Ceftaroline fosamil monotherapy for methicillin resistant staphylococcus aureus bacteremia (MRSAB): a comparative clinical outcomes study

Ceftaroline fosamil monotherapy for methicillin resistant Staphylococcus aureus bacteremia (MRSAB) A comparative clinical outcomes study Accepted Manuscript Title Ceftaroline fosamil monotherapy for m[.]

Accepted Manuscript

Title: Ceftaroline fosamil monotherapy for

methicillin-resistant Staphylococcus aureus bacteremia

(MRSAB): A comparative clinical outcomes study

Authors: Samia Arshad, Vanthida Huang, Pamela Hartman,

Mary B Perri, Daniela Moreno, Marcus J Zervos

DOI: http://dx.doi.org/doi:10.1016/j.ijid.2017.01.019

Reference: IJID 2844

To appear in: International Journal of Infectious Diseases

Received date: 19-10-2016

Revised date: 13-1-2017

Accepted date: 18-1-2017

Please cite this article as: Arshad Samia, Huang Vanthida, Hartman Pamela, Perri Mary B, Moreno Daniela, Zervos Marcus J.Ceftaroline fosamil monotherapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB): A

comparative clinical outcomes study.International Journal of Infectious Diseases

http://dx.doi.org/10.1016/j.ijid.2017.01.019

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Ceftaroline fosamil monotherapy for methicillin-resistant Staphylococcus aureus

bacteremia (MRSAB): A comparative clinical outcomes study

Running Title: Ceftaroline for MRSA bloodstream infections

Samia Arshad1, Vanthida Huang2, Pamela Hartman1, Mary B Perri1, Daniela Moreno1,

Marcus J Zervos1,3

1Division of Infectious Diseases, Henry Ford Hospital, Detroit, MI, USA; 2Midwestern University College of Pharmacy-Glendale, Glendale, AZ, USA; 3Wayne State University

School of Medicine, Detroit, MI, USA

Corresponding Authors: Samia Arshad

Division of Infectious Diseases, Henry Ford Hospital

2799 West Grand Blvd, CFP 314 Detroit, MI 48202

Phone: 917-449-3734 Fax: 313-916-2993 Email: sarshad1@hfhs.org

Objectives: Vancomycin is the treatment of choice for methicillin-resistant

Staphylococcus aureus (MRSA) bacteremia; however, it has been scrutinized due to failure in severe infections Ceftaroline fosamil (CPT-F) is approved for MRSA acute bacterial skin and skin structure infection (ABSSSI) but not in bloodstream infections

We evaluated clinical outcomes of treatment with CPT-F in patients with MRSA

bacteremia (MRSAB)

Methods: Patients diagnosed with MRSAB at Henry Ford Hospital in Detroit, MI due to isolates with vancomycin MIC ≥ 1.0 mg/L, and susceptible in vitro to CPT-F were

systematically reviewed retrospectively CPT-F-treated patients were matched with vancomycin- and daptomycin-treated patients based on age (≥ 65 years), ICU status, and severity of illness Outcomes evaluated included duration of hospitalization,

duration of therapy, adverse events, relapse, hospital readmission, and death Results:

30 consecutive cases of MRSAB treated with CPT-F were identified from May

2011 - June 2013, and matched to 56 vancomycin and 46 daptomycin MRSAB patients Primary sources of CPT-F-treated MRSAB cohort were endocarditis (n=7, 23%),

skin/wound (n=9, 30%), and bone/joint (n=8, 27%) Origin of CPT-F-treated MRSAB was 43% community-acquired, 43% healthcare-associated, and 13% hospital- acquired Mean hospital length of stay for CPT-F pts was 22 days Overall 30-day mortality rate was observed in 13% (n=4) of CPT-F cases versus 24% (n=11) of daptomycin pts and 11% (n=6) in the vancomycin cohort (p=0.188)

Conclusions: Ceftaroline fosamil demonstrated comparable clinical outcomes in

MRSAB patients compared with the other agents, especially as salvage therapy

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Key Words: methicillin-resistant Staphylococcus aureus, bacteremia, bloodstream

infection, ceftaroline fosamil

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI)

continue to have high mortality with rates of 20-30% in recent studies [1], with an attributable 94,360 invasive infections and 18,650 deaths annually in the USA according

to the CDC [2] Due to the high rates of mortality, the key to improving outcomes includes better safety and efficacy of treatment, reduction of infection rates and better prevention measures to decrease readmission rates and hospitalization costs

The initial treatment of choice for serious MRSA infections is vancomycin [3, 4] However, there have been increasing reports of vancomycin failures and failures attributed to elevated vancomycin MIC’s [5] Consensus guidelines recommend consideration of the use of alternative agents in this setting [3,6], thus optimal therapeutic options for serious MRSA infections remains to be determined [3]

Ceftaroline fosamil (CPT-F) is a novel cephalosporin approved by the FDA for the treatment of acute bacterial skin and skin structure infections caused by MRSA and community-acquired bacterial pneumonia [7] Ceftaroline, which is the active metabolite

of the pro-drug ceftaroline fosamil has been used for the treatment of serious infections and reported as case observations [8, 9, 10, 11] There is no data which has evaluated comparative outcomes with this approach, and minimal evidence for the use of

ceftaroline therapy for strains with vancomycin heteroresistance, reduced in vitro

susceptibility within the susceptible range, or in patients that have failed or are intolerant

of vancomycin Currently, the role of ceftaroline has not been evaluated in the treatment

of severe MRSA infections Therefore, we sought to evaluate ceftaroline fosamil as

monotherapy versus daptomycin and vancomycin in the treatment of MRSAB with strains having vancomycin MICs of ≥ 1.0 mg/L

Methods

This was a retrospective matched cohort study conducted at Henry Ford Hospital in Detroit, MI, USA, which was approved by the hospital Institutional Review Board We identified patients ≥ 18 years of age who were diagnosed with MRSAB with vancomycin MIC ≥ 1.0 mg/L and susceptible to CPT-F from November 2009 to December 2013 The selection of antibiotics were at the discretion of the ID physicians caring for the patient Ceftaroline fosamil-treated patients were matched with two vancomycin and two daptomycin-treated control patients based on age (≥ 65 years), intensive care unit (ICU) status during MRSAB related admission, and severity of illness Severity was defined by source of BSI classified into 1 of 3 categories: low-risk sources (related mortality rate,

<10%) which included intravenous catheter, urinary tract, ear-nose-larynx, gynecologic sources and several manipulation-related sources; intermediate-risk sources (associated mortality rate, 10-20%) which included osteoarticular, soft-tissue, and unknown sources; and high-risk sources (mortality rate, >20%) which included endovascular, lower respiratory tract, abdominal, and central nervous system foci sources as previously described [12, 13] Demographic information and outcome measures collected included duration of hospitalization and therapy, adverse events, 42-day relapse, 30-day hospital readmission, and 30-day mortality from onset of infection

The initial identification of isolates and susceptibility testing via Vitek® 2 (BioMérieux,

Inc., Durham, NC) was performed by the clinical microbiology laboratory The MICs for

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CPT-F, daptomycin, and vancomycin were performed on all isolates utilizing Epsilometer tests (Etest; BioMérieux, Durham, NC) according to the manufacturer instructions The MICs for vancomycin were also performed on all isolates using broth microdilution according to CLSI guidelines [14] Isolates were screened for heteroresistance to vancomycin using the macrodilution method E-test (AB-Biodisk, Solna, Sweden) [15]

We estimated a sample size collection of charts on a total of 150 patients who were hospitalized with MRSA bacteremia during the study period, with approximately 30 patients (20%) treated with ceftaroline and 120 patients (80%) treated with other therapeutic agents; patients treated with ceftaroline versus vancomycin or daptomycin were matched 1:4 to yield a sufficient sample size for comparative analysis, using 2- sided significance level for α of 0.05 and 80% power Patient demographics were evaluated using descriptive statistics; categorical variables were compared using a χ2 test or Fisher exact test where sample sizes are small Continuous variables were compared using the 2-sample t test Conditional logistic regression modeling was used throughout to account for the case-control matching P < 0.05 was considered statistically significant All data were analyzed using both SPSS software version 20 and SAS software version 9.2 (SAS Institute Inc, Cary, NC) The primary outcome was composite failure defined as the presence of any of the 3 main efficacy endpoints including mortality within 30 days from onset of infection, infection relapse within 42 days or readmission within 30 days after end of treatment

Results

Overall, of 132 total patients, 30 consecutive cases of MRSAB treated with CPT-F were identified from May 2011 to December 2013 The matched control group consisted of

102 MRSAB patients, 46 daptomycin-treated, and 56 vancomycin-treated patients identified from November 2009 to May 2013 Baseline demographic information between all three treatment groups are shown in Table 1 Baseline demographics were similar in all treatment groups; however, CPT-F-treated patients had a longer duration of bacteremia (p=0.075) than the other two cohorts, which may be attributable to more than half of ceftaroline patients (n=17, 57%) initially failing standard treatment and consequently being switched to CPT-F due to documented poor clinical response per consulting ID physician The origin of MRSAB for CPT-F-treated versus standard of care treatment groups were 43% vs 61% community-acquired, 43% vs 34% healthcare-associated, and 13% vs 6% hospital-acquired, respectively Overall, 30-day mortality from onset of infection was observed in 13.3% of CPT-F-treated patients, 24%

of daptomycin-treated patients, and 11% of vancomycin treated patients (p=0.188) In the CPT-F-treated group, 3 of 4 patients who died were endocarditis bacteremia patients and 2 were left-sided with APACHE II score of 15-20 points The results from tables 2 and 3 indicate that the CPT-F treated patients were not significantly associated (either univariably or multivariably) with composite failure (mortality/relapse/readmission) Data indicates that the composite failure outcome was seen in 7 of 30 CPT-F patients (23.3%) and 22 of 102 non-ceftaroline patients (21.6%), this difference was not statistically significant (p=0.837) Patient-related factors associated with composite failure were African American race (p=0.026, OR: 7.1) and COPD (p=0.038, OR: 6.4) (Table 3) The duration of intravenous therapy for all patients

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was 4 to 8 weeks All but one of CPT-F-treated cases had microbiological cure at the end of treatment (97%) The susceptibility testing in the CPT-F-treated group was as follows: vancomycin MIC90 was 1.7 mg/L by Etest; mean vancomycin MIC was 1.13 mg/L by automation (Vitek® 2 [BioMérieux, Inc., Durham, NC]); mean daptomycin MIC  

was 0.52 mg/L and CPT-F MIC was 0.65 mg/L by E-test For the control group, vancomycin MIC90 was 1.6 mg/L by Etest, and 1.06 mg/L by Vitek The mean MICs for CPT-F and daptomycin were 0.62 mg/L and 0.52 mg/L, respectively, with one isolate which was intermediate-susceptible to CPT-F with a MIC of 1.5 mg/L None of the isolates in either treatment group demonstrated heteroresistance to vancomycin All susceptibilities were performed on all isolates with vancomycin utilizing Etest, Vitek® 2, and manual broth microdilution methods while CPT-F and daptomycin MICs were

performed using only Etest

Discussion

The treatment of choice for MRSAB was vancomycin for over 4 decades from its discovery In the last few decades; however, there has been increasing reports of vancomycin failure in patients with serious MRSA infections, such as bacteremia and infective endocarditis [12, 13] Furthermore, reports of increasing vancomycin MICs poses challenges for clinicians to maximize vancomycin pharmacodynamic parameters

to achieve the appropriate treatment dose for these infections [12, 13, 3, 4] The optimal management of MRSAB is uncertain The current IDSA recommendations for vancomycin are serum trough levels of 15-20 mg/L for serious infections [3] These serum trough levels; however, have not been shown to be safe with an associated risk

of nephrotoxicity in recent studies [16, 17] Nephrotoxicity, recurrence of infection, microbiologic failure, and mortality must be considered in the selection and overall clinical success of therapy Therefore, recommendations have been made for consideration of alternative agents However; most of the alternative agents do not have FDA indications for these serious infections which proven to be challenging for clinicians Daptomycin is recommended as an alternative per IDSA guidelines for the treatment

of MRSAB In 2012, Moore et al demonstrated daptomycin was associated with better

outcomes than vancomycin in the treatment of MRSAB with higher vancomycin MICs

(defined as MIC > 1 mg/L) [18] A year later, Murray et al demonstrated that an early

switch to daptomycin compared to vancomycin for the treatment of MRSAB with vancomycin MIC > 1 mg/L significantly improved outcomes [19] In addition, they have shown a decrease in 30-day mortality with daptomycin (20.0% vs 48.2%; P<0.001)

However, in 2011, Van Hal et al reported daptomycin resistance in a daptomycin-nạve

patient, and the need for optimal management in such cases; thus, investigators have shown the benefit of combination therapy with the addition of a β-lactam antibiotic such

as CPT-F with daptomycin versus daptomycin monotherapy to prevent daptomycin

resistance and sustain killing in the treatment of MRSAB [20, 21, 22] Cunha et al has

also reported a case of daptomycin resistance in an acute bacterial endocarditis patient following a week of vancomycin therapy for MRSAB who subsequently expired [23] A randomized, controlled trial comparing daptomycin vs vancomycin for the treatment of MRSAB due to high vancomycin MIC defined as ≥ 1 mg/L remains ongoing [24] Our experience in addition to the previous published data demonstrates inconsistent results

of daptomycin therapy in MRSAB with an elevated vancomycin MIC [4, 25]

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Previous literature demonstrates the paucity of data for the use of CPT-F in

treatment of MRSAB A case series of 10 patients by Lin et al found CPT-F to effectively

treat severe MRSA infections with a 70% microbiologic cure rate [10] Recently, there were 7 reports that investigated the utility of CPT-F in serious MRSA infections in patients who did not response to standard therapy [8, 9, 10, 11, 26] The largest study was a multicenter retrospective evaluation of CPT-F efficacy and safety in which

Casapao et al evaluated 527 patients who received CPT-F for at least 72 hours [26]

Bacteremia was noted in 28% (148/527) of patients and CPT-F was prescribed after approximately 6 days of vancomycin or daptomycin therapy Ceftaroline was most often

used in the treatment of S aureus infections, especially BSI

Our study demonstrated that CPT-F is not inferior to standard of treatment for MRSAB patients Approximately 90% of patients treated with CPT-F for MRSAB survived, despite difficulties associated with treatment options for MRSAB, an increasingly resistant pathogen We found a high prevalence of left-sided infective endocarditis (27%) in the CPT-F-treated cohort, which is an independent risk factor associated with mortality The CPT-F-treated patients had a longer duration of bacteremia (p=0.0053) than the control group patients, which is likely due to use of ceftaroline for patients with refractory MRSA BSI and alteration from standard therapy to CPT-F which is to the studies performed by Polenakovik and Casapao and their colleagues [8; 26]

The limitations to this study were its retrospective and single center setting; however, the strengths include consecutive patient and strain selection, large sample size for off-