A pilot study of the efficacy and safety of empiric daptomycin therapy in oncology patients with fever and severe neutropenia

Abstract

Objectives:

Patients with extended periods of time spent with low or absent absolute neutrophil counts (ANCs) are at risk for bacterial infections. Febrile neutropenia is a complication in this patient population, requiring administration of antibiotics. The use of daptomycin in treating patients with febrile neutropenia is not well described. Our objective was to describe the clinical course of febrile neutropenic patients that received daptomycin therapy.

Methods:

This was an open-labeled, pilot study of 30 patients with documented febrile neutropenia treated with empiric daptomycin. Eligible patients received daptomycin 6 mg/kg/day, in addition to concomitant broad-spectrum antimicrobials. The Kaplan–Meier method was used to estimate the median days to reach an afebrile state and negative bacterial cultures.

Results:

A total of 30 febrile neutropenic patients were enrolled and received daptomycin as part of an empiric antimicrobial regimen. All patients had severe neutropenia with ANC <100 cells/mm³. Two patients were removed from study due to the development of pneumonia. Clinically, 87% patients improved on daptomycin in combination with Gram-negative coverage, with 73% of patients succeeding therapy. A total of 18 of 19 (95%) subjects with positive blood cultures had microbiological eradication, with the median time to reach an afebrile state of 4.3 days (range 1–13). Four patients were discontinued from daptomycin due to a suspected related adverse event or to clinical failure.

Conclusions:

This pilot study supports future evaluation of the use of empiric daptomycin therapy in combination with Gram-negative coverage compared with vancomycin in patients with neutropenic fever in a large, randomized controlled trial.

Introduction

Febrile neutropenia is a medical emergency that has been associated with significant patient morbidity and mortality, and has significantly contributed to hospital costs [Ammann et al. 2010; Ha et al. 2011; Santolaya et al. 2001]. It is estimated that approximately 80% of patients with an absolute neutrophil count (ANC) of <500 cells/mm³ will have a febrile episode, and 20% of those with an ANC <100 cells/mm³ having bacteremia or an increased risk of infection [Freifeld et al. 2011]. Infection and associated sepsis is the leading cause for mortality in these patients, with the early institution of antimicrobial therapy contributing to a reduction of mortality in cancer patients with febrile neutropenia [Hughes et al. 2002].

The initial choice of antimicrobial therapy is usually broad-spectrum and can be guided by anticipated causative organisms. Both Gram-negative and Gram-positive organisms are identified as the etiologic agents of both bloodstream and deep-tissue infections in oncology patients. Gram-positive bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), have become more prominent pathogens due, in part, to the widespread use of prophylactic antibiotics and the increased presence of intravascular devices [Ramphal, 2004; Yadegarynia et al. 2003]. As a result, the Infectious Diseases Society of America (IDSA) guidelines [Freifeld et al. 2011] recommend the consideration of vancomycin in the initial regimen of certain groups of patients (high baseline risk of MRSA infections), and patients that remain hemodynamically unstable after several doses of the primary regimen. Simultaneously, there have been national efforts to limit the use of vancomycin due to the emergence of antimicrobial resistance associated with its usage and high treatment failures noted, with prior vancomycin exposure, older age, and certain underlying disease states as independent predictors of vancomycin failure [Khatib et al. 2006; Kullar et al. 2011; Soriano et al. 2008].

Daptomycin is a novel lipopeptide that exerts concentration-dependent bactericidal activity against drug-resistant Gram-positive bacteria [Cha et al. 2003; Mortin et al. 2007]. Although daptomycin is generally well tolerated, concerns about potential clinical or biochemical myositis as an adverse reaction warrant creatine phosphokinase (CPK) measurements weekly during therapy [Cubist Pharmaceuticals, Inc., 2003]. The recognition of Gram-positive bacteria as a common causative agent of febrile neutropenia, coupled with the increasing incidence of vancomycin-resistant bacterial strains, emphasizes the basis for assessing additional antimicrobial options for treating patients with febrile neutropenia due to Gram-positive pathogens. Therefore, a pilot study was performed addressing the safety and efficacy of empiric daptomycin therapy in febrile neutropenic patients that were receiving concomitant broad-spectrum antimicrobials with the primary objective to determine the percentage of responders to therapy within 72 hours of starting the study drug.

Methods

Study design

This was an open-labeled, pilot study to evaluate the efficacy and safety of daptomycin in febrile neutropenic cancer patients. All patients signed informed consent prior to inclusion. Eligible patients received daptomycin 6 mg/kg, based on total body weight, as a 30-minute intravenous infusion every 24 hours, in addition to concomitant broad-spectrum antimicrobials. An algorithm of treatment is provided in Figure 1. The study protocol was approved by the Institutional Review Board and the Knight Cancer Institute Research Review Committee at the Oregon Health and Science University.

Figure 1.

Algorithm of treatment.

Study population

Inclusion criteria

Patients who fulfilled the following criteria were eligible to participate in this study: (i) adults ≥18 years of age; (ii) oncology patients with an ANC of <500 cells/mm³ and one or more of mucositis, concomitant skin or soft-tissue infection, indwelling catheter and/or suspected catheter infection, recent quinolone prophylaxis, positive blood cultures for Gram-positive cocci before final identification or a documented infection with another Gram-positive pathogen, colonization with beta-lactam-resistant Gram-positive organisms (commonly, colonization of the nares or the skin), hypotension, tachycardia, narrowed pulse pressures, tachypnea, or other signs of cardiovascular compromise; (iii) temperature of >38.3℃ (101°F) once or ≥38℃ (100.4°F) twice within 12 hours; (iv) expected duration of neutropenia for ≥3 days; (v) life expectancy of ≥2 weeks; (vi) Eastern Cooperative Oncology Group performance status score of ≤2.

Exclusion criteria

Patients were not eligible for participation in the study if any of the following criteria were met: (i) known allergic reaction to daptomycin or product excipients; (ii) suspected meningitis, pneumonia, or osteomyelitis; (iii) known to be infected with a daptomycin-resistant organism or a Gram-negative organism and did not yet meet the criteria for the addition of antimicrobial therapy for the treatment of an infection caused by a Gram-positive organism; (iv) pregnant, positive for serum human chorionic gonadotropin, or lactating; (v) creatinine clearance (CrCl) ≤ 50 ml/min; (vi) psychiatric disorder with an inability to comply with study protocols; (vii) life expectancy of <2 weeks; (viii) suspected or proven endocarditis.

Study objectives and endpoints

The primary objective of this study was to assess the percentage of responders to therapy within 72 hours of starting daptomycin. Response to therapy was measured in a composite endpoint, incorporating resolution of fever and clinical signs of infection and clearance of blood or other sites of infection, when pathogens were isolated, without a change in therapy. Complete response was defined as: resolution of fever and clinical signs/symptoms of infection, including negative cultures for microbiologically defined infections with initial therapy, no recurrence of infection apparent for at least 7 days after drug discontinuation, and/or resolution of symptoms without microbiologic evidence of a Gram-positive infection after addition of daptomycin. Partial response was defined as resolution of fever without resolution of clinical signs of infection; and/or fever persisting greater than 72 hours with Gram-positive isolate. Failure was defined as infections, other than pneumonia, that required a change of therapy or additional agent to clear blood or other sites of infection of Gram-positive organisms, when pathogens were isolated; and/or repeated positive cultures after 72 hours of daptomycin therapy. Continued fever while on daptomycin treatment without the isolation of a Gram-positive pathogen was not considered a daptomycin failure or partial response.

The secondary objectives were to: (1) assess the percentage of bacterial cures in patients with documented Gram-positive infections; (2) assess time to afebrile state; (3) document the incidence of infections that required a change in therapy or additional agents to clear; (4) assess and document adverse events and toxicity of daptomycin in febrile neutropenic patients.

Additional data collected included demographics, malignancy information, and infection and antimicrobial treatment.

Safety

A serious adverse event (SAE) was defined as an event that was fatal, life-threatening, permanently disabling, required inpatient hospitalization, was a congenital anomaly, the development of a new cancer, or an overdose. An adverse event was defined as any new, undesirable medical occurrence or worsening of a pre-existing condition in a subject that occurred during or after treatment, whether or not considered to be product related.

All serious and medically significant adverse events considered related to daptomycin by the investigator were followed until resolved or considered stable. The severity of toxicities were assessed on the following scale with appropriate clinical definitions: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = fatal. The relationship of adverse events to daptomycin was assessed to see if there was a reasonable possibility that the event may have been caused by the study medication. It was left to the investigator's clinical judgment whether or not an adverse event was of sufficient severity to require that the subject should be removed from treatment.

Statistical analysis

All results were summarized descriptively using the median and range. The Kaplan–Meier method was used to estimate the median days to reach an afebrile state and negative bacterial cultures. To evaluate this, the proportion of individuals responding, median number of days to afebrile state, the proportion achieving negative bacterial cultures, and the 95% confidence intervals were estimated for each endpoint. All calculations were computed using PASW, version 19.0 (SPSS Inc, Chicago, IL).

Results

Baseline characteristics

A total of 30 febrile neutropenic patients, without signs of pneumonia, were enrolled and received daptomycin as part of an empiric antimicrobial regimen. Demographics and additional clinical characteristics are outlined in Table 1. All patients received concomitant Gram-negative antimicrobial therapy, with most patients on multiple agents. Antimicrobial therapy received concurrent with daptomycin included aztreonam (n = 5), ceftazidime (n = 14), cefepime (n = 9), imipenem/meropenem (n = 11), clindamycin (n = 1), and piperacillin/tazobactam (n = 1). All patients had severe neutropenia with an ANC of <100 cells/mm³. Duration of neutropenia ranged from 2 to 58 days, variable according to prior treatment. Autologous hematopoietic stem cell transplantation (HSCT) recipients had a median duration of neutropenia of 6.5 days (range 2–18), allogeneic HSCT recipients had a median neutropenic duration of 3.5 days (range 3–17), and others had a median duration of 14 days (range 6–58 days). Duration of fever prior to receipt of daptomycin in the overall population was a median of 1 day (range 0–6), which did not differ based on type of prior therapy (HSCT or other).

Table 1.

Patient characteristics.

Characteristic	Median (range) or n (n = 30)
Gender	20 female/10 male
Age, years	50 (19–74)
Weight, kg	87.9 (56.2–137)
Underlying disease
AML	12
ALL	5
NHL	4
HL	2
MM	6
Germ cell	1
HSCT (All received filgrastim)	18
Allogeneic, matched related	2
Allogeneic, unrelated donor	3
Autologous	13
Cytotoxic therapy regimen (no HSCT, No filgrastim use)
Idarubicin/cytarabine 7 + 3	8
Gemtuzumab	1
Idarubicin/tretinoin	1
Clofarabine	1
HyperCVAD	1
Conditioning regimen (HSCT)
Busulfan/melphalan/thiotepa	3
Melphalan	6
Carmustine/etoposide/cytarabine/melphalan	2
Carboplatin/etoposide	1
Busulfan/etoposide	1
Cyclophosphamide/TBI	4
Cyclophosphamide/busulfan	1

AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; MM, multiple myeloma; HSCT, hematopoietic stem cell transplantation; HyperCVAD, hypervirulent-Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone; TBI, Total body irradiation.

The median duration of time receiving daptomycin for all patients was computed per protocol and in an intent-to treat analysis. Per protocol duration of treatment (excludes the patient with early death and two patients removed for potential pneumonia) was a median of 8 days (range 2–39). Intent to treat duration of therapy was a median of 7.5 days (range 1–39).

Clinical and microbiological outcomes

A total of 22 of 30 subjects (73%) were considered to have had successful therapy, as deemed by the composite clinical endpoint. The secondary objective of becoming afebrile within 72 hours was achieved in 16 of 30 (53%) patients. A partial clinical response, but with delayed fever defervescence, was achieved in 4 of 30 (13%) patients.

A total of 18 of 19 (95%) subjects with positive blood cultures were treated successfully, with the median time for these patients to reach an afebrile state of 4.3 days (range 1–13) (Figure 2). A total of 13 of 30 (40%) patients developed microbiologically documented infections, with sources of infection other than blood cultures. Thirteen cultures were positive from these patients (12 from blood, 1 from urine): coagulase-negative Staphylococcus (5), S. aureus (1), alpha-hemolytic Streptococcus species NOS (1), Streptococcus mitis (1), Streptococcus viridans (1), Pseudomonas aeruginosa, (1) Klebsiella pneumoniae (1), and Escherichia coli (2). Ten of these 13 (77%) subjects were considered to have had successful therapy, as judged by the composite clinical endpoint. Six of 13 (46%) patients became afebrile within 72 hours, with the median time to reaching an afebrile state of 2 days (range 0–8). Eight of nine (89%) patients with documented Gram-positive pathogens achieved clinical success, with six patients (67%) being afebrile at 72 hours. The median time to reach afebrile state in these nine patients was 3 days (range 2–9). Clinical outcomes of patients with Gram-positive infections are displayed in Table 2.

Figure 2.

Kaplan–Meier time to afebrile state in patients with positive cultures.

Table 2.

Outcomes of patients with Gram-positive infections.

Patient	Pathogen	Days on daptomycin	Concomitant antibiotics	Days to afebrile state
1	S. aureus	17	Imipenem	2
2	Alpha hemolytic strep	13	Cefepime, Piperacillin/  Tazobactam	4
3	Coagulase negative staph	19	Ceftazidime Imipenem	3
4	S. mitis	5	Ceftazidime Meropenem	9
5	Coagulase neg staph	37	Cefepime Imipenem	3
6 Therapy Failure	Coagulase negative staph	14	Ceftazidime Linezolid	2
7	Coagulase negative staph	10	Ceftazidime	2
8	Coagulase negative staph	9	Imipenem	5
9	S. viridans	7	Cefepime	2

Three patients were considered to have an unsuccessful outcome. Two patients experienced clinical failure with development of radiographic findings consistent with pneumonia; in these patients, no pathogens were ultimately isolated and the microbial etiology of their radiographic changes remained unknown. One patient had persistently positive blood cultures with coagulase negative Staphylococcus which occurred 1 day after discontinuing daptomycin; in this patient, infection was also unresponsive to second line linezolid therapy and ultimately required removal of the peripherally inserted central catheter (PICC) to clear the infection. An additional patient died early of respiratory failure, with concomitant sepsis caused by a Gram-negative bacteria; no autopsy was performed, and the death was considered to be not related to a Gram-positive infection nor daptomycin. Thus, clinically 26/30 (87%) patients overall improved on daptomycin therapy in combination with their Gram-negative coverage.

Safety and tolerability

Four patients were discontinued from daptomycin therapy due to a suspected related adverse event or to suspected clinical failure as noted above. One patient experienced mental status changes considered possibly related to taking daptomycin. One patient stopped daptomycin secondary to parotitis for which no organism was identified but improved when the patient was empirically changed to vancomycin. Elevations in CPK levels where observed in two patients while on daptomycin therapy. One patient experienced a CPK elevation from 45 to 224 (5-fold increase) and another from 38 to 376 (9-fold increase). However, neither was discontinued from therapy and CPK levels returned to normal within 1 week of stopping daptomycin in both subjects, and no patients experienced symptoms consistent with myositis.

Discussion

There are limited studies evaluating daptomycin use in neutropenic patients, with few prospective case series in a field with little information. Results of our pilot study suggest that daptomycin may be an acceptable alternative to vancomycin for the treatment of fever during neutropenia. Our findings, with consideration of the proportion of patients who responded to therapy, and time to defervescence, is comparable with results of studies evaluating other agents, particularly recognizing that there is not a recognized marrow toxicity associated with daptomycin administration. We found that the median time to reaching an afebrile state with daptomycin was 4.3 days, which is similar to the results of a randomized trial comparing linezolid to vancomycin, in which the time to defervescence was 6.6 and 8.8 days, respectively [Jaksic et al. 2006].

A few case reports have been published documenting daptomycin’s efficacy for Gram-positive infections in neutropenic patients [Barber et al. 2007; Mergenhagen and Pasko, 2007; Poutsiaka et al. 2007; Sakoulas, 2008]. Barber and colleagues reported on the success of daptomycin with gentamicin in a patient with febrile neutropenia with bacteremia caused by a vancomycin-resistant strain of Enterococcus gallinarum [Barber et al. 2007]. Similar outcomes were revealed in a patient with left-sided infective endocarditis associated with MRSA and vancomycin-induced neutropenia treated with daptomycin [Mergenhagen and Pasko, 2007]. Data from an ongoing multicenter study, the Cubicin Registry and Experience (CORE), revealed a response rate of 90% and a median time to improvement of 4 days in 72 neutropenic patients with documented Gram-positive infections, most of whom failed prior antimicrobial therapy [Rolston et al. 2007]. In addition to our study, these reports indicate that daptomycin may be a potential option in patients with febrile neutropenia.

One of the most important findings in this pilot study is that daptomycin appeared to be well-tolerated in this neutropenic population. There was no apparent delay in recovery from neutropenia. CPK levels became mildly elevated in a two patients, with no complications directly associated with daptomycin. Similar findings were found in the CORE study, where from the 84 patients analyzed for safety, 5 (6%) patients experienced an adverse event possibly related to daptomycin [Rolston et al. 2007]. Compared with linezolid and vancomycin, where drug-related adverse events were 17.2% and 24% in neutropenic patients, respectively, daptomycin may be a well-tolerated agent in this patient population [Jaksic et al. 2006].

It is important to note that the results of this study cannot be compared directly with the results of other studies, as the patient population enrolled in this study was very different, with all patients having an ANC < 100 cells/mm³. Further, this study was not blinded, which may have impacted interpretation of efficacy as well as the rate of withdrawal, due to clinician concerns for safety and efficacy. In addition, it is likely that the response rate reported (42%) is both an underestimate and reflects the natural history of fever defervescence, rather than a function of the drug itself; an appropriately powered comparative study would be necessary to determine relative efficacy compared with vancomycin. Lastly, other variables that were not documented may have impacted the percentage of responders to daptomycin, such as susceptibility data, removal of vascular catheters, and resolution of infectious foci.

Funding

This work was supported by an investigator-initiated research grant from Cubist Pharmaceuticals.

Conflict of interest statement

J.B. has received grant support from Cubist. At the time of writing, R.K. received speaking honoraria from Cubist Pharmaceuticals and Forest Laboratories; served on the Advisory Board of Optimer Pharmaceuticals; R.K. now is employed by Cubist Pharmaceuticals and owns Cubist Pharmaceuticals stock, R.T.M. has received grant support from Cubist.