Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment

Abstract

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant β-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.

INTRODUCTION

Staphylococcus aureus is the leading cause of bacteremia and bacterial endocarditis in developed countries and is associated with considerable morbidity and mortality (1, 2). Vancomycin has served as the cornerstone of therapy for serious infections due to methicillin-resistant Staphylococcus aureus (MRSA) for 5 decades (3, 4). In recent years, vancomycin dosing has escalated, driven by concerns of increasing treatment failure, thought to be the result of increasing vancomycin MICs (MIC creep) among S. aureus isolates (4–6). Consequently, this strategy may lead to increased rates of nephrotoxicity (7–10). This risk appears to be highest for patients who are particularly vulnerable to acute kidney injury due to comorbidities such as preexisting renal disease, acute illness, hypoperfusion from sepsis, or concomitant nephrotoxic medication (10, 11). Furthermore, S. aureus bacteremia treatment response rates may be reduced in these patients (12–15), as exemplified in a recent study comparing daptomycin and vancomycin therapy for MRSA bacteremia with a vancomycin MIC of >1 μg/ml that showed renal failure and receipt of vancomycin to be independent mortality predictors (15).

Daptomycin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated skin and soft tissue infections and S. aureus bacteremia, including right-sided endocarditis caused by methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) S. aureus (16). The safety profile of daptomycin suggests that it may offer a less nephrotoxic therapeutic option for patients with invasive S. aureus infections (17), but it has not been studied extensively in patients with baseline predialysis renal impairment. This is clinically important because this patient population is at most risk for additional renal injury from potentially nephrotoxic medications. In light of the recent comparative study finding renal failure as an independent predictor of treatment failure in patients receiving either vancomycin or daptomycin (15), exploring innovative approaches in the management of S. aureus bacteremia in patients with renal insufficiency is of clinical importance.

Recent data suggest that β-lactams may potentiate the activity of daptomycin and innate immunity-derived cationic antimicrobial peptides (CAMPs) against MRSA in vivo and in vitro (18–23). This has translated into clinical benefit in very difficult cases of MRSA bacteremia (20), including cases in which the MRSA strain was daptomycin nonsusceptible (20, 23). Clinical incorporation of this potent combination is wrought with questions, including (i) which β-lactams provide this synergy effect, (ii) whether all cases of S. aureus bacteremia benefit from combination versus monotherapy, and (iii) what doses of daptomycin and/or β-lactam should be employed. This study provided the opportunity to examine the combination of daptomycin with all β-lactams, regardless of dose, in cases of S. aureus bacteremia and to determine if particular groups of patients would benefit from this therapy.

During the years 2003 to 2011, the clinical experience of daptomycin in the United States was captured in the Cubicin Outcomes Registry and Experience (CORE) database, a multicenter, retrospective, observational registry of clinical experience with daptomycin. The aim of the present study was to begin to fill the knowledge gap for patients with predialysis renal insufficiency and S. aureus bacteremia, with particular interests in (i) risks of nephrotoxicity, (ii) risks of creatine phosphokinase (CPK) elevation, (iii) clinical efficacy, and (iv) identifying subsets of patients that may benefit from better treatment outcomes with daptomycin-plus-β-lactam combination therapy.

MATERIALS AND METHODS

Patient selection.

The CORE includes patient data and outcomes collected from over 60 institutions across the United States. For the purpose of this study, we queried the registry for the program years 2005 through 2009, the registry years during which cases for data extraction were selected without a specific focus on infection types and variables relevant to both safety and efficacy were obtained. Prior to 2005, safety data were not collected, and during 2010 to 2011, the data collection focus switched to specific outcomes for specific infection types. In order to reduce bias, those registry years were excluded from this analysis. Institutional review board approval was obtained for all participating sites. The registry inclusion criterion was receipt of at least one dose of daptomycin not part of a clinical trial, as previously described (24). For inclusion in this analysis cohort, subjects from the CORE had to have (i) a positive blood culture(s) for S. aureus, (ii) received daptomycin for bacteremia, and (iii) mild (creatinine clearance [CL_CR] of 30 to 50 ml/min) to moderate (CL_CR of <30 ml/min, not requiring dialysis of any type) renal impairment at the time of initiation of daptomycin therapy. The CORE did not exclude patients with underlying diseases, such as those who were immunocompromised or had severe hepatic or renal impairment.

Clinical and microbiological data collected.

Standardized case report forms were used to collect patient-specific clinical and microbiological data. Patient-specific data included demographic information (e.g., sex and age range), the hospital ward where daptomycin was administered (intensive care unit [ICU] or non-ICU ward), patient location (hospital, community, or nursing home) in the 48 h immediately before daptomycin administration, the nature of the infection being treated with daptomycin as documented in the medical record, initial and final daptomycin doses, dosing interval, length of therapy, prior, concomitant, and follow-up antibiotic therapy, culture results, and susceptibility data for multiple antibiotics. Each patient in this analysis had a positive blood culture(s) for S. aureus. In order to place each patient with more than one reported source of bacteremia into only one category, each patient was assigned to a single category by use of the following hierarchy: endocarditis (including the presence of intracardiac biomedical devices) > biomedical device (including orthopedic pins, plates, replacement joints, bone prostheses, cements, and vascular grafts but excluding central venous catheters) > bone/joint infection (including osteomyelitis and septic arthritis) > central venous line > complicated skin and skin structure infection (cSSSI) > other > unknown source.

Efficacy assessment.

Clinical outcomes were assessed at the end of daptomycin therapy. Infections were considered evaluable for efficacy if the daptomycin treatment response was classified as a cure, improved status, or failure. Patients with an infection response classified as nonevaluable were excluded from the efficacy evaluation. A cure was defined as having resolved clinical signs and symptoms and/or no additional need for antibiotic therapy, or as a negative culture reported at the end of therapy. The infection was classified as improved if there was partial resolution of clinical signs and symptoms and/or additional antibiotic therapy was warranted at the end of therapy to streamline/deescalate treatment. A failure was defined as an inadequate response to therapy, with worsening or new/recurrent signs and symptoms, a need for a change in antibiotic therapy, or a positive S. aureus blood culture reported at the end of therapy. The infection response was classified as nonevaluable if the investigator was unable to determine the response due to insufficient information. The number of treatment successes was defined as the sum of the numbers of cure and improved outcomes.

Mortality.

Thirty-day all-cause mortality was based on patient status 30 days after the end of daptomycin therapy.

Safety assessments.

All patients who received at least 1 dose of daptomycin were eligible for safety analysis. The case report form included collection of all adverse events, whether possibly related to daptomycin or not, from the first dose of daptomycin through 30 days after the last dose of daptomycin. All changes in physical findings, clinical signs and symptoms, and laboratory values consistent with serious and nonserious adverse events were documented. The adverse event was considered serious if it was life-threatening or resulted in death, disability/incapacity, hospitalization, congenital anomaly/birth defect, or an important medical event. Each adverse event was also categorized based on severity, onset, relationship to daptomycin, action taken with daptomycin, other action taken, outcome, and day of resolution. As part of the data collection for CORE, starting in 2007, specific data on the highest CPK range (categorized as ≤1× upper limit of normal (ULN), >1 to 2× ULN, >2 to 5× ULN, >5 to 10× ULN, or >10× ULN) measured during daptomycin therapy were also collected for all subjects.

Statistical methods.

Clinical characteristics associated with the daptomycin treatment response were compared using univariate and multivariate analyses. Dichotomous variables were compared by means of χ² analysis or Fisher's exact test, where appropriate. Continuous and ordinal variables were compared using Kruskal-Wallis analysis of variance and Mann-Whitney U tests. Multivariate analysis to detect potential relationships among clinical factors and the daptomycin treatment response was performed using logistic regression. Statistical significance was defined as having a P value of <0.05. All statistics were performed using JMP 8 (SAS Institute, Cary, NC) and Systat 11 (Systat Software Inc.) software.

RESULTS

From January 2005 through December 2009, 5,482 patients treated with daptomycin for a Gram-positive infection were enrolled in the CORE, among which 106 (1.9%) received daptomycin for S. aureus bacteremia and had mild or moderate renal insufficiency. These 106 patients were from 41 institutions, as follows: large teaching hospitals of >500 beds, 20/41 institutions (49%); medium-sized teaching hospitals with <500 beds, 7/41 institutions (17%); and other practices, including outpatient centers, 11/41 institutions (27%). Sixty-three (59.4%) of the patients were ≥66 years old. There were slightly more men (52.8%) than women. Seventy-six (71.7%) of the cases were MRSA bacteremias.

At baseline, 35 (33.0%) of 106 patients were in an intensive care unit, and 8 (7.5%) had a diagnosis of sepsis or septicemia. In addition to all patients having mild to moderate renal insufficiency, many patients had additional significant comorbidities, such as diabetes (n = 41), congestive heart failure (n = 24), malignancy (n = 20), acute renal failure (n = 19), anemia/hematologic disease (n = 14), and chronic obstructive pulmonary disease (n = 13). Of the 106 patients, 80 (75.5%) were evaluable for efficacy.

Daptomycin dosage regimen.

The median initial daptomycin dose was 6 mg/kg of body weight (range, 3 to 10 mg/kg) for both the 106 subjects and the 80 evaluable cases. Among the evaluable cases, the definitive daptomycin dose was less than the current FDA-approved 6 mg/kg for bacteremia in 22.5% (18/80 patients) of patients. The median duration of daptomycin therapy was 11 days (range, 1 to 265 days), with a median duration of 14 days for the daptomycin treatment success group and 7 days for the daptomycin treatment failure group (P = 0.006).

Bacteremia source.

For infections that were clinically evaluable, the sources of S. aureus bacteremia included skin (n = 21), unknown source (n = 16), central venous catheter (n = 15), infective endocarditis (n = 11), biomedical device (n = 11), and osteomyelitis (n = 6). The daptomycin success rate in the clinically evaluable population was 81.3% (65/80 patients), with the highest success rate occurring when the source was skin and the lowest occurring when the source was unknown (Fig. 1). The efficacies of daptomycin with and without a β-lactam, stratified by bacteremia type, are also summarized in Fig. 1. While the addition of a β-lactam did not provide any therapeutic benefit for cases of bacteremia traditionally considered low risk, such as skin or catheter infections, there was a consistently improved efficacy for the other, potentially higher-risk cases, such as infective endocarditis, unknown source infections (many of which were presumably endovascular septic thrombi that escaped imaging), and osteoarticular infections. However, the benefit of β-lactams did not achieve statistical significance within each category.

Fig 1.

Daptomycin treatment success based on source of Staphylococcus aureus bacteremia, with and without β-lactam therapy. Dark gray bars represent all patients who received daptomycin either with or without a β-lactam. The light gray bars represent the subset of patients who received daptomycin with a β-lactam, and the black bars show the subset who received daptomycin without a β-lactam. When data were stratified by source of bacteremia, a statistical difference in daptomycin treatment success was not seen with the addition of a β-lactam: P = 1.00 for skin, P = 0.757 for central venous catheter, P = 0.333 for bone/joint, P = 0.470 for biomedical device, P = 1.0 for endocarditis, and P = 0.197 for unknown source.

Relationship between clinical characteristics of patients with S. aureus bacteremia and daptomycin efficacy.

Efficacy by patient and clinical characteristics was assessed among the 80 clinically evaluable cases (Table 1). The daptomycin treatment success rate was 81.3% (65/80 patients). Univariate analysis identified a significant relationship between the degree of renal insufficiency (mild versus moderate) and treatment response (P = 0.006) (Table 1), with higher failure rates among those with moderate renal insufficiency. Interestingly, the daptomycin dose was less than the FDA-recommended 6 mg/kg for bacteremia more often for patients with moderate renal insufficiency than for those with mild renal insufficiency (29.5% [13/44 patients] versus 13.9% [5/36 patients]; P = 0.095). Significantly more subjects with moderate renal insufficiency were diagnosed with sepsis (13.6% [6/44 patients] versus 0% [0/36 patients]; P = 0.021). However, no statistically significant relationship was noted between those diagnosed with endocarditis and the degree of renal insufficiency (13.6% [6/44 patients] for moderate renal insufficiency versus 13.9% [5/36 patients] for mild renal insufficiency; P = 0.974).

Table 1.

Univariate analysis of factors associated with response to daptomycin

Characteristic	Value for patients with daptomycin therapy outcomea		P value
	Success (n = 65)	Failure (n = 15)
Age of ≥66 yr	38 (58)	10 (67)	0.559
Male gender	34 (52)	9 (60)	0.590
Weight (kg)	73 (61–92)	80 (69–86)	0.693
Location 2 days before daptomycin therapy
Community	19 (29)	2 (13)	0.207
Hospital	37 (57)	12 (80)	0.098
Nursing home/extended care facility	9 (14)	1 (7)	0.449
Stay in ICU (anytime during daptomycin treatment)	21 (32)	8 (53)	0.127
Comorbid conditions
Acute coronary syndromes	4 (6)	1 (7)	0.941
Congestive heart failure	13 (20)	3 (20)	1.000
Anemia/hematologic diseases	7 (11)	2 (13)	0.777
Liver disease	1 (2)	1 (7)	0.252
Chronic obstructive pulmonary disease (COPD)	8 (12)	2 (13)	0.914
Acute renal failure	13 (20)	3 (20)	1.000
Neurologic disease	5 (8)	3 (20)	0.152
Diabetes mellitus	26 (40)	4 (27)	0.336
T-cell-mediated immunity
Cancer (hematologic)	4 (6)	1 (7)	0.941
Cancer (solid organ)	10 (15)	2 (13)	0.841
HIV positive	1 (2)	0	0.629
Transplant recipient	1 (2)	0	0.629
Peripheral vascular disease	4 (6)	2 (13)	0.341
Sepsis/septicemia	5 (8)	1 (7)	0.892
Renal insufficiency
Mild (CLCR of 30 to 50 ml/min)	34 (52)	2 (13)	0.006
Moderate (CLCR of <30 ml/min, no dialysis)	31 (48)	13 (87)
Other characteristics
Prior antibiotics for S. aureus bloodstream infection (BSI)	51 (78)	14 (93)	0.183
Prior vancomycin for S. aureus BSI	35 (54)	12 (80)	0.232
Prior vancomycin failure	15 (23)	7 (47)	0.065
MRSA	45 (69)	11 (73)	0.755
Initial daptomycin dose (mg/kg)	6 (6–6)	6 (4–6)	0.447
Final daptomycin dose (mg/kg)	6 (6–6)	6 (5–6)	0.430
Duration of daptomycin treatment (days)	14 (8–34)	7 (3–9)	0.006

^aData are numbers (%) of patients or medians (interquartile ranges).

Multivariate logistic regression identified an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5) as factors significantly related to daptomycin treatment failure (Table 2). Efficacies with daptomycin plus a β-lactam in these settings are summarized in Fig. 1 and 2. Again we noted consistent numerical but nonsignificant trends for a higher efficacy with daptomycin plus a β-lactam than that with daptomycin without a β-lactam in each category, with the greatest absolute differences noted for the more severely renally impaired group (CL_CR of <30 ml/min) and an unknown source of bacteremia.

Table 2.

Multivariate analysis of predictors of daptomycin treatment failure in Staphylococcus aureus bacteremia in patients with mild to moderate renal insufficiency

Factor	OR (95% CI)	P value
Unknown source of bacteremia	7.59 (1.55–37.2)	0.012
Moderate renal insufficiency (vs mild insufficiency)	9.11 (1.45–56.8)	0.018
Prior vancomycin treatment failure	11.2 (1.95–64.5)	0.007

Fig 2.

Daptomycin treatment success in S. aureus bacteremia, stratified by concomitant β-lactam use and risk of failure by logistic regression. The dark gray bars represent all patients who received daptomycin either with or without a β-lactam. The light gray bars represent the subset of patients who received daptomycin with a β-lactam, and the black bars show the subset who received daptomycin without a β-lactam. When data were stratified by characteristic, no statistical difference in daptomycin treatment success was seen with the addition of a β-lactam: P = 0.334 for mild renal insufficiency (CL_CR of 30 to 50 ml/min), P = 0.474 for moderate renal insufficiency (CL_CR of <30 ml/min, not requiring dialysis), P = 0.361 for no previous vancomycin failure, and P = 0.823 with prior vancomycin failure.

There was no statistically significant relationship between the presence of MRSA (P = 0.755), acute renal failure (P = 1.000), or diabetes mellitus (P = 0.336) and the response to daptomycin therapy (Table 1). MRSA was found in 70.0% (56/80 patients) of the patients, of which 45 (80.4%) had a successful response to daptomycin therapy. The success rate was 83.3% (20/24 patients) for patients with MSSA. Of the 16 patients with acute renal failure, 13 (81.3%) had a successful response to daptomycin therapy. Among the 30 patients with diabetes, 26 (86.7%) had a successful response to daptomycin.

Prior antibiotic therapy and treatment outcomes.

In most instances, patients received Gram-positive antibiotic therapy before receiving daptomycin. Of the 80 patients with clinically evaluable cases, 65 (81.3%) received prior antibiotics (Table 1). Univariate analysis identified a trend of reduced daptomycin treatment success and prior vancomycin treatment failure compared to no prior vancomycin treatment failure (68.2% [15/22 cases] versus 86.2% [50/58 cases]; P = 0.065). Adjusting for potential confounding factors, multivariate analysis found this relationship between prior vancomycin treatment failure and reduced daptomycin treatment success to be statistically significant (Table 2).

Concomitant therapy.

Seventy-one (67.0%) of 106 patients received concomitant antibiotics with daptomycin. Of the 80 subjects with evaluable efficacy outcomes, 66 (82.5%) received concomitant antibiotics, including a β-lactam (n = 30), rifampin (n = 17), a fluoroquinolone (n = 12), vancomycin (n = 9), gentamicin (n = 8), clindamycin (n = 3), linezolid (n = 2), trimethoprim-sulfamethoxazole (n = 2), and tigecycline (n = 1). Nineteen (36.5%) of the 52 evaluable subjects with available data had surgical intervention.

Efficacy of daptomycin with concomitant β-lactam therapy.

Among evaluable patients, a nonsignificant trend toward outcome benefit was noted for patients receiving concomitant β-lactams with daptomycin compared to those without β-lactams (86.7% [26/30 patients] versus 78.0% [39/50 patients]; P = 0.336). This trend was noted for both MSSA and MRSA bacteremias (Table 3). However, we were particularly interested in examining the efficacy of this daptomycin-plus-β-lactam combination compared to daptomycin without a β-lactam in cases where the S. aureus bacteremia was of primary endovascular origin (infective endocarditis, osteomyelitis, septic arthritis, and unknown source) rather than a primary tissue source (skin; pneumonia was already excluded), eliminating foreign body infections such as infections of venous catheters or other biomedical devices, where successful therapy rested not on antimicrobial therapy but on device removal. Focusing on potentially primary endovascular S. aureus bacteremic states, the addition of a β-lactam to daptomycin trended very strongly toward a successful outcome compared with daptomycin without a β-lactam (90.0% [9/10 cases] versus 56.5% [13/23 cases]; P = 0.061) (Fig. 3).

Table 3.

Daptomycin treatment success in Staphylococcus aureus bacteremia, stratified by methicillin susceptibility (MSSA versus MRSA) and therapies used^a

Therapy	No. of cases with successful daptomycin response/total no. of cases (%)	P value	No. of MSSA cases with successful daptomycin response/total no. of MSSA cases (%)	P value	No. of MRSA cases with successful daptomycin response/total no. of MRSA cases (%)	P value
Daptomycin at initial dose of:
>6 mg/kg	50/60 (83)	0.408	15/17 (88)	0.315	35/43 (81)	0.722
<6 mg/kg	15/20 (75)		5/7 (71)		10/13 (77)
Concomitant β-lactam
With β-lactam	26/30 (87)	0.336	8/8 (100)	0.121	18/22 (82)	0.825
Without β-lactam	39/50 (78)		12/16 (75)		27/34 (79)
Concomitant rifampin
With rifampin	13/17 (76)	0.569	1/2 (50)	0.186	12/15 (80)	0.968
Without rifampin	52/63 (83)		19/22 (86)		33/41 (80)
Concomitant gentamicin
With gentamicin	6/8 (75)	0.633	1/2 (50)	0.186	5/6 (83)	0.846
Without gentamicin	59/72 (82)		19/22 (86)		40/50 (80)
Concomitant vancomycin
With vancomycin	7/9 (78)	0.777	3/4 (75)	0.624	4/5 (80)	0.983
Without vancomycin	58/71 (82)		17/20 (85)		41/51 (80)

^aSome patients received more than one concomitant therapy. Data are not shown for concomitant linezolid (n = 2, both MRSA, with 1 failure and 1 success) and concomitant trimethoprim-sulfamethoxazole (n = 2, both MRSA, with 1 failure and 1 success).

Fig 3.

Infection types showing improved daptomycin outcomes with concomitant β-lactam therapy, i.e., infective endocarditis (IE), bone or joint infection (B/J) (without a biomedical device present), or an unknown source of bacteremia. The figure shows daptomycin treatment success for S. aureus bacteremia, stratified by concomitant β-lactam use. The overall daptomycin treatment success rate in this population was 67% (22/33 patients) (dark gray bar), with success rates of 90% (9/10 patients) with the addition of a β-lactam (light gray bar) and 57% (13/23 patients) without a β-lactam (black bar) (P = 0.061).

Efficacy of daptomycin with concomitant non-β-lactam therapy.

Outcomes based on concomitant therapy used, including stratification based on methicillin susceptibility (MSSA and MRSA), are displayed in Table 3. The addition of rifampin, gentamicin, or vancomycin to daptomycin resulted in no significant changes in outcome (Table 3).

Summary of daptomycin treatment failures.

The clinical characteristics of the 15 patients with S. aureus bacteremia that failed to respond to daptomycin are summarized in Table 4. Of the 15 patients, 14 (93.3%) received antibiotics prior to daptomycin, 8 of which were considered ineffective. None of the daptomycin treatment failures that were categorized as previous vancomycin failures received the current MRSA guideline (3)-recommended dose of 10 mg/kg of daptomycin. In addition, 4 of the subjects received less than the FDA-recommended dose of 6 mg/kg. None of the daptomycin treatment failure cases with bacteremia due to a central catheter or biomedical device had the catheter or device removed during therapy. Five (33.3%) of the 15 daptomycin treatment failures were in patients over 80 years of age who had a number of comorbidities. None of the patients with endocarditis (2 left sided, 1 right sided) had surgical interventions performed. One patient was deemed a treatment failure because of being lost to follow-up, and 1 patient received 7 days of daptomycin therapy and had a recurrence of bacteremia 10 days after daptomycin was discontinued.

Table 4.

Clinical summary of cases of S. aureus bacteremia and mild or moderate renal insufficiency that were classified as daptomycin treatment failures^a

Patient no.	Age range (yr), sex	Underlying condition(s)	MRSA or MSSA, BSI source	Antibiotics received prior to DAP	DAP therapy	Comments
1	>80, M	Neutropenia (ANC, <100), HTN, CV disease, COPD, anemia, acute kidney injury, solid organ malignancy	MRSA, central catheter	VAN	6 mg/kg q24h for 4 days	Switched to alternative therapy; expired after DAP therapy; infected central catheter (Port-A-Cath) not removed
2	>80, F	CHF, CV disease	MRSA, biomedical device infection	VAN (treatment failure)	7 mg/kg q48h for 3 days (CLCR of <30 ml/min)	Medical care was withdrawn after 3 days of DAP; infected biomedical device not removed
3	>80, M	CV disease	MRSA, biomedical device infection	VAN (treatment failure)	8 mg/kg q48h for 7 days (CLCR of <30 ml/min) + RIF	No documentation of device removal; recurrence 10 days after DAP was discontinued; DAP MIC, >3 μg/ml; patient received LZD + ampicillin-sulbactam + RIF
4	66–80, M	HTN	MSSA, unknown source	VAN	4 mg/kg q48h for 2 days (CLCR of <30 ml/min)	DAP dose less than FDA-recommended dose
5	51–65, M	DM, CV disease, CHF, GI bleed	MRSA, unknown source	VAN	3.7 mg/kg, then 5.7 mg/kg q48h for 32 days	DAP dose less than FDA-recommended dose; concomitant vancomycin-resistant Enterococcus faecium bacteremia; patient expired after DAP was discontinued
6	51–65, F	HTN	MSSA, unknown source	Failed antibiotics other than VAN	6 mg/kg q24h for 7 days + RIF	Clinical response was unknown/lost to follow-up, deemed a failure
7	>80, F	DM, HTN	MRSA, unknown source	Received prior antibiotic for BSI, other than VAN	5 mg/kg q24h for 9 days	Dose less than FDA-recommended dose; patient expired after DAP was discontinued
8	66–80, M	DM, HTN, PVD, PE/DVT, acute kidney injury	MRSA, left-sided IE	VAN (treatment failure)	6 mg/kg q48h for 58 days (CLCR of <30 ml/min) + RIF	No surgical intervention; aortic valve involved
9	66–80, M	BPH	MRSA, left-sided IE	VAN (treatment failure)	4 mg/kg for 1 day	Dose less than that recommended by most experts; surgical intervention not documented
10	31–50, F	Acute kidney injury, hematologic malignancy	MRSA, central catheter	VAN (treatment failure)	6 mg/kg q48h for 10 days (CLCR of <30 ml/min)	Prior VAN failure; no documentation of catheter removal during DAP therapy
11	51–65, F	Sepsis/septicemia, acute coronary syndrome, CV disease, CHF, HTN	MSSA, unknown source	None	4 mg/kg q48h (CLCR of <30 ml/min)	DAP dose less than FDA-recommended dose; therapy was switched; patient expired after DAP was discontinued
12	66–80, M	Cardiac arrhythmias, HTN, COPD	MRSA, right-sided IE	VAN	6 mg/kg q48h for 7 days + GEN + RIF	Patient expired during DAP therapy; no surgery documented
13	51–65, M	HTN, liver disease	MSSA, unknown source	VAN	6 mg/kg q24h for 2 days + GEN	After 2 days of DAP, therapy was switched to an alternative regimen
14	66–80, F	DM, HTN, PVD	MRSA, OM	VAN (treatment failure)	6 mg/kg q24h for 9 days	Surgical intervention performed; DAP was discontinued because the case was deemed a DAP treatment failure
15	>80, M	CV disease, anemia/hematologic disease, solid organ malignancy	MRSA, unknown source	VAN (treatment failure)	6 mg/kg q24h for 5 days	Patient expired after 5 days of DAP therapy

^aANC, absolute neutrophil count; BPH, benign prostatic hypertrophy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; DAP, daptomycin; DM, diabetes mellitus; F, female; GEN, gentamicin; GI, gastrointestinal; HTN, hypertension; IE, infective endocarditis; LZD, linezolid; M, male; OM, osteomyelitis; PE/DVT, pulmonary embolism and deep vein thrombosis; PVD, peripheral vascular disease; RIF, rifampin; VAN, vancomycin.

Mortality.

Overall 30-day all-cause mortality involved 8 (10.0%) of the 80 clinically evaluable cases. No significant difference was found between those receiving a concomitant β-lactam and those who did not receive a β-lactam.

Emergence of daptomycin-nonsusceptible MRSA.

Two patients, both with moderate renal insufficiency (CL_CR of <30 ml/min) and non-catheter-related MRSA bacteremia of an unknown source, were reported to have daptomycin-nonsusceptible organisms. The daptomycin treatment response was classified as a success for one and a failure for the other. Antimicrobial therapy for patient 1 (DAP MIC, >1 mg/liter) was daptomycin at 4 mg/kg every 24 h (q24h), with piperacillin-tazobactam, and the infection was deemed improved by day 5. At that time, antimicrobial therapy was switched to linezolid for completion of therapy. Antimicrobial therapy for patient 2 (DAP MIC, >3 mg/liter), after vancomycin treatment failure, was daptomycin at 8 mg/kg plus rifampin for a total of only 7 days. Not surprisingly, MRSA bacteremia relapsed 10 days after discontinuation of therapy. Subsequent therapy consisted of linezolid plus ampicillin-sulbactam plus rifampin, which was also unsuccessful.

Safety.

All 106 cases were evaluated for safety. Among these, an adverse event or abnormal laboratory result was reported for 28 (26.4%). Events reported as possibly or probably related to treatment with daptomycin are summarized in Table 5. An increase in CPK to ≥5 times the upper normal level was a reported adverse event in 2 (1.9%) of the 106 patients, with both cases resolving following discontinuation of daptomycin. It is noteworthy that these CPK elevations occurred relatively early (7 and 8 days) into therapy. Vaginal candidiasis (1 patient) and anemia (1 patient) were also reported (Table 5). None of the patients were noted to have developed worsening renal insufficiency due to daptomycin therapy.

Table 5.

Adverse events possibly or probably related to daptomycin^a

Age range (yr), sex	Wt (kg)	Underlying disease(s)b	DAP dosec	Adverse event	Onset of event/total DAP duration (days)	DAP DC	Outcome
31–50, M	141	CLCR of 30 to <50, OM, DM, HTN, GI disease (no statin)	6 mg/kg q24h	CPK increase	8/13	Yes	Resolved
51–65, F	71	CLCR of 30 to <50, HTN, COPD, anemia/hematologic disease, acute renal failure, solid organ cancer (no statin)	6 mg/kg q24h	CPK increase	7/11	Yes	Resolved
51–65, F	85	CLCR of <30	4 mg/kg q48h	Vaginal candidiasis	8/unknownd	No	Unknown
66–80, M	80	CLCR of <30 ml/min, IE, cardiac arrhythmias, HTN, COPD, renal disease	6 mg/kg q48h	Anemia	1/7	No	Resolved with residual effects

^aNone of the reported adverse events were serious. Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CL_CR, creatinine clearance; CPK, creatine phosphokinase; DAP, daptomycin; DC, discontinued; GI, gastrointestinal; CV, cardiovascular; HTN, hypertension; PVD, peripheral vascular disease; IE, infective endocarditis; OM, osteomyelitis; DM, diabetes mellitus; M, male; F, female.

^bStart-of-treatment and end-of-treatment CL_CR groups did not change for the 4 patients during daptomycin therapy.

^cInitial and final daptomycin doses did not change for the 4 patients.

^dThe patient was monitored for 19 days after the onset of the adverse event; nothing about the vaginal candidiasis outcome was documented.

DISCUSSION

Renal impairment has repeatedly been shown to be a risk factor for adverse outcomes in patients with S. aureus bacteremia. In treating patients with S. aureus bacteremia and predialysis renal insufficiency, clinicians are very careful to avoid nephrotoxic diagnostic and therapeutic interventions to reduce the risk of further kidney injury that could potentially tip a patient over into need of dialysis. For example, use of intravenous contrast is avoided in this population in performing computed tomography (CT) scans, even though the diagnostic yield of such studies is much lower without contrast. Vancomycin, while historically viewed as nephrotoxic in the setting of concomitant aminoglycosides, has increasingly seen rising concerns of nephrotoxicity as monotherapy in patients vulnerable to kidney injury. This vulnerability is multifactorial, including sepsis-induced hypoperfusion leading to acute tubular necrosis, nephrotoxins such as intravenous contrast, and comorbidities such as diabetes, hypertension, and antihypertensive medications.

Daptomycin has shown no evidence of nephrotoxicity in humans or animals. In fact, data from rats suggest that it may provide protection against aminoglycoside nephrotoxicity (25–27). In clinical trials (17, 28), daptomycin did not appear to pose risks of nephrotoxicity among patients with preserved renal function, and in fact, daptomycin has been used as a treatment option for patients with S. aureus infections who developed nephrotoxicity on vancomycin (29). Consistent with these prior data, this study showed no additional renal toxicity of daptomycin in patients with predialysis renal failure. CPK elevations leading to daptomycin discontinuation were noted in 1.9% of patients (2/106 patients), a rate similar to what was seen in randomized clinical trials that studied mostly patients with preserved renal function (17, 28). It is notable that both cases of CPK elevation occurred relatively early into therapy, supporting the package insert recommendation of more frequent CPK monitoring for patients with renal insufficiency. As also suggested by prior studies, this study identified the source of bacteremia, moderate renal impairment, and prior vancomycin failure as independent predictors of reduced daptomycin efficacy (15, 20, 30).

We found consistent trends toward improved daptomycin efficacy for daptomycin used concomitantly with β-lactams. However, none of these trends achieved statistical significance. Despite small sample sizes, we still suspected a potential benefit of daptomycin-plus-β-lactam combination therapy for high-risk patients who did not have an infected catheter or other biomedical device and had a likely primary endovascular infection source. The rationale for this hypothesis was that effective treatment of an infected catheter or other biomedical device rested heavily on source control (i.e., device removal) rather than antimicrobial therapy. Furthermore, based on prior data which seemed to pathophysiologically link bone and joint and bacteremia/endocarditis infections to microbial surface components recognizing adhesive matrix molecules (MSCRAMM), we decided to discriminate the effects of β-lactams between these infection types.

Bacterial CAMP resistance, particularly resistance to platelet microbicidal proteins (PMPs), which are endovascular CAMPs released from activated platelets at sites of endothelial injury, is believed to be linked to prolonged and complicated bacteremia (31). Recent evidence suggests that endovascular PMPs (and not neutrophil-derived CAMPs such as alpha-defensin) may select for a daptomycin MIC creep with prolonged infection (32). Sensitization to CAMPs and daptomycin killing of S. aureus by β-lactams could therefore provide considerable adjunctive therapy in these patients. Indeed, we determined that the addition of β-lactams to daptomycin may offer a therapeutic benefit for patients with primary endovascular foci of bacteremia (infective endocarditis, bone/joint, and unknown foci), as opposed to other sources of bacteremia (Fig. 3). Based on a prior study by Rajendran et al. (33), which showed cephalexin to be almost significantly worse than placebo (P = 0.025) for the treatment of MRSA soft tissue infection, we hypothesized no benefit or possibly worse outcomes for soft tissue-based bacteremia. We found no detrimental effect of adding β-lactams to soft tissue-based infections. Note that overexpression of alpha-toxin, which has been demonstrated by β-lactams in MRSA treatment (34), has potential virulence attenuation features in endocarditis, according to data by Bayer et al. (35).

In considering patients with infective endocarditis, it is important to appreciate that this subset of endovascular infections may represent a pathophysiologic threshold (e.g., due to a combination of a high bacterial burden, pharmacodynamic limitations, and bacterial virulence) at which pharmacotherapy alone cannot be expected to derive a successful outcome. These patients may require prompt adjunctive surgery in addition to potent antimicrobial therapy for a successful outcome. Therefore, focusing further on patients dependent exclusively on medical therapy by examining patients with unknown S. aureus bacteremia foci, who presumably have unidentified endovascular infections, and osteomyelitis, which is frequently hematogenous, the higher treatment success rate of daptomycin with a β-lactam than that of daptomycin without a β-lactam achieved statistical significance (P = 0.04). Therefore, this combination may be beneficial in the treatment course of patients with renal insufficiency who have primary S. aureus bacteremia. It remains to be determined if some β-lactam antibiotics are more potent than others in this regard, but our nondiscrimination of β-lactam subclasses in this study suggests a global class effect.

While previous studies have documented (i) an enhancement of daptomycin killing of MRSA by β-lactam antibiotics, (ii) enhanced daptomycin binding in the membranes of bacteria grown in subinhibitory concentrations of β-lactams, and (iii) enhanced killing by CAMPs of MRSA strains grown in subinhibitory concentrations of β-lactams, evidence exists of potential attenuation of S. aureus virulence by β-lactams. Prior work suggests that β-lactam antibiotics may inhibit surface expression of fibronectin binding proteins (36), thereby diminishing endovascular and osteoarticular virulence (37–39). One study has shown a genotypic similarity of S. aureus strains that cause endocarditis and osteomyelitis in that these strains have two rather than one fibronectin binding protein gene (40). This study is the first to provide clues to the potential clinical relevance of the attenuation of MSCRAMM of S. aureus with drugs such as β-lactams in antagonizing bacterial pathogenicity.

To our knowledge, this is one of the largest studies describing the clinical experience of daptomycin use for the management of S. aureus bacteremia in patients with mild to moderate renal insufficiency, and it is the only multiple-center comparative study of daptomycin with and without concomitant β-lactam therapy. Nevertheless, there are several limitations to this study that warrant discussion. Data obtained from the CORE provide information on the use of daptomycin in clinical practice and do not control for any confounding variables affecting outcome. The retrospective study design always raises concerns of bias, and the study was noncomparative to alternative antimicrobial therapies. Almost a quarter of patients (26/106 patients) were considered clinically nonevaluable for efficacy at the end of therapy and were excluded from the efficacy analysis.

In conclusion, this study provides an important foundation for other clinical trials to determine the ideal therapy for patients with S. aureus bacteremia. It further translates the potential benefit of daptomycin plus β-lactam for select patients with S. aureus bacteremia. While this effect has been suggested highly in vitro and for very difficult cases of S. aureus bacteremia, this is the first study to demonstrate this benefit in a more generalizable patient population and across the entire β-lactam class and dosing spectrum. The tolerability and safety of high-dose daptomycin (>6 mg/kg) will also require further study in patients with underlying renal disease as this dosing strategy becomes more common on the heels of advocacy by experts on MRSA treatment guidelines for bacteremia.