doi:10.1016/j.ccc.2007.12 by Jose Vallejo

Crit Care Clin 24 (2008) 349–363

The Use of Daptomycin for Staphylococcus Aureus Infections in Critical Care Medicine Jeﬀrey Alder, PhD Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA 02421, USA

Staphylococcus aureus infection constitutes a tremendous burden on hospitals in the United States, accounting for nearly 300,000 inpatients per year (0.8% of all hospital inpatients) during 2000 and 2001 [1]. S aureus infections are commonly associated with complicated skin and skin-structure infections (cSSSIs) and bacteremia, but are also found in pulmonary infections. S aureus is a severe pathogen with multiple toxins and virulence factors [2]. The incidence of methicillin-resistant S aureus (MRSA) has grown dramatically in recent years. In 2004, MRSA accounted for 63% of Staphylococcus sp infections in health care settings, up from 22% in 1995 and 2% in 1974 [3]. Among patients in intensive care units, the rate of MRSA infection as a proportion of overall S aureus infection was more than 60% in 2004, up from less than 40% in 1995 [4]. S aureus is a leading cause of both bacteremia and endocarditis [5–7]. S aureus bacteremia is associated with serious complications, including endocarditis, in 30% to 40% of cases [8]. Treatment options for bacteremia and endocarditis caused by S aureus, particularly MRSA, are limited. Vancomycin, the standard therapy for bloodstream infections attributable to MRSA, has been associated with suboptimal outcomes [9]. Reports of clinical failure and decreased susceptibility to vancomycin highlight the challenges of therapy [10,11]. Treatment failures associated with vancomycin heteroresistance to S aureus demonstrate the challenges of therapy [12]. New agents for the treatment of S aureus bacteremia and endocarditis are needed.

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Current antibiotic therapy options for critical care S aureus infections Vancomycin, which is efficacious against a broad range of gram-positive organisms, has been available in clinical practice since the mid-1970s [13]. Its use increased notably in the mid-1980s, partly because it became available in an oral formulation for Clostridium difficile infection. The number of prescriptions of vancomycin continued to increase for another decade before concerns about vancomycin-resistant bacteria led to efforts aimed at reducing its use [13]. The emergence of multiple new resistant S aureus strains, including heteroresistant glycopeptide–intermediate susceptible S aureus (hGISA), glycopeptide (vancomycin) intermediate susceptible S aureus (GISA, VISA), and vancomycin-resistant S aureus (VRSA), highlights the potential decreasing potency of vancomycin against S aureus. Increasing tolerance of S aureus to the relatively slow bactericidal activity of vancomycin further demonstrates the potential erosion of vancomycin efficacy [14–16]. Outcomes with vancomycin treatment may be adversely affected by these multiple factors [11]. The limitations of vancomycin’s clinical efficacy are illustrated by two meta-analyses of mortality risk in patients with MRSA compared with patients with methicillin-sensitive S aureus (MSSA). Both meta-analyses found a higher rate of mortality in patients with MRSA, even when correcting for the severity of infection and other contributing factors. The study investigators suggested that the efficacy of vancomycin for the treatment of MRSA might be a contributing factor to the higher mortality rate versus MSSA infections, which were typically treated with a semisynthetic penicillin [17,18]. The limitations of treatment with vancomycin have also been observed in MSSA. Several trials comparing vancomycin to semisynthetic penicillins, such as nafcillin, have found vancomycin to be inferior in efficacy as MSSA therapy (Fig. 1) [19–25]. It has been suggested that use of b-lactam agents might be preferable to vancomycin in the treatment of MSSA [18,26]. Aggressive dosing strategies for vancomycin to increase trough levels may not offer an advantage over traditional dosing strategies [27]. Taken together, these data highlight the limitations of vancomycin-based treatment and the need to develop newer, more efficacious therapies for gram-positive infections. The side effects most commonly associated with vancomycin use include nephrotoxicity, neutropenia, ‘‘red man syndrome’’ (a rash involving the face, neck, and upper torso), phlebitis, fever, and chills [28,29]. Patients receiving vancomycin commonly require measurements of serum drug concentrations, evaluations of white blood cells counts, and monitoring for renal toxicity. Monitoring and treating patients for vancomycin-related side effects, especially in the case of nephrotoxicity, can add substantially to overall treatment costs [29,30]. Recent data from a study by Von Drygalski and colleagues [31] have increased concerns of potentially serious adverse events with vancomycin related to production of antiplatelet antibodies. This study found that among patients with vancomycin-dependent

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MSSA Bacteremia (endocarditis excluded)

MRSA Bacteremia (endocarditis excluded)

15/70 Nafcillin Vancomycin

13/70

Vancomycin

Percent

8/70

8/83

5/70 5/83

1/18

0/18

Persistent Persistent >3 days >7 days

0/18

Relapse Bacteriologic failure

4/83

0 Persistent Persistent >3 days >7 days

Relapse Bacteriologic failure

Fig. 1. Eﬃcacy of nafcillin versus vancomycin in preventing persistent bacteremia. Persistence of bacteremia and failure was associated with vancomycin therapy.

antibodies, there was a mean reduction of 93% in platelet levels compared with the prevancomycin treatment baseline. Severe bleeding was seen in 10% of patients, and several patients experienced acute and severe thrombocytopenia within 24 hours of vancomycin infusion [31]. Linezolid Linezolid is the first oxazolidinone approved for use. Linezolid inhibits the initiation of protein synthesis at the 50S ribosome [32]. The Food and Drug Administration has approved linezolid for the treatment of cSSSIs and nosocomial pneumonia caused by susceptible pathogens, including MRSA. Development of resistance has been rare in S aureus. Linezolid is a bacteristatic drug. Several retrospective analyses of pooled data from randomized trials have compared linezolid with vancomycin in patients with MRSA infection. A post hoc analysis of two studies of patients with MRSA nosocomial pneumonia found that patients treated with linezolid had survival rates that were significantly higher than those of patients treated with vancomycin, possibly because of better lung penetration [33]. However, great care must be exercised when evaluating post hoc analysis because of the potential for ‘‘data mining’’ for favorable outcomes. While linezolid has demonstrated efficacy in the treatment of MRSA infections, concerns about safety often limit its use. The association of linezolid with serotonin toxicity and thrombocytopenia is salient [34,35]. Linezolid exhibits reversible inhibition of monoamine oxidase and can induce toxicity when used in combination with agents that have serotonergic

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activity. With monitoring, linezolid may be used concomitantly with selective serotonin re-uptake inhibitors. The occurrence of thrombocytopenia and associated risk factors are not yet well understood. Patients with renal insuﬃciency or those undergoing prolonged therapy may be at higher risk of developing this toxicity [36]. Daptomycin Daptomycin is the ﬁrst of a new class of antimicrobials known as the lipopeptides. Daptomycin has broad and potent activity against gram-positive bacteria, including isolates resistant to other antibiotic agents, such as vancomycin, linezolid, and penicillin (Table 1). Daptomycin has potency against hGISA and VRSA with minimum inhibitory concentration (MIC) Table 1 In vitro potency of daptomycin, vancomycin, and linezolid against bacterial isolates collected in North American hospitals from 2004 to 2006 Bacteria/agent

Minimum inhibitory Minimum inhibitory Percent concentration of 50% concentration of 90% susceptible

MSSA (N ¼ 5659) Daptomycin 0.25 Linezolid 2 Vancomycin 1 MRSA (N ¼ 5659) Daptomycin 0.25 Linezolid 2 Vancomycin 1 Enterococcus faecalis vancomycin susceptible (N ¼ 2444) Daptomycin 0.5 Linezolid 1 Vancomycin 1 Enterococcus faecalis vancomycin resistant (N ¼ 80) Daptomycin 0.5 Linezolid 1 Vancomycin O16 Enterococcus faecalis vancomycin susceptible (N ¼ 385) Daptomycin 2 Linezolid 1 Vancomycin 1 Enterococcus faecalis vancomycin resistant (N ¼ 713) Daptomycin 2 Linezolid 1 Vancomycin O16 Beta-hemolytic streptococci (N ¼ 1223) Daptomycin %0.06 Linezolid 1 Vancomycin 0.5

0.5 2 1

O99.9 100 100

0.5 2 1

O99.9 O99.9 O99.9

1 2 2

O99.9 99.8 96.8

1 2 O16

100 97.5 0

4 2 1

99.7 99.5 100

4 2 O16

99.9 97.9 0

0.25 1 0.5

100 100 100

Data from Sader H, Fritsch T, Jones RN. Antimicrobial susceptibility of gram-positive organisms isolated from North American hospitals: results from the daptomycin surveillance program, 2004–2006. Infectious Diseases Society America, 2007 Annual Conference, poster # 477.

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values of 1 mg/mL or less. Against the extremely rare GISA (vancomycin MIC: 8 or 16 mg/mL), the MIC range for daptomycin increased to 0.5 to 4 mg/mL [37]. Daptomycin maintained bactericidal activity against all S aureus isolates, including wild-type, hGISA, and GISA [37]. The mechanism of action of daptomycin (Fig. 2) involves disruption of the bacterial cytoplasmic membrane, resulting in rapid depolarization [38,39]. The depolarization of the membrane causes the immediate cessation of the biosynthesis of RNA, DNA, and proteins. This cessation rapidly induces cell death [40]. Daptomycin has demonstrated more rapid in vivo bactericidal activity than vancomycin or linezolid against S aureus in a mouse model of bacteremia (Fig. 3) [41]. Daptomycin at a dosage of 4 mg/kg intravenously once daily is indicated for the treatment of cSSSIs caused by MRSA and MSSA, as well as Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only) [42]. Daptomycin activity has been observed in all clinically relevant gram-positive pathogens [40]. Most importantly, daptomycin at a dosage of 6 mg/kg intravenously once daily is also indicated for treatment of S aureus bacteremia (both MRSA and MSSA) and right-sided endocarditis. Daptomycin is not indicated for the treatment of pneumonia [42]. The primary dose-limiting toxicity is a reversible muscle myopathy, which can be monitored by elevations of serum creatinine phosphokinase (CPK). Because daptomycin is excreted primarily via the kidney, a modiďŹ cation of dosage is required in patients with renal insuďŹ&#x192;ciency. Among patients with creatinine clearance of 30 mL/min or less, the recommended dosing interval is once every 48 hours at 4 mg/kg for cSSSI or 6 mg/kg for bacteremia and right-sided endocarditis [42]. The mean half-life of daptomycin is between 8 and 9 hours, and it is associated with linear pharmacokinetics and a limited degree of accumulation

Fig. 2. Daptomycin mechanism of action. Calcium-dependent binding leads to depolarization and cessation of bacterial DNA, RNA, and protein synthesis, leading to rapid bactericidal activity.

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Fig. 3. Luminescent images of MRSA (Xen-1) peritonitis in neutropenic mice. Groups of mice (n ¼ 5 per group) were rendered neutropenic before infection. Luminescent images are shown just before dosing (0 hr, row 1), 2 hours after dosing (2 hr, row 2), and 4 hours after dosing (4 hr, row 3) for mice treated with 10 mL/kg saline subcutaneous (ﬁrst column), 50 mg/kg daptomycin subcutaneous (second column), 100 mg/kg vancomycin subcutaneous (third column), or 100 mg/kg linezolid via gavage by mouth (fourth column). Note the dramatic decline in luminescence for the daptomycin-treated mice 4 hours after dosing (row 3, column 2). Note the dramatic increase in red luminescence, representing the highest levels of ﬂux, in the saline-treated mice 2 and 4 hours postdosing. (Data from Mortin LI, Li T, Van Praagh AD, et al. Rapid bactericidal activity of daptomycin against methicillin-resistant and methicillin-susceptible Staphylococcus aureus peritonitis in mice as measured with bioluminescent bacteria. Antimicrob Agents Chemother 2007;51(5):1787–94.)

in healthy patients receiving doses of 6 mg/kg or less [40]. The half-life of daptomycin increases to approximately 11 hours in patients with mild renal impairment (creatinine clearance 50–80 mL/min) and to approximately 15 hours in patients with moderate renal impairment (creatinine clearance 30–50 mL/min). For patients with severe renal impairment (creatinine clearance !30 mL/min), the half-life increases to more than 24 hours [40]. Daptomycin clinical data Treatment of complicated skin and skin-structure infections Daptomycin was ﬁrst approved for the treatment of cSSSIs in 2003. Two randomized, multicenter, investigator-blinded trials were undertaken to determine the safety and eﬃcacy of daptomycin for the treatment of cSSSIs in 1092 patients (ages 18 to 85) [43]. The daptomycin group received

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intravenous daptomycin (4 mg/kg once a day). The comparator group received treatment with either intravenous vancomycin (1 g every 12 hours) or an intravenous penicillinase-resistant penicillin (eg, cloxacillin, nafcillin, oxacillin, or flucoxacillin) 4 to 12 g once a day, depending upon the risk of MRSA infection. The primary outcome of this study was clinical success defined as the resolution of symptoms with no need for further antibiotic therapy. Proof of cure was assessed 6 to 20 days after cessation of therapy [43]. Daptomycin produced similar success for the treatment of cSSSIs as in the two comparator groups. Among patients with MSSA infection, the treatment success rate for daptomycin was 85.9% compared with 87.0% for patients receiving comparator treatment. Patients suffering from MRSA infection experienced a 75.0% treatment success rate if they received daptomycin therapy compared with a 69.4% treatment success rate if they received the comparator drug (vancomycin) [43]. There were no statistically significant differences in rates of treatment success. The safety profile of daptomycin was statistically similar to that of the comparator treatments. Most adverse events were judged to be mild to moderate and were in most cases unrelated to the study medications [43]. Elevations of serum CPK were similar between the two groups, with 2.8% of the daptomycin group experiencing a CPK elevation compared with 1.8% of patients in the comparator group [43]. Treatment of bacteremia and endocarditis Daptomycin was studied in the largest ever phase-three bacteremia and endocarditis trial. This randomized, open-label, noninferiority trial compared daptomycin with standard therapy in 246 patients with positive blood cultures for S aureus bacteremia (both MSSA and MRSA) with or without endocarditis [9]. Patients in the study were randomized to receive either intravenous daptomycin 6 mg/kg monotherapy once daily compared with dual therapy with either intravenous vancomycin 1 g every 12 hours or an intravenous penicillinase-resistant penicillin six times daily, both with intravenous gentamicin 1 mg/kg three times daily for the first 4 days of treatment [9]. The primary end point was treatment success measured 42 days after the cessation of therapy. Results from the trial established the efficacy of daptomycin compared with the dual therapy comparator treatment. The overall treatment success rate for patients treated with daptomycin monotherapy (n ¼ 120) was 44.2% compared with 41.7% for dual therapy with comparator (n ¼ 115) [9]. There was a trend toward higher efficacy in the treatment of MRSA with daptomycin (44.4% treatment success) compared with vancomycin plus gentamicin therapy (31.8%), which was not statistically significant (95% CI, 7.4, 32.6). Treatment success for MSSA was similar between the two groups, with daptomycin achieving a 44.6% success rate compared with 48.6% for standard therapy (95% CI, 20.3, 12.3) (Table 2) [9].

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Table 2 Daptomycin and comparator success at the test of cure in the intention-to-treat and per-protocol populations overall and by prespeciﬁed diagnostic criteria in treatment of bacteremia and endocarditis Daptomycin n/N (%)

Comparator n/N (%)

Diﬀerences in success rates (95% CI)

Intention-to-treat success 53/120 (44.2%) 48/115 (41.7%) 2.4% Per-protocol success 43/79 (54.4%) 32/60 (53.3%) 1.1% Success according to methicillin susceptibility of Staphylococcus aureus MSSA 33/74 (44.6%) 34/70 (48.6%) 4.0 MRSA 20/45 (44.4%) 14/44 (31.8%) 12.6% Success according to ﬁnal diagnosis (intention-to-treat population) Uncomplicated bacteremia 18/32 (56.3%) 16/29 (55.2%) 1.1% Complicated bacteremia 26/60 (43.3%) 23/61 (37.7%) 5.6% Uncomplicated right-sided 3/6 (50.0%) 1/4 (25.0%) 25.0% endocarditis Complicated right-sided 5/13 (38.5%) 6/12 (50.0%) 11.5% endocarditis Left-sided endocarditis 1/9 (11.1%) 2/9 (22.2%) 11.1%

( 10.2, 15.1) ( 15.6, 17.8) ( 20.3, 12.3) ( 7.4, 32.6) ( 23.9, 26.0) ( 11.8, 23.1) ( 33.3, 83.3) ( 50.3, 27.2) ( 45.2, 22.9)

Data from Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355(7):653–65.

A significantly larger proportion of patients receiving comparator therapies of semi-synthetic penicillin plus gentamicin or vancomycin plus gentamicin (26.3%) experienced a clinically significant decrease in renal function during the course of treatment compared with those receiving daptomycin (11.0%; P ¼ .004). The decrease in renal function in these patients may have been related to the use of gentamicin in the comparator-treated patients. Adverse events involving musculoskeletal and connective tissue were generally similar between treatment groups, although arthralgia was significantly more common in the standard therapy group (11.2%) compared with the daptomycin group (3.3%; P ¼ .02) [9]. There was a significantly greater incidence of CPK elevation in the daptomycin group (6.7%) than in the comparator group (0.9%; P ¼ .04), which led to the withdrawal of 3 out of the 120 (2.5%) daptomycin-treated patients [9]. Adverse events related to the peripheral nervous system occurred significantly more frequently in daptomycin-treated patients compared with those in the comparator group (9.2% versus 1.7%; P ¼ .02). All neurologic events in both groups were evaluated as mild to moderate in severity and resolved during continued treatment [9]. The overall rate of other adverse events was generally similar between the two treatment groups. In summary, the results of the bacteremia and endocarditis trial demonstrated that daptomycin is an effective alternative for the treatment of S aureus bacteremia, including right-sided endocarditis. In addition, the results showed that the use of daptomycin is associated with a lower rate of adverse renal events than the comparator combination therapies that included gentamicin.

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Case study reports also document the efficacy of daptomycin in treating bacteremia and endocarditis [44–46]. A recent systematic review of daptomycin treatment for endocarditis and bacteremia conducted by Falagas and colleagues [47] observed daptomycin to be safe and effective in both short- and longer-term treatment of these conditions. Recent case series data have demonstrated the potential utility of daptomycin as a community-based treatment of bacteremia and endocarditis [48], as well as efficacy in treatment of left-sided endocarditis [49]. Daptomycin was also effective in treatment of community-associated MRSA bacteremia [50]. Treatment of other infection types A small retrospective analysis of patients with bone and joint infections observed successful treatment using daptomycin for eight out of nine patients, including six with osteomyelitis [51]. Daptomycin efficacy was demonstrated in a recurrent MRSA joint infection that was unresponsive to vancomycin [52]. Recent case-series data also demonstrated the efficacy of daptomycin in treatment of prosthetic joint infections [53] and community-associated MRSA osteomyelitis [54]. Treatment of chronic MRSA experimental osteomyelitis using in vivo studies in rat models indicate that daptomycin has significant efficacy and was similar to vancomycin treatment [55]. These data suggest the potential efficacy of daptomycin for the treatment of persistent bone and joint infections. Case study data have also shown that daptomycin demonstrates efficacy in treating infections associated with indwelling medical devices. One case study involved a 33-year-old woman who experienced MSSA acute endocarditis resulting from the use of a peripherally inserted central catheter [56]. Treatment with cefazolin was initiated but ultimately failed. It was replaced with daptomycin therapy, which cured the patient. Another case study involved a 65year-old man with S aureus acute bacterial endocarditis associated with a pacemaker and persistent S aureus bacteremia resulting from a coronary stent. Prolonged high-dose treatment with daptomycin was administered and effectively produced a cure without toxicity to the patient [57]. Daptomycin should not be used to treat pulmonary infections. Data from two clinical trials have found daptomycin to be less effective than ceftriaxone in the treatment of gram-positive bacterial community-acquired pneumonia. Researchers have found that daptomycin binds to and is inhibited by pulmonary surfactant [58]. Animal model data suggest the potential efficacy of daptomycin in treating meningitis. An experimental rabbit meningitis model found daptomycin to be superior to vancomycin in both in vivo bactericidal activity and in vitro killing curve assays against S aureus [59]. A separate study, also using an experimental rabbit meningitis model, found daptomycin to be highly efficacious and superior to vancomycin or ceftriaxone therapy against penicillin-resistant and penicillin- and quinolone-resistant pneumococci [60].

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Value of bactericidal antibiotics in critical care medicine The potential value of bactericidal antibiotics over static agents has been advanced in both bacteremia and meningitis. In these critical care infections, the speed of response may play an important role in successful outcomes. The issue of bactericidal versus static antibiotics for bacteremia and endocarditis treatment regimens remains unresolved. Gentamicin, a bactericidal antibiotic, is commonly added to vancomycin to increase the bactericidal activity for treatment of MRSA bacteremia and endocarditis. However, the value of gentamicin is open to question as therapy is associated with an increase in renal toxicity [9]. For treatment of enterococcal endocarditis, the addition of an aminoglycoside, such as gentamicin, is necessary to produce bactericidal activity [61–63]. In combination, penicillin and aminoglycoside treatment provided a synergistic therapeutic effect that has been observed to produce improved cure rates compared with penicillin alone [5,64], demonstrating the potential value of bactericidal activity in endocarditis. Two older studies in streptococcus pneumoniae meningitis demonstrated that a bactericidal antibiotic alone (penicillin or ampicillin) produced a lower mortality rate than combination therapy between a static agent (chlortetracycline or chlortetracycline) combined with the bactericidal agent [65,66]. Both studies found that the bactericidal antibiotic alone resulted in a lower mortality rate compared with treatment with combination therapy. In these trials, the static agent may have reduced the bactericidal activity of the bactericidal agent. The role of bactericidal activity in the treatment of osteomyelitis remains unidentified, but has been an area of some speculation, with data suggesting that a bactericidal agent is required for effective treatment [67]. Suppression of bacterial triggering of host inflammatory response Bactericidal antibiotics often cause the rapid lysis of killed bacteria. It may be that lysis of bacteria could lead to a host inflammatory response directed against internal bacterial components, with potentially adverse effects on patient outcome [61]. The risk of provoking an inflammatory response in the treatment of S aureus caused by triggering inflammatory mediators, such as tumor necrosis factor (TNF) and nitric oxide, remains a potential drawback in many bactericidal antibiotic treatments [2]. Although daptomycin is a bactericidal agent, it does not induce lysis in the process of causing grampositive cell death. Electron microscopy studies demonstrated that treatment of S aureus with four times the MIC of daptomycin resulted in bacterial cell death, but the bacterial cell structure remained otherwise intact for up to 24 hours after the bactericidal activity of daptomycin [68]. Recent in vitro data using six different isolates of S aureus found that bactericidal concentrations of daptomycin resulted in significantly less TNF response and reduced the accumulation of inducible nitric oxide, compared with

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either vancomycin or oxacillin [2]. The value of bactericidal activity without lysis is supported by results from an experimental rat pneumococcal meningitis model in which both daptomycin and ceftriaxone treatment cleared the cerebrospinal fluid of infection. However, daptomycin was also associated with a decrease in inflammation, no cortical damage, and less release of inflammatory markers compared with ceftriaxone treatment, which was associated with inflammation and cortical damage [69]. Lower release of pro-inflammatory bacterial compounds has been shown to be associated with reduced mortality in animal models of pneumococcal meningitis [70]. Activity in biofilms The capacity for bacteria to produce biofilm, a matrix of microbial cells embedded in polysaccharide material, has resulted in a further challenge still to the efficacy of some antibiotic agents [71]. Some MRSA agents have limited efficacy in eradicating staphylococci embedded within a biofilm [72].

Summary Daptomycin should be considered as an alternative for use in appropriate critical care infections caused by gram-positive bacteria. The current indications for daptomycin include treatment of cSSSIs caused by gram-positive bacteria, as well as MRSA and MSSA bacteremia and right-sided endocarditis. The rationale for use of daptomycin in the critical care setting is further supported by case study data demonstrating utility in the treatment of left-sided endocarditis, osteomyelitis, and complicated persistent bacteremic infections associated with indwelling medical devices. Daptomycin also demonstrates rapid bactericidal activity in vitro and in animal models, causing a more rapid clearance of bacteria. The efficacy that daptomycin exhibits in many serious infections is optimal for patients in the critical care setting who should benefit from rapid and effective intervention.

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