Efficacy and safety of daptomycin in the treatment of Gram-positive catheter-related bloodstream infections in cancer patients

doi:10.1016/j.ijantimicag.2010.03.015

International Journal of Antimicrobial Agents

Volume 36, Issue 2, August 2010, Pages 182-186

https://doi.org/10.1016/j.ijantimicag.2010.03.015 Get rights and content

Abstract

Excessive vancomycin usage has contributed to the emergence of vancomycin-resistant enterococci, and a high vancomycin minimal inhibitory concentration (MIC) >1.0 μg/mL has been associated with poor outcome in patients with meticillin-resistant Staphylococcus aureus (MRSA) infection. In view of these limitations, there is a need for an alternative agent. We evaluated the clinical efficacy and safety of daptomycin given as an alternative agent in the treatment of Gram-positive catheter-related bloodstream infections (CRBSIs) in cancer patients. Between June 2006 and March 2008, 40 patients with probable or definite CRBSI caused by Gram-positive organisms were prospectively enrolled to receive daptomycin intravenous 6 mg/kg/day for up to 4 weeks. In addition, 40 historical matched control patients treated with vancomycin were retrospectively identified. The control group was matched based on underlying disease, organism and neutropenic status. The daptomycin group was comparable with the vancomycin group in terms of neutropenia rate, complications, adverse events, length of hospital stay and death. However, more patients in the daptomycin group achieved symptom resolution at 48 h compared with the vancomycin group (76% vs. 53%; P = 0.04). Similarly, more patients in the daptomycin group achieved microbiological eradication at 48 h compared with the vancomycin group (78% vs. 34%; P < 0.001). Although not significant, nephrotoxicity was almost three-fold lower in the daptomycin group. The overall response was significantly better for daptomycin compared with vancomycin (68% vs. 32%; P = 0.003). In conclusion, compared with vancomycin, daptomycin treatment of Gram-positive CRBSI in cancer patients was significantly associated with earlier clinical and microbiological response as well as improved overall response.

Introduction

Gram-positive bacteria represent a leading cause of catheter-related bloodstream infection (CRBSI) in cancer patients [1].

Vancomycin is considered the agent of choice for the treatment of resistant Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) infections [2]. However, its excessive use has contributed to the emergence of vancomycin-resistant enterococci (VRE), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) [3]. In addition, vancomycin minimal inhibitory concentrations (MICs) >1.0 μg/mL have been associated with poor outcome in patients with MRSA infection [4]. Furthermore, because vancomycin has been shown to be ineffective in eradicating Gram-positive organisms embedded in the biofilm of infected central venous catheters (CVCs) in vitro, concerns have been raised as to whether vancomycin is the appropriate antibiotic for the treatment of CRBSIs [5].

Considering these limitations, there is a need for alternative agents. Daptomycin is a semisynthetic lipopeptide antibiotic that is active against various Gram-positive bacteria. Data from our laboratory showed that daptomycin is significantly more effective than vancomycin in eradicating MRSA embedded in the biofilm layer on catheter surfaces [5]. Furthermore, unlike vancomycin, daptomycin does not predispose to the emergence of VRE colonisation or infection and may be associated with a better safety profile, in particular lower nephrotoxicity [6], [7].

In this study, we evaluated daptomycin as an alternative agent for the treatment of Gram-positive CRBSI.

Section snippets

Study patients

Between June 2006 and March 2008, 40 patients with probable or definite CRBSI with Gram-positive organisms were prospectively enrolled to receive daptomycin intravenous (i.v.) 6 mg/kg/day for up to 4 weeks. These patients were compared with 40 historical matched control patients with CRBSI who were treated with vancomycin. The control group was matched by underlying disease, type of organism and neutropenic status.

Eligible patients were aged ≥18 years, with Gram-positive CRBSI, without a source

Results

During the study period, 575 patients with probable or definite Gram-positive CRBSI were screened. In total, 40 patients were prospectively enrolled in the daptomycin arm. In this cancer setting, most of the ineligible patients had received therapy with an antibiotic such as vancomycin for more than 48 h within 72 h of study medication initiation. The analysis included 38 patients who received daptomycin: 2 patients were excluded from analysis because they were diagnosed with pneumonia at study

Discussion

Cancer patients treated with daptomycin achieved earlier symptom resolution and microbiological eradication compared with patients treated with vancomycin. Furthermore, daptomycin was associated with a superior overall response that included an outcome free of infection-related complications, mortality and relapse. There are several reasons that can account for these findings.

First, several studies showed a greater likelihood of treatment failure when vancomycin was used to treat patients

Conclusions

In cancer patients with CRBSI, daptomycin was significantly associated with earlier clinical and microbiological response compared with vancomycin. In addition, daptomycin was associated with a significantly better overall response and tended to be associated with a lower nephrotoxicity rate.

Further prospective randomised clinical trials are needed to evaluate the cost savings as well as the improved quality of life associated with the use of daptomycin.

Funding: This study was supported by a

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Daptomycin in the treatment of bacteremia
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Sources and outcome of bloodstream infections in cancer patients: the role of central venous catheters
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Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia
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Cited by (35)

Catheter-related infections in patients with haematological malignancies: novel preventive and therapeutic strategies
2016, The Lancet Infectious Diseases
Citation Excerpt :
If the patient has persistent positive blood cultures up to 72 h after initiation of appropriate therapy, the catheter should be removed. Vancomycin is still the gold standard of empirical treatment of Gram-positive CRBSI, pending culture results and susceptibilities, and for meticillin-resistant organisms; however, daptomycin has been shown to be at least equally efficacious as vancomycin in the treatment of Gram-positive CRBSI in patients with cancer and may be associated with faster symptom resolution and microbiological eradication as well as better overall outcome.93 Daptomycin is thus a good alternative in patients with haematological malignancies who might be at increased risk of harbouring vancomycin-intermediate or vancomycin-resistant S aureus, or in patients who are at increased risk of vancomycin-associated nephrotoxicity, such as those receiving other nephrotoxic drugs.94
Central venous catheters are essential for the treatment of patients with haematological malignancies and the recipients of stem-cell transplant. This patient population is, however, at high risk for catheter-related bloodstream infections that can result in substantial morbidity, mortality, and health-care-associated costs. Efficient prevention, early diagnosis, and effective treatment are essential to providing the best care to these patients. Although confirming the catheter as a source of infection remains challenging, the Infectious Diseases Society of America definition of catheter-related bloodstream infection remains the most precise definition to use in these patients. Gram-positive bacteria, particularly coagulase-negative Staphylococcus spp, remain the leading cause of catheter-related bloodstream infection, although an increase in Gram-negative bacteria as the causative agent has been noted. Although removal of the line and appropriate intravenous antibiotics remain the mainstay of treatment in most cases, novel technologies, including exchange with antibiotic-coated catheters and treatment with lock solutions, are particularly relevant in this patient population. In this Review we present the types of central venous catheters used in this patient population and analyse the different definitions of catheter-related infections, with an overview of their prevention and management.
Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia with Vancomycin MIC >1 mg/L: A Multicenter Evaluation
2016, Clinical Therapeutics
Citation Excerpt :
In studies of immunocompromised animals, an advantage of daptomycin over vancomycin was shown in a neutropenic mouse model of MRSA peritonitis; daptomycin exhibited greater and more rapid bactericidal activity than vancomycin.21 Furthermore, these findings are consistent with a clinical study that showed the benefits of daptomycin over vancomycin among cancer patients with catheter-related bacteremia; significantly earlier symptom resolution (76% vs 53% by 48 hours; P = 0.04) and microbiologic eradication (78% vs 34% clearance by 48 hours; P < 0.001) occurred with daptomycin compared with vancomycin.22 Because these patients are highly dependent on antimicrobial potency for a successful outcome due to their lack of a fully functioning immune system, the enhanced performance of daptomycin over vancomycin in this subset may be of interest.
Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation.
This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance.
A total of 170 patients were included. The median (interquartile range) age was 60 years (50–74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10–18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035).
Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.
Sepsis syndrome, bloodstream infections, and device-related infections
2012, Medical Clinics of North America
Citation Excerpt :
Given the difficulty of eradicating the biofilm, the antibiotic concentration in the lock solution should be 10 to 1000 higher than the MIC in most cases, and even higher in patients who receive vancomycin-based ALT (>1000 higher than the MIC).65 In 1 study, daptomycin-containing ALT was superior to vancomycin in the management of CRBSI in patients who have cancer.67 Catheter exchange is another option when catheter removal is not performed because of increased risk of mechanical complications.68
Safety and efficacy of daptomycin therapy in older adults with pluripathology
2012, Enfermedades Infecciosas y Microbiologia Clinica
Las infecciones por bacterias grampositivas tienen una gran morbimortalidad entre los pacientes ancianos y, en muchas ocasiones, suponen un verdadero reto para los profesionales que atienden a estos pacientes. A pesar de que este grupo poblacional concentra más del 50% de los pacientes que han recibido tratamiento con daptomicina tras su comercialización, hay muy pocos datos acerca de la eficacia y seguridad en ancianos. El análisis de los pacientes mayores de 65 años incluidos en los registros CORE (Cubicin Outcomes Registry and Experience), estudio multicéntrico, retrospectivo, diseñado para recoger datos clínicos poscomercialización de los pacientes que han recibido daptomicina, y de su versión europea, EUCORE, muestra unas tasas de eficacia y una seguridad comparables a las de los pacientes más jóvenes, por lo que la daptomicina siempre debe considerarse una opción en el tratamiento de las infecciones graves por grampositivos.
Serious Gram-positive bacterial infections are a major cause of morbidity and mortality among older adults and can pose a significant challenge to clinicians. Although more than 50% of patients treated with daptomycin are > 65 years old, there are few data evaluating the efficacy and safety of daptomcyn in this population. Analysis of data from patients > 65 years old included in the Cubicin Outcomes Registry and Experience (CORE), a multicenter, retrospective registry designed to collect post-marketing clinical data on patients who received daptomycin, and in its European version, the EUCORE, showed similar rates of efficacy and safety in this population to those in younger patients, suggesting that daptomycin is also a valuable option in older patients with serious Gram-positive infections.
Daptomycin in Gram-positive bacterial infections in oncohematological patients and transplant recipients
2012, Enfermedades Infecciosas y Microbiologia Clinica
Las infecciones por bacterias grampositivas son una causa importante de morbilidad y mortalidad en los pacientes oncohematológicos y en los receptores de trasplante. Los estafilococos coagulasa negativa, Staphylococcus aureus, Enterococcus spp. y los estreptococos del grupo viridans son los organismos grampositivos aislados con mayor frecuencia. La resistencia antibiótica en estos organismos es un problema en aumento y supone un reto terapéutico. Daptomicina es un antibiótico con una rápida actividad bactericida, de amplio espectro frente a bacterias grampositivas, incluidas las cepas resistentes a otros fármacos. En este artículo se revisan algunos aspectos de las infecciones por organismos grampositivos en estos pacientes inmunodeprimidos y se analiza con detalle la experiencia con daptomicina en el tratamiento de tales infecciones.
Gram-positive infections are a major cause of morbidity and mortality in oncohematological patients and transplant recipients. The most frequently isolated Gram-positive organisms are the coagulase-negative staphylococci, Staphylococcus aureus and Enterococcus spp., and viridans group streptococci. Antibiotic resistance in these organisms is increasing and poses a challenge to clinicians. Daptomycin is rapidly bactericidal against a broad spectrum of gram-positive bacteria, including strains resistant to other drugs. The present article reviews some aspects of Gram-positive infections in these immunocompromised patients and provides a detailed analysis of experience with daptomycin in the treatment of these infections.
New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance
2012, International Journal of Antimicrobial Agents
Citation Excerpt :
According to a pre-specified subset analysis of a randomised trial, daptomycin (6 mg/kg/day) was as effective as vancomycin plus gentamicin in patients (total n = 88) with MRSA bacteraemia or endocarditis [39]. More recently, data on 38 cancer patients with catheter-related BSI caused by Gram-positive bacteria treated with daptomycin were matched with data for historical controls treated with vancomycin [40]; 68% of patients in the daptomycin group and 80% in the vancomycin group had organisms with vancomycin MICs of 1–2 mg/L. Results from this small study suggest that daptomycin may be associated with improved 48-h clinical and microbiological response, improved overall response and lower risk of nephrotoxicity, although the two groups were comparable with respect to length of hospital stay and death. The approved dose of daptomycin is 4 mg/kg once daily in non-bacteraemic cSSSI and 6 mg/kg once daily in bacteraemic cSSSI and endocarditis [38].
Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton–Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.

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International Journal of Antimicrobial Agents

Abstract

Introduction

Section snippets

Study patients

Results

Discussion

Conclusions

References (15)

A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia

Clin Ther

Activity of daptomycin on biofilms produced on a plastic support by Staphylococcus spp

Int J Antimicrob Agents

Daptomycin in the treatment of bacteremia

Am J Med

Sources and outcome of bloodstream infections in cancer patients: the role of central venous catheters

Eur J Clin Microbiol Infect Dis

Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America

Clin Infect Dis

The effect of vancomycin and third-generation cephalosporins on prevalence of vancomycin-resistant enterococci in 126 U.S. adult intensive care units

Ann Intern Med

Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia

J Clin Microbiol

Cited by (35)

Catheter-related infections in patients with haematological malignancies: novel preventive and therapeutic strategies

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia with Vancomycin MIC >1 mg/L: A Multicenter Evaluation

Sepsis syndrome, bloodstream infections, and device-related infections

Safety and efficacy of daptomycin therapy in older adults with pluripathology

Daptomycin in Gram-positive bacterial infections in oncohematological patients and transplant recipients

New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance

Short communicationEfficacy and safety of daptomycin in the treatment of Gram-positive catheter-related bloodstream infections in cancer patients

Abstract

Introduction

Section snippets

Study patients

Results

Discussion

Conclusions

Clin Ther

Int J Antimicrob Agents

Am J Med

Sources and outcome of bloodstream infections in cancer patients: the role of central venous catheters

Eur J Clin Microbiol Infect Dis

Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America

Clin Infect Dis

The effect of vancomycin and third-generation cephalosporins on prevalence of vancomycin-resistant enterococci in 126 U.S. adult intensive care units

Ann Intern Med

Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia

J Clin Microbiol

Short communication
Efficacy and safety of daptomycin in the treatment of Gram-positive catheter-related bloodstream infections in cancer patients