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Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations
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Short communication
Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations夽 Joseph A. Paladino a,b,c,∗ , David M. Jacobs a,b , Ryan K. Shields d , Jerusha Taylor e , Justin Bader a , Martin H. Adelman b , Greg J. Wilton b , John K. Crane c,f , Jerome J. Schentag a,b a
University at Buffalo School of Pharmacy and Pharmaceutical Sciences, 213 Kapoor Hall, Buffalo, NY 14214, USA CPL Associates, LLC, 73 High St., Buffalo, NY 14203, USA c Erie County Medical Center, 462 Grider St., Buffalo, NY 14215, USA d University of Pittsburgh, Department of Medicine, 3601 Fifth Ave., Falk Medical Building, Suite 3A, Pittsburgh, PA 15213, USA e Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA f University at Buffalo School of Medicine, 326 Biomedical Research Building, 3435 Main St., Buffalo, NY 14214, USA b
a r t i c l e
i n f o
Article history: Received 6 February 2014 Accepted 14 July 2014 Keywords: Ceftaroline fosamil Vancomycin MRSA bacteraemia
a b s t r a c t Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2–4 g/mL). This multicentre, retrospective, case–control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 g/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3–15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3–7.5 days) vs. 8 days (IQR, 5.8–19.5 days); P = 0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P = 0.06) and 6% vs. 38% (P = 0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections. © 2014 Published by Elsevier B.V.
1. Introduction Meticillin-resistant Staphylococcus aureus bacteraemia (MRSAB) is a growing clinical concern that is associated with significant morbidity and mortality [1]. Vancomycin remains the first-line treatment for infections caused by MRSA. The susceptibility breakpoint for vancomycin has been set at ≤2 g/mL and on this basis
夽 These data were presented in part at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10–13 September 2013, Denver, CO. ∗ Corresponding author at: University at Buffalo, 213 Kapoor Hall, Buffalo, NY 14214, USA. Tel.: +1 716 713 5243; fax: +1 716 829 6093. E-mail address: [email protected] (J.A. Paladino).
the frequency of in vitro resistance to vancomycin remains low in most institutions. However, multiple reports have been published on the occurrence of elevated minimum inhibitory concentrations (MICs) among MRSA strains and the associated detrimental effect on the efficacy of vancomycin [2,3]. Indeed, a recent meta-analysis reported a vancomycin MIC ≥ 1 g/mL as a factor independently predictive of treatment failure [odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.60–4.51] and mortality among patients with MRSAB (OR = 1.58, 95% CI, 1.06–2.37) [4]. Adding to the concern with using vancomycin as firstline therapy for MRSAB is the emergence of heteroresistant vancomycin-intermediate S. aureus (hVISA) [5]. The frequency of hVISA has been shown to be MIC-dependent, with prevalence increasing steadily among strains with elevated MICs [6]. For MRSA
http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024 0924-8579/© 2014 Published by Elsevier B.V.
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
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isolates with elevated vancomycin MICs (≥1.5 g/mL) or strains that harbour the hVISA phenotype, the treatment of choice remains unclear. Ceftaroline, the active agent of the prodrug ceftaroline fosamil, is an extended-spectrum cephalosporin with activity against MRSA [7]. Use of ceftaroline in MRSAB and endocarditis with low vancomycin MICs has been described [8]. The objective of this study was to compare the time to pathogen eradication as well as the relationship with the time to clinical improvement between ceftaroline and case-matched high MIC (2–4 g/mL) vancomycin-treated controls in the treatment of adults with MRSAB and other serious infections. 2. Materials and methods 2.1. Study design and sites This was a retrospective, multicentre (Erie County Medical Center, Buffalo, NY; University of Pittsburgh Medical Center, Pittsburgh, PA; Oregon Health and Science University, Portland, OR; and Robert Wood Johnson Medical Center, New Brunswick, NJ), matched, case–control study conducted from November 2012 to August 2013. The institutional review boards (IRBs) at each of the participating medical centres approved the study. Owing to the retrospective nature of the data collection procedures, subject informed consent was not mandated by any of the IRBs.
if life expectancy was <3 months from the underlying disease, or patients who were on a prior antibiotic and showed clinical or microbiological cure before treatment with ceftaroline or vancomycin. 2.4. Definitions MRSA bloodstream infection was defined as patients with MRSA in blood cultures (MRSAB) that met the US Centers for Disease Control and Prevention (CDC) criteria for bloodstream infection [9]. The concomitant site with MRSA infection was determined by assessment of other MRSA-positive cultures at the time of onset of MRSAB. In the ceftaroline group, MRSA therapy included vancomycin, daptomycin, linezolid, tigecycline and rifampicin preceding a switch to ceftaroline. The control group encompassed treatment with all MRSA therapies as described above (except for ceftaroline). Time to eradication was calculated from the first day of ceftaroline in the ceftaroline treatment group and from the first day of MRSA therapy in the control group. Total days to eradication was calculated from the first day of any anti-MRSA therapy in the ceftaroline and control groups. Infection-related length of hospital stay (LOSIR ) was calculated from the first day of antibiotic therapy for MRSAB until the last day of antibiotic therapy or discharge, whichever occurred first [10]. 2.5. Microbiological response
Pertinent demographic and clinical data were obtained from electronic medical records for all patients. Variables collected include age, sex, weight, empirical treatment, in vitro susceptibility, duration of all antibiotics active against MRSA, time to eradication (days) and length of hospital stay associated with initiation of antibiotics. Results of any follow-up cultures obtained and documented in the medical records were examined to determine whether MRSA was eradicated from the primary infection site and/or blood.
A positive baseline infection site culture and/or blood culture provided the basis for evaluating microbiological results on the final day of anti-MRSA therapy or at discharge, whichever occurred first. Eradication was declared if MRSA was eliminated from the initial infection site during or upon completion of therapy. Eradication was presumed if the patient was improved clinically and there was an absence of appropriate material for culture or if further sampling of blood cultures was not clinically indicated. Time to eradication was calculated using the first day the causative pathogen was absent on repeat cultures, or when a presumed eradication was documented.
2.3. Study groups and analysis groups
2.6. Clinical outcomes assessment
Eligible case subjects were hospitalised patients aged ≥18 years identified with infections caused by MRSA (concomitant bacteraemia preferred) and treated with vancomycin (MIC = 2–4 g/mL) initially then switched to ceftaroline (MIC ≤ 1 g/mL), or placed on ceftaroline empirically. Additional inclusion criteria included clinical signs and symptoms of infection (body temperature >38 ◦ C or <36.1 ◦ C, white blood cell count >10 000 cells/mm3 and >10% bands at baseline), radiological findings consistent with pneumonia (chest radiograph with progressive infiltrate or consolidation), or wound redness, swelling or purulence in the case of acute bacterial skin and skin-structure infection (ABSSSI). An eligible control subject included similar patients with MRSA (concomitant bacteraemia preferred), treated with vancomycin (MIC = 2–4 g/mL), then continued on vancomycin or placed on an alternative antibiotic active against MRSA (excluding ceftaroline). Additional inclusion criteria included the clinical signs and symptoms or findings as described above. Controls were matched at a 1:1 ratio with cases, and matching parameters included vancomycin MIC, age (±15 years) and primary site of infection. For the purpose of matching, patients were placed into one of the following categories based on the primary source of bacteraemia: ABSSSI; endocarditis; osteomyelitis; pneumonia; complicated intra-abdominal infection; or automatic implantable cardioverter–defibrillator (AICD) infection. Patients were excluded if bacteraemia was determined to be catheter-related with no definitive evidence of secondary source,
Patients were placed in three groups: (i) case patients treated with other MRSA therapy prior to ceftaroline; (ii) case patients in the time period after initiation of ceftaroline; and (iii) vancomycintreated control patients. A pre-post assessment was performed to analyse case patients before and after ceftaroline use. A secondary comparison was done to assess the case patients versus vancomycin-matched controls. Outcomes included clinical success and LOSIR . Response was assessed for clinical success on the last day of antibiotic treatment [end of treatment (EOT)]. Success included cure or improvement. Cure was defined as complete resolution of all symptoms and signs of infection or a return to patient’s baseline state, and improvement was defined as clear improvement but incomplete resolution of all pre-therapy symptoms, or signs of incomplete return to the patient’s baseline status, with no further antibiotic treatment necessary. Failure was defined as persistence or progression of symptoms and signs of infection or any of the following: new clinical findings consistent with active infection; death due to infection; inability to complete study of antibiotic treatment due to adverse events; or treatment required with another antimicrobial regimen.
2.2. Data collection
2.7. Statistical methods Student’s t-test or Mann–Whitney U-test were used to compare continuous variables. Categorical variables were compared by
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
101
60/M
106
61/F
102
45/F
104
30/M
105
28/M
114
62/F
201
55/M
112
36/M
301
79/F
303
69/F
302
57/M
108
53/F
305
61/M
113
60/M
306
50/M
103
60/M
307
54/M
110
65/F
308
92/M
115
75/M
309
67/F
116
68/F
401
59/M
111
59/M
403
81/M
Infection site
ABSSSI
Antibiotic treatment
Previous MRSA therapy (days)a
Microbiological characteristics Time to eradication (days)
Total days to eradication
Total therapy (days)
Recurrence at Day 7
4
5
9
24
N
Y
–
19
19
32
N
N
3
3
6
11
N
Y
–
6
6
11
Y
Y
4
2
6
51
N
Y
–
34
34
34
Y
N
18
7
25
25
I
Y
–
5
5
19
N
Y
11
9
20
72
I
Y
VAN
–
4
4
33
N
N
CTR
0
5
5
48
I
Y
VAN
–
3
3
22
N
Y
2
13
15
22
Y
N
–
18
18
18
I
N
15
3
18
62
I
Y
–
6
6
44
Y
N
1
3
4
21
N
Y
–
4
4
10
N
Y
3
3
6
8
I
N
1
2
VAN
CTR
3
4
VAN ABSSSI
VAN
CTR
VAN Endo
VAN
CTR
VAN cIAI
Osteo
ABSSSI
AICD
Osteo
VAN
DAP
VAN
DAP
VAN
DAP
VAN
CTR
LZD
VAN
VAN
DAP
LZD
CTR
RIF
CTR
VAN ABSSSI
VAN
CTR
VAN LRTI
LRTI
VAN
CTR
VAN
LZD
TIG
–
78
78
84
Y
N
VAN
LZD
CTR
70
23
93
111
N
Y
–
7
7
15
N
Y
35
3
38
89
I
Y
9
9
9
I
Y
7
11
120
N
Y
VAN ABSSSI
CTR
VAN
DAP
CTR
VAN Osteo
Cure at end of treatment
VAN
CTR
4
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Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
Table 1 Patient characteristics and clinical outcomes of ceftaroline-treated cases versus matched vancomycin-treated controls.
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TIG 77/F 304
Endo
VAN
VAN 63/M 202
DAP
CTR
VAN 54/M 118
DAP
DAP VAN 44/M 310
CTR VAN 69/M 402
Endo
Endo
VAN 66/F 404
RIF
CTR DAP
VAN 88/F 117
TIG
3 2
MRSA, meticillin-resistant Staphylococcus aureus; ABSSSI, acute bacterial skin and skin-structure infection; Endo, endocarditis; cIAI, complicated intra-abdominal infection; Osteo, osteomyelitis; AICD, automatic implantable cardioverter-defibrillator; LRTI, lower respiratory tract infection; VAN, vancomycin; CTR, ceftaroline; DAP, daptomycin; LZD, linezolid; RIF, rifampicin; TIG, tigecycline; N, no; Y, yes; I, indeterminate. a Number of days patient received anti-MRSA therapy including VAN, DAP, LZD, TIG or RIF prior to CFT.
Y 81 –
12
12
N
Y I 21 19 6
13
9 –
6
6
I
N 26 14
3
17
I
N 35 –
21
21
Y
Y 93 88
2
90
N
N 52 –
52
52
Y
Cure at end of treatment Total therapy (days) Time to eradication (days)
Total days to eradication
Recurrence at Day 7 Table 1 (Continued)
Infection site
1
Age (years)/sex Case/control no.
Antibiotic treatment
4
Previous MRSA therapy (days)a
Microbiological characteristics
N
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Fisher’s exact test. P-values of ≤0.05 were considered statistically significant, and all tests were two-tailed. All statistical analyses were performed using SYSTAT v.12 (SYSTAT Software, Chicago, IL). 3. Results 3.1. Baseline demographics During the study period, 16 patients were identified as being treated with ceftaroline, primarily for MRSAB. The case patients were matched with 16 patients treated with vancomycin for MRSA; only 2 patients did not have a concurrent bacteraemia (Table 1). The mean (±standard deviation) age of the study subjects (N = 32) was 60.8 ± 14.5 years, and 20 patients (63%) were male. Sources of infection were ABSSSI (10 patients), endocarditis (8), osteomyelitis (6), pneumonia (4), complicated intra-abdominal infection (2) and AICD infection (2). No significant demographic differences existed between treatment groups. MRSA MICs to vancomycin were similar between groups, with a range of 2–4 g/mL (Table 2). The percent of MRSA isolates susceptible to vancomycin in the case and control groups was 81% and 100%, respectively. Daptomycin MICs ranged from 0.25 g/mL to 4 g/mL, with four non-susceptible strains found within the case group. All isolates of MRSA tested were susceptible to ceftaroline (MIC ≤ 1 g/mL). 3.2. Case groups: before and after ceftaroline Of the 16 patients in the case group, 15 (94%) first received vancomycin, whilst 1 patient received ceftaroline. Following failure of initial vancomycin treatment, 6 (40%) of the 15 patients were changed to daptomycin, and 2 (13%) to linezolid, prior to receiving ceftaroline. Overall, 14/15 patients (93%) receiving vancomycin, daptomycin or linezolid had persistently positive blood cultures and were treated for a median of 5 days [interquartile range (IQR), 3–15.8 days] prior to initiation of ceftaroline. MRSA was eradicated from the bloodstream in case patients at a median of 4 days (IQR, 3–7.5 days) after initiating ceftaroline (Table 3). There was one documented recurrence of MRSAB (Day 7) in a patient with an infected AICD with leads that were not removed. MRSAB reoccurred in this patient after 6 weeks of ceftaroline therapy. Thirteen (87%) of the 15 patients were treated successfully with ceftaroline following failure of previous MRSA therapy, and overall 14/16 ceftaroline-treated patients (88%) were successes. Thirteen patients received ceftaroline at the US Food and Drug Administration (FDA)- recommended dose of 600 mg every 12 h (q12 h) or a renally- adjusted dose based on the package insert [11]. Three patients received ceftaroline 600 mg every 8 h for the treatment of ABSSSI (n = 2) and osteomyelitis (n = 1). Ceftaroline combination therapy at the time of eradication was utilised in three patients including one each with rifampicin, daptomycin and vancomycin. Two patients with pneumonia and concurrent bacteraemia were treated with ceftaroline following failure of vancomycin or linezolid to eradicate MRSA. A 92-year-old male was treated with 3 days of vancomycin (MIC = 2 g/mL) for healthcare-associated pneumonia. Ceftaroline 600 mg q12 h was then initiated and MRSA was eradicated from the bloodstream in 3 days. The patient died in the intensive care unit on Day 8 of treatment owing to respiratory failure. In the other case, a 67-year-old female was treated for 70 days with vancomycin (MIC = 2 g/mL) followed by linezolid (MIC = 1.5 g/mL) for hospital-acquired pneumonia. She was switched to ceftaroline 300 mg q12 h and MRSAB was finally eradicated in 23 days. The patient received a total of 111 days of therapy: 70 days of vancomycin then linezolid followed by 41 days
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
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Table 2 Comparison of minimum inhibitory concentrations (MICs, in g/mL) between ceftaroline-treated cases and vancomycin-treated controls. Case
VAN MIC
CTR MIC
Other MICs
Matched control
VAN MIC
CTR MIC
Other MICs
101
2
0.75
106
2
1a
102
2
0.75
DAP = 1 RIF ≤1 RIF ≤ 1
104
2
105
2
0.75
114
2
TIG = 0.38a RIF ≤ 1 DAP = 1 RIF ≤ 1 RIF ≤ 1
201
2
0.5
112
2
DAP = 0.5
301
2
1.0
302 305
2 4
0.75 0.5
306 307 308 309 401 403 404 310
2 2 2 2 4 2 2 2
1 1 1 1a 0.5 0.5 1 0.5
202
4
0.5
LZD = 2 RIF ≤ 1 DAP = 1 LZD = 4 DAP = 0.5 LZD = 1.5 LZD = 2a DAP = 1
303
2
108 113
2 2
LZD = 1.5 DAP = 4 DAP = 4 DAP = 0.25 DAP = 1.5
103 110 115b 116 111 117a 402 118
2 2 2 2 2 2 2 2
304
2
a
0.5
0.5
1
DAP = 1 LZD = 4 RIF ≤ 1 LZD ≤ 2 RIF ≤ 1 RIF ≤1 RIF ≤1 RIF > 2 RIF ≤1 RIF ≤ 1 DAP = 0.25 DAP = 1 RIF ≤ 1 DAP = 1
VAN, vancomycin; CTR, ceftaroline; DAP, daptomycin; RIF, rifampicin; TIG, tigecycline; LZD, linezolid. a,b Data are from blood cultures unless indicated. a Wound. b Sputum.
of ceftaroline. She was discharged from hospital and treatment was deemed to be a success. 3.3. Ceftaroline cases versus vancomycin controls In the control group, 15/16 patients (94%) were started on vancomycin and 1 patient was started on linezolid for the treatment of MRSA. Following failure of vancomycin or linezolid to eradicate MRSA from the bloodstream, three patients transitioned to daptomycin, two patients to linezolid and three patients to tigecycline. In the ceftaroline cohort, median time to eradication of MRSA was 4 days shorter than in the vancomycin-treated controls: 4 days (IQR, 3–7.5 days) vs. 8 days (IQR, 5.8–19.5 days), respectively (P = 0.02) (Table 3). Patients treated with ceftaroline had a higher
rate of clinical success at EOT although the difference did not quite attain statistical significance (81% vs. 44%, respectively; P = 0.06). When counting initial days of vancomycin treatment, median total duration of therapy to eradicate MRSA was 9 days longer in the ceftaroline group [17 days (IQR, 6–21.3) vs. 8 days (IQR, 5.8–19.5 days), respectively; P = 0.18]. Ceftaroline-treated patients had a documented microbiological cure of 100% (16/16) compared with 88% (14/16) in vancomycin-treated controls (P = 0.48). In addition, recurrence of MRSA at Day 7 was documented in 6 (38%) vancomycin control patients compared with 1 (6%) ceftaroline patient. No difference in median LOSIR was detected between ceftaroline and vancomycin treatment groups [37 days (IQR, 21.8–76.3 days) vs. 22 days (IQR, 12–39.5 days), respectively; P = 0.12]. Overall, patients in the study (combined ceftaroline group and vancomycin controls) received vancomycin for a mean of 12 days
Table 3 Clinical characteristics and features of ceftaroline-treated cases versus vancomycin-treated controls.
Days of prior MRSA therapy Microbiological success Time to eradication (days)a Median (IQR) Mean ± S.D. Total days to eradicationb Median (IQR) Mean ± S.D. Recurrence at Day 7 Yes No Indeterminate Clinical success End of treatment Success Failure Length of stay (days)b
Ceftaroline (N = 16)
Vancomycin (N = 16)
5 (3–15.8) 16 (100)
– 14 (88)
4 (3–7.5) 6.5 ± 5.5
8 (5.8–19.5) 17.8 ± 20.1
17 (6–21.3) 23.9 ± 26.1
8 (5.8–19.5) 17.8 ± 20.1
1 (6) 7 (44) 8 (50)
6 (38) 7 (44) 3 (19)
13 (81) 3 (19) 37 (21.8–76.3)
7 (44) 9 (56) 22 (12–39.5)
P-value 0.48 0.02
0.18
0.08
0.06
0.12
MRSA, meticillin-resistant Staphylococcus aureus; IQR, interquartile range; S.D., standard deviation. Data are presented as N (%) or median (interquartile range), unless otherwise indicated. a Calculated from the first day of ceftaroline in the ceftaroline treatment group and from the first day of MRSA therapy in the control group. b Calculated from the first day of MRSA therapy in the ceftaroline and control groups.
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
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(N = 31), daptomycin for 13 days (N = 9) and linezolid for 11 days (N = 3).
4. Discussion Most patients are initiated on vancomycin when MRSA is a suspected or documented pathogen. For this reason, assessment of alternative treatment options are difficult in observational studies owing to confounding variables. Multiple reports document treatment failure of vancomycin against MRSA with elevated yet susceptible MICs, therefore a new paradigm in clinical practice may need to be considered [12]. In the current study, a novel prepost analysis, nested in a case–control study, was performed to examine time to eradication and clinical success in MRSA patients treated with various anti-MRSA medications. This method allowed for interpatient evaluation of MRSA in those treated with ceftaroline, and intrapatient evaluation between ceftaroline cases and vancomycin controls. The results of the pre-post analysis indicate MRSAB clearance in a median of 4 days following initiation of ceftaroline therapy in patients who failed prior MRSA therapy. Polenakovik and Pleiman reported a case series of 31 patients treated with ceftaroline for MRSAB [8]. Similar to the current findings, MRSAB was eradicated in a median of 3.5 days with ceftaroline following treatment failure with vancomycin, daptomycin or linezolid. The MICs of vancomycin to S. aureus in the abovementioned study ranged between 1 g/mL and 2 g/mL, whilst all of the patients in the present study had a vancomycin MIC of ≥2 g/mL. With higher vancomycin MICs becoming more prevalent and difficult to treat, ceftaroline may become a viable alternative. More than 80% of ceftaroline-treated patients in the current cohort met the criteria for clinical success. The failure rate in the vancomycin-treated controls was ca. 50%, which is similar to recent studies [13,14]. Time to eradication for vancomycin in the vancomycin-treated controls ranged from 3 days to 78 days, indicating that some patients given vancomycin for MRSAB with MICs ≥2 g/mL achieve eradication quickly, an observation that was surprising to us. Therefore, despite the mean day of eradication difference in otherwise matched patients, the variability in vancomycin time to eradication led to a case-matched study population underpowered to show a statistically significant difference in clinical success between the two groups. The lack of statistical power is likely due to the small number of patients examined, with only 16 patients in each group. Bacterial eradication after treatment of MRSAB has been shown to decrease the risk of all-cause 30-day mortality [15]. In the current study, the time to eradication in patients after treatment with ceftaroline was 4 days less than the vancomycin-treated controls. A study by Murray et al. examined daptomycin in patients with high vancomycin MICs (>1 g/mL) to S. aureus [14]. Time to eradication of MRSAB was shorter in the daptomycin-treated group than the vancomycin-treated cohort. However, that study excluded patients who received ≥72 h of alternative MRSA therapy, including patients switched from vancomycin to daptomycin. As seen in the current study, patients in the real world are often treated with multiple antibiotics for varying durations for MRSAB. As bacterial eradication is an important outcome to decrease all-cause mortality of MRSAB, utilising time to eradication as an endpoint may be necessary in the era of increasing resistance. The primary limitation to this study was the small number of patients. We had only 32 patients (16 cases and 16 controls). As we do concede the power of the study was undersized it may be due to the fact that ceftaroline for the treatment of MRSAB is relatively novel and we only included patients with a vancomycin MIC of ≥2 g/mL. Another limitation is the retrospective design. As this
was a multicentre study, we were able to enhance the external validity of the findings, but additional limitations are present within the study design. In summary, vancomycin is particularly unsuccessful in patients having an infection caused by MRSA with vancomycin MICs ≥ 2 g/mL, with persistence of bacteraemia in non-catheter infection sites. Ceftaroline fosamil added at the point of failure resolves bacteraemia more rapidly than would have occurred if the vancomycin regimen had been continued. Furthermore, patients treated with ceftaroline had a higher rate of success and a lower percentage of recurrence of MRSAB. In addition, we attempted a novel pre-post analysis within the ceftaroline-treated cohort to assess ‘real world’ patients. Commonly, patients with antimicrobial-resistant infections are put on multiple antibiotics prior to initiation of an acceptable regimen. Alternative methods of assessment for these patients are necessary in order to properly gauge their impact on the healthcare system. Based on these findings, ceftaroline was an efficacious alternative for the treatment of MRSAB with high vancomycin MICs. Funding: This study was funded by a grant from Forest Laboratories, Inc. Competing interests: JAP and JJS are on the speaker’s bureau for Forest Pharmaceuticals, Inc.; RKS has received funding from Astellas and Pfizer and is currently supported by the National Institutes of Health (NIH) [grant no. KL2TR00146]; JKC has received funding for research through the National Institute of Allergy and Infectious Diseases (NIAID, NIH) and the University at Buffalo Civic Engagement Research Fellowship. All other authors declare no competing interests. Ethical approval: The study protocol was approved by the Institutional Review Board (IRB) at the co-ordinating centre (SUNY University at Buffalo Health Sciences, Buffalo, NY) [392398–4]. The IRBs at each of the participating medical centres approved the study. Owing to the retrospective nature of the data collection procedures, subject informed consent was not mandated by any of the IRBs.
References [1] Jarvis WR, Jarvis AA, Chinn RY. National prevalence of methicillin-resistant Staphylococcus aureus in inpatients at United States health care facilities, 2010. Am J Infect Control 2012;40:194–200. [2] Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, et al. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother 2008;52:3315–20. [3] Moise PA, Sakoulas G, Forrest A, Schentag JJ. Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance of methicillinresistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2007;51:2582–6. [4] van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 2012;54:755–71. [5] Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003;47:3040–5. [6] Musta AC, Riederer K, Shemes S, Chase P, Jose J, Johnson LB, et al. Vancomycin MIC plus heteroresistance and outcome of methicillin-resistant Staphylococcus aureus bacteremia: trends over 11 years. J Clin Microbiol 2009;47: 1640–4. [7] Steed ME, Rybak MJ. Ceftaroline: a new cephalosporin with activity against resistant Gram-positive pathogens. Pharmacotherapy 2010;30:375– 89. [8] Polenakovik HM, Pleiman CM. Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature. Int J Antimicrob Agents 2013;42:450–5. [9] Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128–40. [10] Paladino JA, Fell RE. Pharmacoeconomic analysis of cefmenoxime dual individualization in the treatment of nosocomial pneumonia. Ann Pharmacother 1994;28:384–9. [11] Forest Laboratories. Teflaro (ceftaroline) package insert. New York, NY: Forest Laboratories; 2013.
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
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[12] Wi YM, Kim JM, Joo EJ, Ha YE, Kang CI, Ko KS, et al. High vancomycin minimum inhibitory concentration is a predictor of mortality in meticillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents 2012;40:108–13. [13] Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ. Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case-control study. Clin Infect Dis 2012;54:51–8.
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[14] Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P, et al. Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study. Clin Infect Dis 2013;56:1562–9. [15] Park SY, Oh IH, Lee HJ, Ihm CG, Son JS, Lee MS, et al. Impact of reduced vancomycin MIC on clinical outcomes of methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2013;57:5536–42.
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Contents lists available at ScienceDirect
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Short communication
Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations夽 Joseph A. Paladino a,b,c,∗ , David M. Jacobs a,b , Ryan K. Shields d , Jerusha Taylor e , Justin Bader a , Martin H. Adelman b , Greg J. Wilton b , John K. Crane c,f , Jerome J. Schentag a,b a
University at Buffalo School of Pharmacy and Pharmaceutical Sciences, 213 Kapoor Hall, Buffalo, NY 14214, USA CPL Associates, LLC, 73 High St., Buffalo, NY 14203, USA c Erie County Medical Center, 462 Grider St., Buffalo, NY 14215, USA d University of Pittsburgh, Department of Medicine, 3601 Fifth Ave., Falk Medical Building, Suite 3A, Pittsburgh, PA 15213, USA e Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA f University at Buffalo School of Medicine, 326 Biomedical Research Building, 3435 Main St., Buffalo, NY 14214, USA b
a r t i c l e
i n f o
Article history: Received 6 February 2014 Accepted 14 July 2014 Keywords: Ceftaroline fosamil Vancomycin MRSA bacteraemia
a b s t r a c t Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2–4 g/mL). This multicentre, retrospective, case–control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 g/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3–15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3–7.5 days) vs. 8 days (IQR, 5.8–19.5 days); P = 0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P = 0.06) and 6% vs. 38% (P = 0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections. © 2014 Published by Elsevier B.V.
1. Introduction Meticillin-resistant Staphylococcus aureus bacteraemia (MRSAB) is a growing clinical concern that is associated with significant morbidity and mortality [1]. Vancomycin remains the first-line treatment for infections caused by MRSA. The susceptibility breakpoint for vancomycin has been set at ≤2 g/mL and on this basis
夽 These data were presented in part at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10–13 September 2013, Denver, CO. ∗ Corresponding author at: University at Buffalo, 213 Kapoor Hall, Buffalo, NY 14214, USA. Tel.: +1 716 713 5243; fax: +1 716 829 6093. E-mail address: [email protected] (J.A. Paladino).
the frequency of in vitro resistance to vancomycin remains low in most institutions. However, multiple reports have been published on the occurrence of elevated minimum inhibitory concentrations (MICs) among MRSA strains and the associated detrimental effect on the efficacy of vancomycin [2,3]. Indeed, a recent meta-analysis reported a vancomycin MIC ≥ 1 g/mL as a factor independently predictive of treatment failure [odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.60–4.51] and mortality among patients with MRSAB (OR = 1.58, 95% CI, 1.06–2.37) [4]. Adding to the concern with using vancomycin as firstline therapy for MRSAB is the emergence of heteroresistant vancomycin-intermediate S. aureus (hVISA) [5]. The frequency of hVISA has been shown to be MIC-dependent, with prevalence increasing steadily among strains with elevated MICs [6]. For MRSA
http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024 0924-8579/© 2014 Published by Elsevier B.V.
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isolates with elevated vancomycin MICs (≥1.5 g/mL) or strains that harbour the hVISA phenotype, the treatment of choice remains unclear. Ceftaroline, the active agent of the prodrug ceftaroline fosamil, is an extended-spectrum cephalosporin with activity against MRSA [7]. Use of ceftaroline in MRSAB and endocarditis with low vancomycin MICs has been described [8]. The objective of this study was to compare the time to pathogen eradication as well as the relationship with the time to clinical improvement between ceftaroline and case-matched high MIC (2–4 g/mL) vancomycin-treated controls in the treatment of adults with MRSAB and other serious infections. 2. Materials and methods 2.1. Study design and sites This was a retrospective, multicentre (Erie County Medical Center, Buffalo, NY; University of Pittsburgh Medical Center, Pittsburgh, PA; Oregon Health and Science University, Portland, OR; and Robert Wood Johnson Medical Center, New Brunswick, NJ), matched, case–control study conducted from November 2012 to August 2013. The institutional review boards (IRBs) at each of the participating medical centres approved the study. Owing to the retrospective nature of the data collection procedures, subject informed consent was not mandated by any of the IRBs.
if life expectancy was <3 months from the underlying disease, or patients who were on a prior antibiotic and showed clinical or microbiological cure before treatment with ceftaroline or vancomycin. 2.4. Definitions MRSA bloodstream infection was defined as patients with MRSA in blood cultures (MRSAB) that met the US Centers for Disease Control and Prevention (CDC) criteria for bloodstream infection [9]. The concomitant site with MRSA infection was determined by assessment of other MRSA-positive cultures at the time of onset of MRSAB. In the ceftaroline group, MRSA therapy included vancomycin, daptomycin, linezolid, tigecycline and rifampicin preceding a switch to ceftaroline. The control group encompassed treatment with all MRSA therapies as described above (except for ceftaroline). Time to eradication was calculated from the first day of ceftaroline in the ceftaroline treatment group and from the first day of MRSA therapy in the control group. Total days to eradication was calculated from the first day of any anti-MRSA therapy in the ceftaroline and control groups. Infection-related length of hospital stay (LOSIR ) was calculated from the first day of antibiotic therapy for MRSAB until the last day of antibiotic therapy or discharge, whichever occurred first [10]. 2.5. Microbiological response
Pertinent demographic and clinical data were obtained from electronic medical records for all patients. Variables collected include age, sex, weight, empirical treatment, in vitro susceptibility, duration of all antibiotics active against MRSA, time to eradication (days) and length of hospital stay associated with initiation of antibiotics. Results of any follow-up cultures obtained and documented in the medical records were examined to determine whether MRSA was eradicated from the primary infection site and/or blood.
A positive baseline infection site culture and/or blood culture provided the basis for evaluating microbiological results on the final day of anti-MRSA therapy or at discharge, whichever occurred first. Eradication was declared if MRSA was eliminated from the initial infection site during or upon completion of therapy. Eradication was presumed if the patient was improved clinically and there was an absence of appropriate material for culture or if further sampling of blood cultures was not clinically indicated. Time to eradication was calculated using the first day the causative pathogen was absent on repeat cultures, or when a presumed eradication was documented.
2.3. Study groups and analysis groups
2.6. Clinical outcomes assessment
Eligible case subjects were hospitalised patients aged ≥18 years identified with infections caused by MRSA (concomitant bacteraemia preferred) and treated with vancomycin (MIC = 2–4 g/mL) initially then switched to ceftaroline (MIC ≤ 1 g/mL), or placed on ceftaroline empirically. Additional inclusion criteria included clinical signs and symptoms of infection (body temperature >38 ◦ C or <36.1 ◦ C, white blood cell count >10 000 cells/mm3 and >10% bands at baseline), radiological findings consistent with pneumonia (chest radiograph with progressive infiltrate or consolidation), or wound redness, swelling or purulence in the case of acute bacterial skin and skin-structure infection (ABSSSI). An eligible control subject included similar patients with MRSA (concomitant bacteraemia preferred), treated with vancomycin (MIC = 2–4 g/mL), then continued on vancomycin or placed on an alternative antibiotic active against MRSA (excluding ceftaroline). Additional inclusion criteria included the clinical signs and symptoms or findings as described above. Controls were matched at a 1:1 ratio with cases, and matching parameters included vancomycin MIC, age (±15 years) and primary site of infection. For the purpose of matching, patients were placed into one of the following categories based on the primary source of bacteraemia: ABSSSI; endocarditis; osteomyelitis; pneumonia; complicated intra-abdominal infection; or automatic implantable cardioverter–defibrillator (AICD) infection. Patients were excluded if bacteraemia was determined to be catheter-related with no definitive evidence of secondary source,
Patients were placed in three groups: (i) case patients treated with other MRSA therapy prior to ceftaroline; (ii) case patients in the time period after initiation of ceftaroline; and (iii) vancomycintreated control patients. A pre-post assessment was performed to analyse case patients before and after ceftaroline use. A secondary comparison was done to assess the case patients versus vancomycin-matched controls. Outcomes included clinical success and LOSIR . Response was assessed for clinical success on the last day of antibiotic treatment [end of treatment (EOT)]. Success included cure or improvement. Cure was defined as complete resolution of all symptoms and signs of infection or a return to patient’s baseline state, and improvement was defined as clear improvement but incomplete resolution of all pre-therapy symptoms, or signs of incomplete return to the patient’s baseline status, with no further antibiotic treatment necessary. Failure was defined as persistence or progression of symptoms and signs of infection or any of the following: new clinical findings consistent with active infection; death due to infection; inability to complete study of antibiotic treatment due to adverse events; or treatment required with another antimicrobial regimen.
2.2. Data collection
2.7. Statistical methods Student’s t-test or Mann–Whitney U-test were used to compare continuous variables. Categorical variables were compared by
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
101
60/M
106
61/F
102
45/F
104
30/M
105
28/M
114
62/F
201
55/M
112
36/M
301
79/F
303
69/F
302
57/M
108
53/F
305
61/M
113
60/M
306
50/M
103
60/M
307
54/M
110
65/F
308
92/M
115
75/M
309
67/F
116
68/F
401
59/M
111
59/M
403
81/M
Infection site
ABSSSI
Antibiotic treatment
Previous MRSA therapy (days)a
Microbiological characteristics Time to eradication (days)
Total days to eradication
Total therapy (days)
Recurrence at Day 7
4
5
9
24
N
Y
–
19
19
32
N
N
3
3
6
11
N
Y
–
6
6
11
Y
Y
4
2
6
51
N
Y
–
34
34
34
Y
N
18
7
25
25
I
Y
–
5
5
19
N
Y
11
9
20
72
I
Y
VAN
–
4
4
33
N
N
CTR
0
5
5
48
I
Y
VAN
–
3
3
22
N
Y
2
13
15
22
Y
N
–
18
18
18
I
N
15
3
18
62
I
Y
–
6
6
44
Y
N
1
3
4
21
N
Y
–
4
4
10
N
Y
3
3
6
8
I
N
1
2
VAN
CTR
3
4
VAN ABSSSI
VAN
CTR
VAN Endo
VAN
CTR
VAN cIAI
Osteo
ABSSSI
AICD
Osteo
VAN
DAP
VAN
DAP
VAN
DAP
VAN
CTR
LZD
VAN
VAN
DAP
LZD
CTR
RIF
CTR
VAN ABSSSI
VAN
CTR
VAN LRTI
LRTI
VAN
CTR
VAN
LZD
TIG
–
78
78
84
Y
N
VAN
LZD
CTR
70
23
93
111
N
Y
–
7
7
15
N
Y
35
3
38
89
I
Y
9
9
9
I
Y
7
11
120
N
Y
VAN ABSSSI
CTR
VAN
DAP
CTR
VAN Osteo
Cure at end of treatment
VAN
CTR
4
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Table 1 Patient characteristics and clinical outcomes of ceftaroline-treated cases versus matched vancomycin-treated controls.
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TIG 77/F 304
Endo
VAN
VAN 63/M 202
DAP
CTR
VAN 54/M 118
DAP
DAP VAN 44/M 310
CTR VAN 69/M 402
Endo
Endo
VAN 66/F 404
RIF
CTR DAP
VAN 88/F 117
TIG
3 2
MRSA, meticillin-resistant Staphylococcus aureus; ABSSSI, acute bacterial skin and skin-structure infection; Endo, endocarditis; cIAI, complicated intra-abdominal infection; Osteo, osteomyelitis; AICD, automatic implantable cardioverter-defibrillator; LRTI, lower respiratory tract infection; VAN, vancomycin; CTR, ceftaroline; DAP, daptomycin; LZD, linezolid; RIF, rifampicin; TIG, tigecycline; N, no; Y, yes; I, indeterminate. a Number of days patient received anti-MRSA therapy including VAN, DAP, LZD, TIG or RIF prior to CFT.
Y 81 –
12
12
N
Y I 21 19 6
13
9 –
6
6
I
N 26 14
3
17
I
N 35 –
21
21
Y
Y 93 88
2
90
N
N 52 –
52
52
Y
Cure at end of treatment Total therapy (days) Time to eradication (days)
Total days to eradication
Recurrence at Day 7 Table 1 (Continued)
Infection site
1
Age (years)/sex Case/control no.
Antibiotic treatment
4
Previous MRSA therapy (days)a
Microbiological characteristics
N
J.A. Paladino et al. / International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
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Fisher’s exact test. P-values of ≤0.05 were considered statistically significant, and all tests were two-tailed. All statistical analyses were performed using SYSTAT v.12 (SYSTAT Software, Chicago, IL). 3. Results 3.1. Baseline demographics During the study period, 16 patients were identified as being treated with ceftaroline, primarily for MRSAB. The case patients were matched with 16 patients treated with vancomycin for MRSA; only 2 patients did not have a concurrent bacteraemia (Table 1). The mean (±standard deviation) age of the study subjects (N = 32) was 60.8 ± 14.5 years, and 20 patients (63%) were male. Sources of infection were ABSSSI (10 patients), endocarditis (8), osteomyelitis (6), pneumonia (4), complicated intra-abdominal infection (2) and AICD infection (2). No significant demographic differences existed between treatment groups. MRSA MICs to vancomycin were similar between groups, with a range of 2–4 g/mL (Table 2). The percent of MRSA isolates susceptible to vancomycin in the case and control groups was 81% and 100%, respectively. Daptomycin MICs ranged from 0.25 g/mL to 4 g/mL, with four non-susceptible strains found within the case group. All isolates of MRSA tested were susceptible to ceftaroline (MIC ≤ 1 g/mL). 3.2. Case groups: before and after ceftaroline Of the 16 patients in the case group, 15 (94%) first received vancomycin, whilst 1 patient received ceftaroline. Following failure of initial vancomycin treatment, 6 (40%) of the 15 patients were changed to daptomycin, and 2 (13%) to linezolid, prior to receiving ceftaroline. Overall, 14/15 patients (93%) receiving vancomycin, daptomycin or linezolid had persistently positive blood cultures and were treated for a median of 5 days [interquartile range (IQR), 3–15.8 days] prior to initiation of ceftaroline. MRSA was eradicated from the bloodstream in case patients at a median of 4 days (IQR, 3–7.5 days) after initiating ceftaroline (Table 3). There was one documented recurrence of MRSAB (Day 7) in a patient with an infected AICD with leads that were not removed. MRSAB reoccurred in this patient after 6 weeks of ceftaroline therapy. Thirteen (87%) of the 15 patients were treated successfully with ceftaroline following failure of previous MRSA therapy, and overall 14/16 ceftaroline-treated patients (88%) were successes. Thirteen patients received ceftaroline at the US Food and Drug Administration (FDA)- recommended dose of 600 mg every 12 h (q12 h) or a renally- adjusted dose based on the package insert [11]. Three patients received ceftaroline 600 mg every 8 h for the treatment of ABSSSI (n = 2) and osteomyelitis (n = 1). Ceftaroline combination therapy at the time of eradication was utilised in three patients including one each with rifampicin, daptomycin and vancomycin. Two patients with pneumonia and concurrent bacteraemia were treated with ceftaroline following failure of vancomycin or linezolid to eradicate MRSA. A 92-year-old male was treated with 3 days of vancomycin (MIC = 2 g/mL) for healthcare-associated pneumonia. Ceftaroline 600 mg q12 h was then initiated and MRSA was eradicated from the bloodstream in 3 days. The patient died in the intensive care unit on Day 8 of treatment owing to respiratory failure. In the other case, a 67-year-old female was treated for 70 days with vancomycin (MIC = 2 g/mL) followed by linezolid (MIC = 1.5 g/mL) for hospital-acquired pneumonia. She was switched to ceftaroline 300 mg q12 h and MRSAB was finally eradicated in 23 days. The patient received a total of 111 days of therapy: 70 days of vancomycin then linezolid followed by 41 days
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
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Table 2 Comparison of minimum inhibitory concentrations (MICs, in g/mL) between ceftaroline-treated cases and vancomycin-treated controls. Case
VAN MIC
CTR MIC
Other MICs
Matched control
VAN MIC
CTR MIC
Other MICs
101
2
0.75
106
2
1a
102
2
0.75
DAP = 1 RIF ≤1 RIF ≤ 1
104
2
105
2
0.75
114
2
TIG = 0.38a RIF ≤ 1 DAP = 1 RIF ≤ 1 RIF ≤ 1
201
2
0.5
112
2
DAP = 0.5
301
2
1.0
302 305
2 4
0.75 0.5
306 307 308 309 401 403 404 310
2 2 2 2 4 2 2 2
1 1 1 1a 0.5 0.5 1 0.5
202
4
0.5
LZD = 2 RIF ≤ 1 DAP = 1 LZD = 4 DAP = 0.5 LZD = 1.5 LZD = 2a DAP = 1
303
2
108 113
2 2
LZD = 1.5 DAP = 4 DAP = 4 DAP = 0.25 DAP = 1.5
103 110 115b 116 111 117a 402 118
2 2 2 2 2 2 2 2
304
2
a
0.5
0.5
1
DAP = 1 LZD = 4 RIF ≤ 1 LZD ≤ 2 RIF ≤ 1 RIF ≤1 RIF ≤1 RIF > 2 RIF ≤1 RIF ≤ 1 DAP = 0.25 DAP = 1 RIF ≤ 1 DAP = 1
VAN, vancomycin; CTR, ceftaroline; DAP, daptomycin; RIF, rifampicin; TIG, tigecycline; LZD, linezolid. a,b Data are from blood cultures unless indicated. a Wound. b Sputum.
of ceftaroline. She was discharged from hospital and treatment was deemed to be a success. 3.3. Ceftaroline cases versus vancomycin controls In the control group, 15/16 patients (94%) were started on vancomycin and 1 patient was started on linezolid for the treatment of MRSA. Following failure of vancomycin or linezolid to eradicate MRSA from the bloodstream, three patients transitioned to daptomycin, two patients to linezolid and three patients to tigecycline. In the ceftaroline cohort, median time to eradication of MRSA was 4 days shorter than in the vancomycin-treated controls: 4 days (IQR, 3–7.5 days) vs. 8 days (IQR, 5.8–19.5 days), respectively (P = 0.02) (Table 3). Patients treated with ceftaroline had a higher
rate of clinical success at EOT although the difference did not quite attain statistical significance (81% vs. 44%, respectively; P = 0.06). When counting initial days of vancomycin treatment, median total duration of therapy to eradicate MRSA was 9 days longer in the ceftaroline group [17 days (IQR, 6–21.3) vs. 8 days (IQR, 5.8–19.5 days), respectively; P = 0.18]. Ceftaroline-treated patients had a documented microbiological cure of 100% (16/16) compared with 88% (14/16) in vancomycin-treated controls (P = 0.48). In addition, recurrence of MRSA at Day 7 was documented in 6 (38%) vancomycin control patients compared with 1 (6%) ceftaroline patient. No difference in median LOSIR was detected between ceftaroline and vancomycin treatment groups [37 days (IQR, 21.8–76.3 days) vs. 22 days (IQR, 12–39.5 days), respectively; P = 0.12]. Overall, patients in the study (combined ceftaroline group and vancomycin controls) received vancomycin for a mean of 12 days
Table 3 Clinical characteristics and features of ceftaroline-treated cases versus vancomycin-treated controls.
Days of prior MRSA therapy Microbiological success Time to eradication (days)a Median (IQR) Mean ± S.D. Total days to eradicationb Median (IQR) Mean ± S.D. Recurrence at Day 7 Yes No Indeterminate Clinical success End of treatment Success Failure Length of stay (days)b
Ceftaroline (N = 16)
Vancomycin (N = 16)
5 (3–15.8) 16 (100)
– 14 (88)
4 (3–7.5) 6.5 ± 5.5
8 (5.8–19.5) 17.8 ± 20.1
17 (6–21.3) 23.9 ± 26.1
8 (5.8–19.5) 17.8 ± 20.1
1 (6) 7 (44) 8 (50)
6 (38) 7 (44) 3 (19)
13 (81) 3 (19) 37 (21.8–76.3)
7 (44) 9 (56) 22 (12–39.5)
P-value 0.48 0.02
0.18
0.08
0.06
0.12
MRSA, meticillin-resistant Staphylococcus aureus; IQR, interquartile range; S.D., standard deviation. Data are presented as N (%) or median (interquartile range), unless otherwise indicated. a Calculated from the first day of ceftaroline in the ceftaroline treatment group and from the first day of MRSA therapy in the control group. b Calculated from the first day of MRSA therapy in the ceftaroline and control groups.
Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024
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(N = 31), daptomycin for 13 days (N = 9) and linezolid for 11 days (N = 3).
4. Discussion Most patients are initiated on vancomycin when MRSA is a suspected or documented pathogen. For this reason, assessment of alternative treatment options are difficult in observational studies owing to confounding variables. Multiple reports document treatment failure of vancomycin against MRSA with elevated yet susceptible MICs, therefore a new paradigm in clinical practice may need to be considered [12]. In the current study, a novel prepost analysis, nested in a case–control study, was performed to examine time to eradication and clinical success in MRSA patients treated with various anti-MRSA medications. This method allowed for interpatient evaluation of MRSA in those treated with ceftaroline, and intrapatient evaluation between ceftaroline cases and vancomycin controls. The results of the pre-post analysis indicate MRSAB clearance in a median of 4 days following initiation of ceftaroline therapy in patients who failed prior MRSA therapy. Polenakovik and Pleiman reported a case series of 31 patients treated with ceftaroline for MRSAB [8]. Similar to the current findings, MRSAB was eradicated in a median of 3.5 days with ceftaroline following treatment failure with vancomycin, daptomycin or linezolid. The MICs of vancomycin to S. aureus in the abovementioned study ranged between 1 g/mL and 2 g/mL, whilst all of the patients in the present study had a vancomycin MIC of ≥2 g/mL. With higher vancomycin MICs becoming more prevalent and difficult to treat, ceftaroline may become a viable alternative. More than 80% of ceftaroline-treated patients in the current cohort met the criteria for clinical success. The failure rate in the vancomycin-treated controls was ca. 50%, which is similar to recent studies [13,14]. Time to eradication for vancomycin in the vancomycin-treated controls ranged from 3 days to 78 days, indicating that some patients given vancomycin for MRSAB with MICs ≥2 g/mL achieve eradication quickly, an observation that was surprising to us. Therefore, despite the mean day of eradication difference in otherwise matched patients, the variability in vancomycin time to eradication led to a case-matched study population underpowered to show a statistically significant difference in clinical success between the two groups. The lack of statistical power is likely due to the small number of patients examined, with only 16 patients in each group. Bacterial eradication after treatment of MRSAB has been shown to decrease the risk of all-cause 30-day mortality [15]. In the current study, the time to eradication in patients after treatment with ceftaroline was 4 days less than the vancomycin-treated controls. A study by Murray et al. examined daptomycin in patients with high vancomycin MICs (>1 g/mL) to S. aureus [14]. Time to eradication of MRSAB was shorter in the daptomycin-treated group than the vancomycin-treated cohort. However, that study excluded patients who received ≥72 h of alternative MRSA therapy, including patients switched from vancomycin to daptomycin. As seen in the current study, patients in the real world are often treated with multiple antibiotics for varying durations for MRSAB. As bacterial eradication is an important outcome to decrease all-cause mortality of MRSAB, utilising time to eradication as an endpoint may be necessary in the era of increasing resistance. The primary limitation to this study was the small number of patients. We had only 32 patients (16 cases and 16 controls). As we do concede the power of the study was undersized it may be due to the fact that ceftaroline for the treatment of MRSAB is relatively novel and we only included patients with a vancomycin MIC of ≥2 g/mL. Another limitation is the retrospective design. As this
was a multicentre study, we were able to enhance the external validity of the findings, but additional limitations are present within the study design. In summary, vancomycin is particularly unsuccessful in patients having an infection caused by MRSA with vancomycin MICs ≥ 2 g/mL, with persistence of bacteraemia in non-catheter infection sites. Ceftaroline fosamil added at the point of failure resolves bacteraemia more rapidly than would have occurred if the vancomycin regimen had been continued. Furthermore, patients treated with ceftaroline had a higher rate of success and a lower percentage of recurrence of MRSAB. In addition, we attempted a novel pre-post analysis within the ceftaroline-treated cohort to assess ‘real world’ patients. Commonly, patients with antimicrobial-resistant infections are put on multiple antibiotics prior to initiation of an acceptable regimen. Alternative methods of assessment for these patients are necessary in order to properly gauge their impact on the healthcare system. Based on these findings, ceftaroline was an efficacious alternative for the treatment of MRSAB with high vancomycin MICs. Funding: This study was funded by a grant from Forest Laboratories, Inc. Competing interests: JAP and JJS are on the speaker’s bureau for Forest Pharmaceuticals, Inc.; RKS has received funding from Astellas and Pfizer and is currently supported by the National Institutes of Health (NIH) [grant no. KL2TR00146]; JKC has received funding for research through the National Institute of Allergy and Infectious Diseases (NIAID, NIH) and the University at Buffalo Civic Engagement Research Fellowship. All other authors declare no competing interests. Ethical approval: The study protocol was approved by the Institutional Review Board (IRB) at the co-ordinating centre (SUNY University at Buffalo Health Sciences, Buffalo, NY) [392398–4]. The IRBs at each of the participating medical centres approved the study. Owing to the retrospective nature of the data collection procedures, subject informed consent was not mandated by any of the IRBs.
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Please cite this article in press as: Paladino JA, et al. Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.07.024