
Low concentrations of daptomycin have been detected in breast milk (0.1 percent of the maternal dose) [95-97]; daptomycin is felt to be unlikely to cause adverse effects in breastfed infants [98]. A small number of case reports have described no adverse effects among breastfed infants during treatment and follow-up [95,96].
Role of combination therapy — The role of combination therapy of daptomycin with other antimicrobials continues to show promise in both in vitro and in vivo studies, which have demonstrated enhanced bacterial killing and prevention of daptomycin resistance. Many studies have focused on the treatment of MRSA infection [99,100], however, combination therapy for VRE [43,55,101] and viridans-group streptococci have also been described [102]. (See 'Resistance' above.)
Overall, combination therapy with daptomycin and a beta-lactam antibiotic appear to be the most promising, although further clinical trials are needed. Fosfomycin in combination with daptomycin has also shown some promise, providing synergistic therapeutic activity against both MRSA and VRE infections [43,103-107]. Other agents with support for use in combination with daptomycin include gentamicin, trimethoprim-sulfamethoxazole, rifampicin, fusidic acid, and linezolid [41,108].
MONITORING — Patients receiving daptomycin should be monitored for muscle pain or weakness, new or worsening peripheral neuropathy, and signs or symptoms of eosinophilic pneumonia. Routine laboratory monitoring includes baseline and weekly creatine phosphokinase (CPK), basic metabolic panel, and complete blood count. More frequent CPK monitoring (twice weekly) is warranted for patients with baseline renal impairment and/or patients on concomitant statin therapy. Daptomycin should be discontinued in patients with symptomatic myopathy and CPK ≥5 times the upper limit of normal (ULN; or ≥1000 units/L), or in asymptomatic patients with CPK ≥10 times the ULN (or ≥2000 units/L).
ADVERSE EFFECTS — The most important severe adverse effects of daptomycin include muscle toxicity (eg, myopathy/rhabdomyolysis) and eosinophilic pneumonia. Other severe adverse effects include drug reaction with eosinophilia and systemic symptoms (DRESS), tubulointerstitial nephritis, peripheral neuropathy, and neutropenia [109-111].
Less severe adverse effects include constipation, nausea, vomiting, and headache [112].
Myopathy and rhabdomyolysis — Daptomycin-induced myopathy has been described in 2 to 14 percent of patients receiving daptomycin [113] and can occur in patients with normal or abnormal baseline kidney function [114]. Rhabdomyolysis has been reported in up to 5 percent of treated patients receiving daptomycin [22,115-117].
Factors conferring increased risk for daptomycin-associated myopathy or rhabdomyolysis include [83,113,118]:
●Baseline renal impairment − Data on the risk for daptomycin toxicity in patients with renal impairment are limited and conflicting. In one retrospective study including 108 patients with renal impairment treated with daptomycin, a higher incidence of creatine phosphokinase (CPK) elevation was observed among those who received high-dose daptomycin (≥9 mg/kg) than among those who received standard dose (<9 mg/kg) (10.8 versus 1.6 percent); however, follow-up CPK levels were available for only 66 percent of patients [119]. In contrast, a cohort study including 50 patients with renal impairment treated with ≥7.5 mg/kg observed only one patient with CPK elevation [120].
●Concomitant statin administration − Concomitant administration of daptomycin with HMG-CoA reductase inhibitors (“statins”) may increase the risk of CPK elevation and myopathy. Patients receiving daptomycin in the setting of concomitant statin use warrant careful CPK monitoring. Issues related to temporary statin discontinuation are discussed below. (See 'Monitoring' above and 'Statins' below and "Statin muscle-related adverse events".)
In a case-control study, patients treated with daptomycin who developed myopathy (CPK above the upper limit of normal [ULN]) during treatment were matched with controls who were treated with daptomycin but did not develop myopathy; statin coadministration was an independent risk factor for myopathy (odds ratio 2.60) [113]. However, a number of retrospective studies have observed no increased risk of CPK elevation with concomitant statin use [121-126], including in the setting of high-dose daptomycin therapy (≥10 mg/kg/day) [77].
●Obesity − In patients with obesity, daptomycin has been associated with higher rates of CPK elevation, rhabdomyolysis, and drug discontinuation when dosed based on total body weight [83,113]. In obesity, daptomycin peak concentration and area under the curve values are increased [84,127], while the volume of distribution remains unchanged [84], resulting in a potential increase in daptomycin exposure [127,128].
Issues related to daptomycin dosing in patients with obesity are discussed above. (See 'Patients with obesity' above.)
Daptomycin-induced myopathy may develop with or without symptoms. In symptomatic patients, clinical manifestations range from mild myalgias (with or without mild weakness), to chronic myopathy with severe weakness, to massive rhabdomyolysis with acute renal failure [129-132]. In addition, patients with rhabdomyolysis may have dark urine (red to brown) due to myoglobinuria. (See "Drug-induced myopathies" and "Rhabdomyolysis: Clinical manifestations and diagnosis".)
Elevation in serum CPK concentration may occur in the presence or absence of symptoms. In one case-control study including 128 patients with daptomycin-associated myopathy, the mean duration of daptomycin administration before CPK elevation was 16.7 days (range 1 to 58 days) [113].
The diagnosis of daptomycin-induced myopathy is based on clinical manifestations and CPK elevation (at least five times the ULN). Management consists of drug discontinuation. Symptoms generally resolve within two to three days, although CPK elevation may persist up for to two weeks. (See "Drug-induced myopathies".)
The diagnosis of rhabdomyolysis is established based on CPK elevation in the setting of an acute neuromuscular illness and/or dark urine. Issues related to management of rhabdomyolysis are discussed further separately. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)
Patients on daptomycin should be monitored clinically for development of muscle pain or weakness and should undergo CPK monitoring during drug administration. For patients on statin therapy, issues related to consideration of temporary statin discontinuation during daptomycin therapy are discussed below. (See 'Monitoring' above and 'Statins' below.)
Daptomycin should be discontinued in patients with symptomatic myopathy (eg, weakness and pain) and an elevated CPK ≥5 times the ULN (or ≥1000 units/L) or in patients without symptoms with an elevated CPK ≥10 times the ULN (or ≥2000 units/L) [24].
Eosinophilic pneumonia — Daptomycin is one of the most common drugs implicated in drug-induced eosinophilic pneumonia [133]. The incidence may range between 1.7 and 4.8 percent [134,135]. Reported associated patient characteristics include male sex, baseline renal dysfunction, older age, presence of hypertension, and duration of treatment >2 weeks at symptom onset [134,136,137].
Overall, drug-induced eosinophilic pneumonia is rare. One retrospective review noted 228 cases were reported between 1990 and 2017, of which the authors reviewed 196; of these, 32 cases were attributed to daptomycin [133]. Between 2004 and 2010, the US Food and Drug Administration (FDA) identified six cases reported to its adverse events reporting system [138].
The pathophysiology is not well understood. It has been proposed that accumulation of daptomycin binding to pulmonary surfactant may cause cellular damage, oxidant injury, and lung epithelial inflammation. Alternatively, daptomycin may induce an allergic reaction causing the release of T lymphocytes, followed by interleukins and eosinophil migration [136,139-141]. It is unclear whether there is an association between the concentration of daptomycin (in serum, lung tissue, or epithelial lining fluid) and the likelihood of developing eosinophilic pneumonia.
Clinical data are conflicting regarding the correlation between daptomycin dose and risk of eosinophilic pneumonia. One 2016 systematic review identified no correlation [137]. In contrast, a 2021 retrospective study including 229 patients with osteoarticular infections identified a correlation among patients who received a total cumulative daptomycin dose >10 g (hazard ratio 5.3, 95% CI 1.1-24.6) [135]. In a 2022 retrospective review including 330 patients (of whom than 40 percent had body mass index >30 kg/m2), eosinophilic pneumonia occurred in 11.5 percent of patients after a primary course of daptomycin at a median of 26 days (range 2 to 60 days) and 16 percent of patients who received a second course of daptomycin at a median of 3 days (range 2 to 58 days) after re-exposure [142].
Clinical manifestations may include fever (57 to 100 percent), hypoxia (40 to 87 percent), and dyspnea (75 to 94 percent) [134,136,137]. Physical examination may demonstrate fine crackles on chest auscultation. Symptoms typically develop two to four weeks after initiation of daptomycin; however, some patients present subacutely with average time of five months between symptom onset to diagnosis [133,136,137]. (See "Idiopathic acute eosinophilic pneumonia" and "Chronic eosinophilic pneumonia".)
Chest radiography may be notable for pulmonary infiltrates or organizing pneumonia [143]. In one series including 49 cases, chest radiography demonstrated findings consistent with chronic eosinophilic pneumonia, including multiple subpleural reticulonodular infiltrates and diffuse bilateral pulmonary infiltrates with ground-glass opacities; however, pleural effusion, a feature of acute eosinophilic pneumonia, was also observed in two-thirds of cases [136].
Diagnostic evaluation may include bronchoscopy with bronchoalveolar lavage (BAL) for evaluation of eosinophils. However, in one series, BAL demonstrated >25 percent eosinophils (a criterion for the diagnosis of drug-induced eosinophilic pneumonia) in less than half of cases [136]. The role of peripheral blood eosinophilia to predict daptomycin-related eosinophilic pneumonia is uncertain. In a retrospective review including 330 patients, 81.5 percent developed peripheral eosinophilia during daptomycin treatment; the authors suggested that eosinophilia ≥5 percent may be a risk factor for the development of eosinophilic pneumonia and as a predictor that eosinophilic pneumonia may occur on re-exposure to daptomycin [142].
Management consists of supportive care (including mechanical ventilation in some cases), drug discontinuation, and systemic glucocorticoid therapy; in three series including 101 cases, all patients recovered [134,136,137].
DRUG INTERACTIONS
General principles — Daptomycin is neither an inducer nor an inhibitor of the hepatic CYP450 system.
Daptomycin may falsely prolong prothrombin time and elevate international normalized ratio, depending on daptomycin serum concentrations and the recombinant thromboplastin reagents used [144].
Additional information on drug interactions may be found using the drug interactions tool within UpToDate.
Statins — Administration of daptomycin with concomitant statin therapy has been variably reported to increase the risk of creatine phosphokinase and myopathy [145]. (See 'Myopathy and rhabdomyolysis' above.)
In general, we do not favor temporary statin discontinuation for patients treated with daptomycin doses ≤8 mg/kg/day. For patients receiving higher daptomycin doses (>8 mg/kg/day), particularly if the planned treatment duration is ≥14 days, we consider temporary statin discontinuation; the decision should be individualized based on clinical factors including cardiovascular risk.
SUMMARY
●Daptomycin is a lipopeptide antimicrobial with activity against gram-positive organisms, including antimicrobial-resistant pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. The primary mechanism of action is calcium-dependent depolarization of the bacterial cell membrane. The drug has a lipophilic tail that binds and inserts itself into the bacterial membrane, forming a channel causing efflux of intracellular potassium and subsequent cell membrane depolarization. (See 'Introduction' above and 'Mechanism of action' above.)
●Daptomycin may be used for (1) targeted treatment against gram-positive infections for situations in which standard therapy is not possible due to bacterial resistance or intolerance to other antibiotic agents or (2) empiric treatment of serious infection in patients known to be colonized with a resistant gram-positive organism. Daptomycin should never be used for treatment of bronchopneumonia, since pulmonary surfactant greatly reduces binding to the bacterial cell membrane and thereby preventing activity of the drug. (See 'General principles' above.)
●Daptomycin is administered parenterally. The half-life is approximately eight hours in adults and the drug is primarily excreted unchanged via the kidneys. Dose adjustment is required for renal impairment but not for mild to moderate hepatic dysfunction. (See 'Pharmacokinetics' above and 'Pharmacodynamics' above and 'Dosing' above.)
●Patients receiving daptomycin should be monitored for muscle pain or weakness, new or worsening peripheral neuropathy, and signs or symptoms of eosinophilic pneumonia. Routine laboratory monitoring includes baseline and weekly creatine phosphokinase (CPK), basic metabolic panel, and complete blood count. More frequent CPK monitoring (twice weekly) is warranted for patients with baseline renal impairment and/or patients on concomitant statin therapy. Daptomycin should be discontinued in patients with symptomatic myopathy and CPK ≥5 times the upper limit of normal (ULN; or ≥1000 units/L), or in asymptomatic patients with CPK ≥10 times the ULN (or ≥2000 units/L). (See 'Monitoring' above.)
●Important adverse effects of daptomycin include muscle toxicity (eg, myopathy/rhabdomyolysis) and eosinophilic pneumonia. Factors conferring increased risk for myopathy/rhabdomyolysis include baseline renal impairment, concomitant statin administration, and obesity. (See 'Adverse effects' above.)
●In general, we do not favor temporary statin discontinuation for patients treated with daptomycin doses ≤8 mg/kg/day. For patients receiving higher daptomycin doses (>8 mg/kg/day), particularly if the planned treatment duration is ≥14 days, we consider temporary statin discontinuation; the decision should be individualized based on clinical factors including cardiovascular risk. (See 'Statins' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
