Multicenter Cohort of Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia Receiving Daptomycin Plus Ceftaroline Compared With Other MRSA Treatments

Design

Retrospective, matched cohort study

N= 171

Objective

To provide a descriptive exploratory analysis of patients placed on (daptomycin plus ceftaroline) DAP-CPT at any point in the treatment course vs. matched patients receiving standard of care (SOC) for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB).

Study Groups

DAP-CPT (n= 58)

SOC (n= 113)

Inclusion Criteria

≥18 years of age

Exclusion Criteria

≤72 hours of treatment with SOC or DAP-CPT, polymicrobial bacteremia

Methods

Participants were matched 2:1 when feasible, otherwise 1:1, prioritizing infection source, then age, and renal function. SOC included empiric vancomycin or daptomycin with any subsequent combination of antibiotics, excluding DAP-CPT.

Duration

January 2013 to October 2017

Outcome Measures

All cause 30-day mortality, duration of bacteremia, bacteremia relapse/recurrence

Baseline Characteristics

DAPT-CPT (n= 58)

SOC (n= 113)

Age, years

Female

Weight, kg

Source

Endovascular

Secondary

Catheter

31 (53%)

24 (42%)

3 (5%)

60 (53%)

47 (42%)

6 (5%)

Creatinine clearance

Hemodialysis

<50 mL/min

≥50 mL/min

33 (22%)

15 (26%)

30 (52%)

25 (22%)

27 (24%)

61 (54%)

Vancomycin MIC

≤1.0 mg/L

1.5-2.0 mg/L

33 (57%)

25 (43%)

62 (55%)

51 (45%)

 Pitt Score (IQR)

2 (0-9)

1 (0-10)

Comorbidities

Diabetes

Liver dysfunction

Cancer

Immune suppression

20 (34%)

13 (225)

2 (3%)

5 (9%)

48 (42%)

18 (16%)

4 (4%)

9 (8%)

Source control

17 (29%)

45 (40%)

MIC, minimum inhibitor concentration; IQR, interquartile range

Results

Endpoint

DAPT-CPT (n= 58)

SOC (n= 113)

p-value

30-day mortality rate

4 (6.8%)

16 (14.2%)

Not reported

Mean duration of bacteremia, days

Patients were escalated to DAP-CPT after a mean of 6 days of persistent bacteremia. Mean continued bacteremia after escalation was 3.3 days overall, with earlier escalation associated with shorter bacteremia: 3.6 days if switched within 24 h, 5.2 days within 72 h, and 12.2 days if after 72 h. There was a linear association between time to switch and bacteremia duration (p<0 .001).

Among patients receiving DAP-CPT within 72 hours, the overall 30-day mortality was 8.3%, (p> 0.05), with 4.3% in those with a primary endovascular source (p= 0.162). There was no difference in bacteremia relapse or recurrence at 90 days after initial microbiological clearance between DAP-CPT and SOC.

Adverse Events

Not disclosed

Study Author Conclusions

The authors concluded that receiving DAP-CPT early in the infection course may be more beneficial for survival, as opposed to its use as salvage therapy, especially in patients with endovascular sources or those at high risk of death.

InpharmD Researcher Critique

The study is limited by its retrospective, non-randomized design with inherent bias and by incomplete data on drug monitoring, susceptibility, and safety outcomes.

Clinical Data on Daptomycin plus Ceftaroline versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia

Design

Prospective, randomized, open-label pilot study

N= 40

Objective

To compare daptomycin plus ceftaroline (DAPCPT) versus standard of care vancomycin (VAN) or daptomycin (DAP) monotherapy in the treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) bacteremia

Study Groups

Daptomycin (DAP + CPT) plus ceftaroline (n= 17)

Vancomycin (VAN) (n= 21)

daptomycin (DAP) (n= 2)

Inclusion Criteria

Adult patients (age ≥ 18 years) with MRSA bacteremia identified in the clinical microbiology laboratory by the Nanosphere Verigene Gram-positive blood culture assay; infectious disease consultation at enrollment

Exclusion Criteria

Transfer from another facility, ≥ 72 h of pre-enrollment antibiotics, polymicrobial bacteremia, terminally ill with comfort-only measures at time of enrollment, or moribund with anticipated death within 72 h despite full therapy

Methods

Patients were randomized within ≤ 72 h of initial blood culture. The study group received 6 to 8 mg/kg/day DAP plus 600 mg with CPT every 8 hours. The control group received VAN (dosed at a trough 15 to 20 mg/L) or 6 to 8 mg/kg/day DAP as monotherapy. Blood cultures were obtained every 24 h until clearance (two consecutive negative days). Patients remained on randomized regimen ≥ 4 days; subsequent therapy was at the physician's discretion. If the patient was bacteremic for >5 days or failing clinically, the physician was able to alter the treatment regimen.

Duration

Enrollment: February 15, 2016, to December 1, 2016

Duration: 18 months at 3 hospitals 

Stopped early after enrollment of 40 patients due to the mortality difference

Outcome Measures

Primary outcomes: duration of bacteremia and in-hospital mortality

Secondary outcomes: 60- and 90-day mortality and length of hospital stay

Baseline Characteristics

DAP +CPT (n= 17)

VAN or DAP (n= 23)

Age, years

Male

Comorbidities

Cardiovascular Disease

Diabetes 

Cerebovascualr 

End-stage renal 

9 (53%)

6 (35%)

3 (18%)

3 (18%) 

10 (43%)

11 (48%)

0

6 (26%) 

Charlson index, median

Pitt bacteremia score 

Acute renal failure 

Intensive care 

3 (18%)

3 (18%)

5 (22%)

3 (13%)

Results

Endpoint

DAP +CPT (n= 17)

VAN or DAP (n= 23) 

p-value

Mortality 

In hospital 

30 day 

90 day 

0 

0

0

6 (26%)

6 (26%)

7 (30%)

0.02

0.02

0.03

Bacteremia duration, days (IQR)

3 (1.5 to 5.5)

3 (1 to 5.3)

0.56

Length of stay, days (IQR)

11 (6 to 14)

12 (8 to 23)

0.24

Event

Treatment failure

AKI

Asymptomatic elevated CPK

Eosinophillic pneumonia

1*

0

0

1***

3**

1

1

0 

IQR= interquartile range; CPK=creatine phosphokinase; AKI=Acute Kindey Injury

*Occurred after de-escalation to ceftaroline monotherapy.

*Early failure prompting switch to combination therapy at day 5 of therapy 

*Occurred after de-escalation to daptomycin monotherapy

Adverse Events

Adverse Events: See results

Study Author Conclusions

In summary, this exploratory study showed with a very small number of patients that initial therapy with DAP CPT may be associated with reduced in-hospital mortality compared with the treatment standards of VAN or DAP monotherapy in patients with MRSA bacteremia. The survival benefit, if any, may be limited to patients with high-risk endovascular sources and those with interleukin-10 (IL-10) of ≥5 pg/ml on the day of the first positive blood culture. Given what is potentially at stake in this pre-eminent nosocomial infection with unacceptably high treatment failure rates, we strongly encourage a larger prospective study conducted blindly to determine (i) the role of combination therapy, particularly with a β-lactam, in improving MRSA bacteremia outcomes; and (ii) employing biomarkers, such as IL-10, as potential risk stratification tools for allocating combination therapy to those at high risk.

InpharmD Researcher Critique

The trial was prospective, randomized, and multicenter with clinically meaningful endpoints. However, the open-label design, small sample with early termination, unequal group sizes, and baseline imbalances (e.g., higher malignancy in the monotherapy arm) may overstate the apparent mortality benefit of daptomycin + ceftaroline. Post hoc IL-10 stratification and allowance for rescue crossover/de-escalation further limit internal validity and generalizability; a larger, blinded RCT with prespecified stratification and standardized regimens is needed.

Daptomycin and Combination Daptomycin-Ceftaroline as Salvage Therapy for Persistent Methicillin-Resistant Staphylococcus Aureus Bacteremia

Design

Retrospective chart review

N= 17

Objective

To evaluate combination therapy with daptomycin plus ceftaroline and other regimens in treating persistent Methicillin-Resistant Staphylococcus Aureus (MRSA) bacteremia 

Study Groups

Daptomycin monotherapy, 2nd line (n= 5)

Daptomycin + ceftaroline, 2nd line (n= 4)

Daptomycin + ceftaroline, 3rd line (n= 8)

Inclusion Criteria

Patients with at least two blood cultures positive for MRSA over a period of at least 72 hours while receiving IV vancomycin and subsequently switched to therapy with daptomycin or daptomycin plus ceftaroline for at least 72 hours

Exclusion Criteria

Patients with no documented MRSA bacteremia on or after the date of switch from vancomycin to the second-line regimen

Methods

Retrospective chart review of patients switched to daptomycin or daptomycin plus ceftaroline after persistent MRSA bacteremia on vancomycin. Data, collected and reviewed from pharmacy records, included patient demographics, comorbidities, lab values, vancomycin trough levels, MRSA bacteremia source, antibiotic regimens, timing of therapy changes, and the dates of the first positive and persistently negative blood cultures (absence of recurrent bacteremia for at least 2 weeks). 

Duration

January 2012 through June 2015

Outcome Measures

Duration of bacteremia after change in therapy, incidence of recurrent MRSA bacteremia within 90 days of first persistently negative blood cultures, mortality during admission or within 90 days of the first persistently negative blood culture

Baseline Characteristics

Daptomycin monotherapy, 2nd line (n= 5)

Daptomycin + Ceftaroline, 2nd line (n= 4)

Daptomycin + Ceftaroline, 3rd line (n= 8)*

Age, years

Male

Ethnicity

Caucasian

African-American

40%

60% 

0%

100%

38%

62%

Weight, kg

Charlson Comorbidity Index Score (CCI)

Rate of ICU admission

Initial Cr, mean, mg/dL

Vancomycin MICs (mcg/mL)

1 or lower

1.5

2.0

1

3

2 

1

2

1 

0

5

3 

Median daptomycin MIC (mcg/mL)

Daptomycin plus ceftaroline given as third-line therapy after 2^nd line therapy with daptomycin (n=7) or vancomycin plus ceftaroline (n=1)

Results

Endpoint

Daptomycin monotherapy, 2nd line (n= 5)

Daptomycin + Ceftaroline, 2nd line (n= 4)

Daptomycin + Ceftaroline, 3rd line (n= 8)

Duration of bacteremia, days

Duration of bacteremia before switch to daptomycin-ceftaroline, days

Duration of bacteremia after switch to daptomycin-ceftaroline, days

Recurrent MRSA bacteremia within 90 days of initial bacteremia eradication 

Patients alive at 90 days after eradication of bacteremia

Significant clinical findings: There was a significant trend toward shorter durations of bacteremia before the switch to combination daptomycin-ceftaroline in patients who received that combination as 2nd rather than 3rd line therapy (6.8 vs. 11.5 days, p = 0.08). However, both groups experienced similar 90-day mortality rates.

Subpopulation analysis: Patients who survived their infections received combination daptomycin-ceftaroline a mean 2.1 days earlier than the patients who died.

Adverse Events

Study Author Conclusions

Early combination therapy with daptomycin and ceftaroline shortens prolonged MRSA bacteremia and may be helpful in securing favorable clinical outcomes. Larger, adequately-powered studies should be performed to better evaluate the role of early combination daptomycin and ceftaroline in improving survival among patients with persistent MRSA bacteremia and high risk for mortality.

InpharmD Researcher Critique

The study's retrospective nature and small sample size limit the generalizability of the findings. The lack of association between combination therapy and mortality benefit may have been confounded by physician's preference for more aggressive therapy in patients predicted to have a poor outcome.

Single-centre retrospective cohort study

N= 60

DAP + CPT (n= 30)

SoC (n= 30)