Vol. VII, No. 4
  July/August 2004

  Amy Hirsch, Pharm.D.

 Return to
 Pharmacotherapy
 Update Index

Daptomycin (CubicinT):
A New Treatment Option
from Gram-Positive Infections

Introduction:
Over the past few decades, the incidence of infections due to resistant gram-positive organisms has increased. A report from the National Nosocomial Infections Surveillance (NNIS) system documented a 13% increase of methicillin-resistant Staphylococcus aureus (MRSA) isolated from Intensive Care Unit (ICU) patients in 2002 compared to the previous 5 years. In many institutions, the proportion of S. aureus isolates that are methicillin-resistant has reached 50%. Once thought to be primarily a nosocomial or health care-associated pathogen, recent reports of community-acquired MRSA have led to more concern. Due to the increased rates of resistance, vancomycin has become a mainstay of therapy for the empiric treatment of gram-positive infections. However, overuse of vancomycin may correlate with the increase of vancomycin-resistant enterococci (VRE) and more recently, reports of vancomycin-intermediate and vancomycin-resistant S. aureus (VISA and VRSA, respectively).^1,2

The emergence of the multidrug-resistant pathogens (e.g., MRSA, VRE, and VISA) is one reason for the development of newer antimicrobial agents with enhanced gram-positive activity. Quinupristin/dalfopristin (Synercid^®; King Pharmaceuticals), belonging to the streptogramin anti-microbial class, was approved in 1999 by the Food and Drug Administration (FDA). This agent has demonstrated in vitro and in vivo activity against streptococci, methicillin-susceptible S. aureus (MSSA), MRSA, and vancomycin-resistant Enterococcus faecium. While Enterococcus faecalis is intrinsically resistant to Synercid^®, reports of induced resistance in susceptible pathogens is rare. However, several factors have limited its use clinically including severe arthralgias and myalgias, availability in intravenous (IV) form only, and the requirement of multiple daily infusions.³

Linezolid (Zyvox^®; Pfizer) was the first oxazolidinone approved by the FDA. Linezolid has a spectrum of activity similar to Synercid^®, however, it has activity against E. faecalis. An additional advantage to linezolid is that it is not only available as an IV formulation, but also as an oral tablet. Even though linezolid has only been on the market since 2001, reports of resistance have emerged, and although rare, the development of further resistance is a concern. Furthermore, the incidence and degree of hematological side effects, most commonly thrombocytopenia, serve as the main limitation to its use.³

Daptomycin is a novel antimicrobial which was originally developed by Eli Lilly in the early 1980s. However, concerns about skeletal muscle toxicity led to voluntary suspension of clinical trials in 1991. Prompted by the perceived increase in need for new gram-positive agents, Cubist Pharmaceuticals licensed daptomycin from Eli Lilly in the late 1990s and began further investigations. These investigations led to an increased understanding of the pharmacokinetic and pharmacodynamic properties of the agent, resulting in dose modification and decreased skeletal muscle toxicity.⁴

Mechanism of Action: The exact mechanism of action for daptomycin has not been fully elucidated. It is known to bind to the cytoplasmic membrane of gram-positive bacteria via calcium-dependent binding. Once bound, the lipopeptide tail of the molecule is inserted into the bacterial cell membrane. This tail serves as an ion channel through which an efflux of potassium and, potentially other ions, can pass, thereby causing the bacterial cell to rapidly depolarize. Depolarization results in multiple failures in the DNA, RNA, and protein synthesis of the bacteria, ultimately resulting in bacterial cell death.^4,5 After exposure to daptomycin, bacteria are killed but not lysed and therefore, bacterial cell contents are contained. As a result, there should be minimal activation of the inflammatory cascade in response to bacterial cell wall components, and thus is a potential advantage of daptomycin over other gram-positive agents. The activity of daptomycin is dependent on the presence of calcium ions, while clinically not relevant, it does impact the conditions required for in vitro testing.

Spectrum of Activity:
Daptomycin has a spectrum of activity similar to quinupristin/dalfopristin and linezolid. Daptomycin is active against S. aureus, including MSSA and MRSA. In vitro data demonstrate that daptomycin may have activity against VISA and VRSA.⁶ Coagulase-negative staphylococci, including methicillin-sensitive and methicillin-resistant strains are also sensitive to daptomycin. Daptomycin has activity against Streptococcus spp. including penicillin-susceptible and penicillin-resistant strains of S. pneumoniae, beta-hemolytic streptococci, and Viridans streptococci. Daptomycin exhibits rapid bactericidal activity against Enterococcus spp., including vancomycin-susceptible and vancomycin-resistant strains of E. faecium and E. faecalis. In vitro activity of daptomycin has also been documented for Cornybacterium spp., Bacillus spp., and Listeria monocytogenes.^7-9

A few in vitro studies have shown daptomycin and oxacillin to be synergistic for MRSA.¹⁰ Other in vitro studies have shown synergy with daptomycin, rifampin, and ampicillin against VRE strains with high-level ampicillin resistance.¹¹ These data will need to be correlated with clinical studies.

Daptomycin has no activity against gram-negative bacteria, as it is unable to penetrate the outer membrane of these organisms.

Resistance has been induced in vitro in S. aureus isolates after serial passage, however, these daptomycin-resistant strains appear to be less virulent. The exact mechanism by which this resistance is conferred is not known; one proposed mechanism is reduced binding to the cytoplasmic membrane.^12-14 To date, there have been no reported clinical isolates resistant to daptomycin. In early trials, however, two isolates developed resistance when a dosing regimen of 3 mg/kg IV every 12 hours was utilized.¹⁵

Pharmacokinetics/Pharmacodynamics:
Daptomycin is only available in the IV form since oral dosage forms have poor bioavailability and are unable to achieve clinically effective concentrations. It exhibits linear pharmacokinetics at doses up to 6 mg/kg, but becomes slightly non-linear when doses approach 8 mg/kg. The lipophilic properties of daptomycin result in approximately 90% protein binding, which is independent of the drug concentration. The low volume of distribution for daptomycin (0.09 L/kg) is secondary to its inability to cross cell membranes and its higher affinity for plasma proteins compared to tissue binding.¹⁶ Animal data have demonstrated poor penetration of daptomycin into animal lung and epithelial lining fluid, which may account for decreased efficacy when daptomycin is used in the treatment of pulmonary infections, especially pneumonia. Human studies with daptomycin have shown good penetration into blister fluid and blood-clot tissue. Daptomycin does not appear to be an inhibitor or an inducer of the cytochrome P450 (CYP) isoenzyme system, however, it is not known at this time whether daptomycin is a substrate of this system.⁴ Approximately 80% of daptomycin is excreted via the kidneys, 66% of which is active drug, with the remainder eliminated in the feces. The elimination half-life of daptomycin is between 7-11 hours for patients with normal renal function. The half-life may be prolonged up to 30 hours in patients with impaired renal function (creatinine clearance [CrCl] < 30 mL/min) or those on conventional hemodialysis or peritoneal dialysis.^17,18 Therefore, dose adjustments are necessary for patients with renal impairment (see Indications and Dosing section). In vitro studies show daptomycin to be rapidly bactericidal for all gram-positive organisms, including drug-resistant strains. It is active in a concentration-dependent manner and has a significant post-antibiotic effect. Since skeletal muscle toxicity was thought to be related to high drug trough levels as a result of multiple daily doses, employing higher doses administered once daily will not only improve efficacy, but will also minimize toxicity.

Clinical Trials:
The FDA-approval of daptomycin for complicated skin and skin structure infections (cSSSIs) was based on the results of two pooled, multicenter, randomized, double-blinded studies. The types of cSSSIs in these trials included abscesses, wound infections, diabetic ulcers, and ulcers due to other causes. Patients were excluded if they were known to have bacteremia at the time of enrollment, required surgery, or had a concomitant infection at another site. The primary objective of these studies was to compare the clinical success rates between groups. Patients were randomized to receive daptomycin 4 mg/kg IV every 24 hours (n=534) or standard therapy (n=558) consisting of either a semi-synthetic penicillin (e.g., oxacillin or nafcillin) 4-12 gm/day IV in four divided doses or vancomycin 1 gm IV every 12 hours. Anaerobic and gram-negative coverage with metronidazole (Flagyl^®) and aztreonam (Azactam^®), respectively, could be added when appropriate. Among 902 clinically evaluable patients, clinical success rates were 83.4% and 84.2% for daptomycin and standard therapy groups, respectively. Sixty-three percent of daptomycin-treated patients required only 4-7 days of therapy compared to 33% of the comparator group. Adverse events did not differ between groups, including rates of creatine phosphokinase (CPK) elevations in both groups. Daptomycin was discontinued in two patients because of elevated CPK levels, however, both levels returned to normal at follow-up.^19,20 The authors concluded that the daptomycin was equivalent to its comparators. However, even though the study protocol permitted conversion to oral therapy, data regarding the number of patients converted, agents utilized, and outcomes, were not reported.

Daptomycin was also studied for the treatment of complicated urinary tract infections (UTIs). The multicenter, randomized, open-label study enrolled 68 patients. These patients received either daptomycin 4 mg/kg IV every 24 hours (n=29) or ciprofloxacin (Cipro^®) 400 mg IV every 12 hours (n=26). Microbiologic efficacy, the primary endpoint, was 83% for daptomycin and 85% for ciprofloxacin. The trial did not enroll enough patients to reach statistical power, and it is therefore difficult to draw meaningful conclusions from this study. It is unclear why daptomycin was comparable to ciprofloxacin in terms of efficacy, as daptomycin has no activity against gram-negative pathogens. Further study is warranted to evaluate the utility of daptomycin in the treatment of UTIs.¹⁵

Because of its in vitro activity against S. pneumoniae, a study was designed to compare daptomycin 4 mg/kg IV every 24 hours to ceftriaxone (Rocephin^®) 2 gm IV every 24 hours for patients hospitalized with community-acquired pneumonia (CAP). The success rate, which was the primary endpoint, was 78.8% for daptomycin and 86.6% for ceftriaxone. The lack of efficacy demonstrated by daptomycin may be due to its poor penetration into the lung and epithelial lining fluid. A second trial using daptomycin in the treatment of CAP was discontinued based on these results. Therefore, according to the product labeling, daptomycin should not be used for the treatment of pneumonia.¹⁵

Currently, trials are ongoing to evaluate the use of daptomycin in the treatment of S. aureus endocarditis or bacteremia. These trials are comparing daptomycin 6 mg/kg IV every 24 hours to standard therapy with vancomycin 1 gm IV every 12 hours or a semi-synthetic penicillin (e.g., oxacillin or nafcillin) 2 gm IV every 4 hours.²¹

A compassionate use study of daptomycin for the treatment of serious and life threatening gram-positive infections, in patients intolerant or refractory to other treatments, is also ongoing. In this study, daptomycin 6 mg/kg IV is being administered every 24 hours, and the duration of therapy is based on the site of infection with a maximum duration of 12 weeks.²¹

A study comparing daptomycin 6 mg/kg IV every 24 hours to linezolid 600 mg IV every 12 hours for the treatment of VRE was closed due to slow recruitment. The trial enrolled 50 patients and analysis of the data is pending.²¹

Adverse Reactions: In clinical trials, the most commonly reported adverse effects included constipation (6%), nausea (6%), and headache (5%). Insomnia, diarrhea, dermatitis, vomiting, and pruritis were also rarely reported.¹⁹

In the early trials conducted by Eli Lilly and Company, adverse skeletal muscle effects were noted including muscle weakness, myalgia, and elevations in CPK. Later studies conducted in animals demonstrated that muscle degeneration was the result of inflammation. The toxicities appeared to correlate with the frequency of the dosing interval, thus leading to the conclusion that elevated trough levels are a predisposing factor for this toxicity. Based on these findings and an increased understanding of the concentration-dependent activity of daptomycin, the dosing scheme was changed to 4-6 mg/kg IV every 24 hours, thus potentially increasing efficacy by maximizing the peak minimum inhibitory concentration ratio and decreasing toxicity by lowering trough levels. In recent clinical trials utilizing daptomycin doses of 4-6 mg/kg IV every 24 hours, the incidence of elevations in CPK did not differ significantly from comparators, 3.4% vs. 3.6%, respectively.¹⁹ It is, however, still recommended to monitor for signs and symptoms of muscle toxicity and check CPK levels weekly in patients receiving daptomycin. According to the product labeling, daptomycin should be discontinued if CPK levels reach 5X the upper limit of normal (ULN) in symptomatic patients or 10X ULN in asymptomatic patients.^{20, 22}

Drug Interactions: Because daptomycin is not an inducer or inhibitor of CYP450, there are minimal drug-drug interactions. A pharmacokinetic study, involving six healthy males, evaluated the levels of daptomycin when it was administered concurrently with tobramycin.^4,20 The study reported a slight decrease in the C_max and AUC_24h for daptomycin and lower tobramycin levels, however, these differences were not significant. Although reported in the product labeling, this interaction is not thought to be clinically significant. In other small studies involving healthy volunteers, no drug interactions were noted when warfarin (Coumadin^®), probenecid, aztreonam (Azactam^®), or simvastatin (Zocor^®) were coadministered with daptomycin.²⁰ Despite the lack of pharmacokinetic interaction with HMG-CoA reductase inhibitors ("statins"), it is recommended to temporarily discontinue these agents or closely monitor patients receiving HMG-CoA reductase inhibitors and daptomycin because of the potential for additive muscle toxicity.²⁰

Indications and Dosing: The dosing recommendations for the FDA-approved indications are listed in Table 1. Trials are still underway utilizing higher daily doses of daptomycin for the treatment of bacteremia, endocarditis, or VRE infections and are provided in Table 2. Little information is available regarding dosing in obese patients, however, based on pharmacokinetic properties, dosing based on an adjusted body weight is probably sufficient. Renal dose adjustments are necessary when the CrCl falls below 30 mL/min and are listed in Table 3.

Cost:
The Cleveland Clinic cost of daptomycin, linezolid, and quinupristin/dalfopristin are listed in Table 4.

Formulary Restrictions:
Currently, at The Cleveland Clinic Foundation, daptomycin is restricted to the Department of Infectious Diseases for the treatment of VRE and MRSA infections in patients who are intolerant to or have failed vancomycin therapy.

Conclusion:
Daptomycin is a new addition to the armamentarium of agents available for the treatment of resistant gram-positive infections. Its rapid bactericidal activity, once-daily dosing, and safety profile make it an attractive alternative. A proven agent for the treatment of cSSSIs, the promise in daptomycin is if clinical trials will demonstrate its effectiveness in the treatment of more severe infections such as bloodstream infections and endocarditis.

References:

1. NNIS system (authors). National Nosocomial Infections Surveillance System Report. Am J Infect Control 2003;31:481-98.
2. Anon. Brief report: Vancomycin-resistant Staphylococcus aureus. MMWR Weekly 2004;53:322-23.
3. Eliopoulous GM, Quinupristin-dalfopristin and linezolid: Evidence and opinion. Clin Infect Dis 2003;36:473-81.
4. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis 2004;38:994-1000.
5. Silverman JA, Perlmutter NG, Shapiro HM. Correlation of daptomycin bactericidal activity and membrane depolarization in staphylococcus aureus. Antimicrob Agents Chemother 2003;47:2538-44.
6. Howe RA, Noel AR, Tomaselli S, Bowker KE, Walsh TR, Macgowan AP. Killing activity of daptomycin against vancomycin intermediate staphylococcus aureus (VISA) and hetero-VISA. Abstract C1-1641 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Illinois.
7. Rybak MJ, Hershberger E, Moldovan T, Grucz RG. In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against staphylococci and enterococci, including vancomycin-intermediate and -resistant strains. Antimicrob Agents Chemother 2000;44:1062-6.
8. Wise R , Andrews JM, and Ashby JP. Activity of daptomycin against gram-positive pathogens; a comparison with other agents and the determination of a tentative breakpoint. J Antimicrob Chemo 2000;46:563-7.
9. Streit JM, Jones RN, Sader HS. Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms. J Antimicrob Chemother 2004;53:669-74.
10. Rand KH and Houch H. Daptomycin synergy with oxacillin against methicillin resistant Staphylococcus aureus. Abstract C-091. 103rd Annual Meeting of American Society for Microbiology. May 18-22, 2003; Washington, DC.
11. Rand KH and Houck H. Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci. J Antimicrob Chemother 2004;53(3):530-2.
12. Silverman JA, Oliver N, Andrew T, Tongchuani L. Resistance studies with daptomycin. Antimicrob Agents Chemother 2001;45:1799-1802.
13. Silverman JA. Mode of action and mechanisms of resistance to the lipopeptide daptomycin. Abstract 615. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. September 27-30, 2002; San Diego, California.
14. Kaatz GW, Seo SM. Analysis of the mechanism(s) of daptomycin resistance in Staphylococcus aureus. 42nd Interscience Conference of Antimicrobial Agents and Chemotherapy; December 16-19, 2002; Chicago, Illinois.
15. Daptomycin Webpage [Resource on the World Wide Web]. URL: http://www.daptomycin.com. Available from the Internet. Accessed 2003 March 17.[Abstract]
16. Dvorchik B, Brazier D, DeBruin M, Arbeit R. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003;47:1318-23.
17. Dvorchik B, Sica D, and Gehr T. Pharmacokinetics (PK) and safety of single-dose daptomycin in subjects with graded renal insufficiency and end-stage renal disease (ESRD). Abstract A-1387. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2002;Chicago, Illinois.
18. Sica DA, Gehr T, and Dvorchik BH. Pharmacokinetics and safety of single-dose daptomycin in subjects with graded renal insufficiency and end-stage renal disease. Abstract A-1387. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. September 27-30, 2002; San Diego, California.
19. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI, and the Daptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004;38:1673-81.
20. CubicinTM package insert. Lexington, MA. Cubist Pharmaceuticals, Inc; 2003 September.
21. Cubist Pharmaceuticals, Inc., Customer Service (personal communications). July 12, 2004.
22. Tally FP and DeBruin MF. Development of daptomycin for gram-positive infections. J Antimicrob Chemo 2000;46:523-6.
23. Keys TF, Long JK, Goldman MP, eds. Guidelines for Antimicrobial Usage. 2004-2005. Caddo (OK); Professional Communications, Inc.; 2004.