Diagnostic Microbiology and Infectious Disease 84 (2016) 141–143
Contents lists available at ScienceDirect
Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio
In vitro activity of ceftaroline against staphylococci from prosthetic joint infection☆ Kyung-Hwa Park a,c, Kerryl E. Greenwood-Quaintance a, Robin Patel a,b,⁎ a b c
Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905 Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, South Korea
a r t i c l e
i n f o
Article history: Received 19 June 2015 Received in revised form 14 October 2015 Accepted 18 October 2015 Available online 21 October 2015 Keywords: Ceftaroline Prosthetic joint infection Staphylococcus aureus Staphylococcus epidermidis
a b s t r a c t We tested the in vitro activity of ceftaroline by Etest against staphylococci recovered from patients with prosthetic joint infection, including 97 Staphylococcus aureus isolates (36%, oxacillin resistant) and 74 Staphylococcus epidermidis isolates (74%, oxacillin resistant). Ceftaroline inhibited all staphylococci at ≤0.5 μg/mL. The ceftaroline MIC90/50 values for methicillin-susceptible S. aureus, methicillin-susceptible S. epidermidis, methicillin-resistant S. aureus, and methicillin-resistant S. epidermidis were 0.19/0.125, 0.094/0.047, 0.5/0.38, and 0.38/0.19 μg/mL, respectively. Based on these in vitro findings, ceftaroline should be further evaluated as a potential therapeutic option for the treatment of prosthetic joint infection caused by methicillin-susceptible and methicillinresistant S. aureus and S. epidermidis. © 2016 Elsevier Inc. All rights reserved.
1. Introduction
2. Materials and methods
Orthopedic joint replacement is an increasingly common surgical procedure worldwide, reflecting the aging population and increased acceptance of arthroplasty as a management strategy for osteoarthritic joints (Darouiche, 2004). With the increased number of prosthetic joint placements, there has been an increase in the number of cases of prosthetic joint infection (PJI) (Kurtz et al., 2014). Organisms associated with PJI attach to the implant, polymethylmethacrylate, and/or bone surfaces, where they grow in biofilms. Over half of PJI cases are caused by staphylococci, with Staphylococcus aureus and Staphylococcus epidermidis being most common (Del Pozo and Patel, 2009). These microorganisms are often resistant to many commonly used antibiotics. Moreover, bacteria growing in biofilms can be challenging to treat. Ceftaroline is a novel cephalosporin with high affinity for penicillinbinding protein 2a, conferring activity against both methicillinsusceptible and methicillin-resistant staphylococci (Biek et al., 2010; Flamm et al., 2012). Currently, ceftaroline is Food and Drug Administration approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia (File et al., 2012; Forest Pharmaceuticals, 2015). It was effective against methicillin-resistant S. aureus (MRSA) in rabbit models of acute osteomyelitis and PJI (Gatin et al., 2014; Jacqueline et al., 2010). We assessed the in vitro activity of ceftaroline against isolates of staphylococci associated with PJI.
2.1. Organism collection
☆ This study was supported by Actavis (Allergan). ⁎ Corresponding author. Tel.: +1-507-538-0579; fax: +1-507-284-4272. E-mail address: [email protected] (R. Patel). http://dx.doi.org/10.1016/j.diagmicrobio.2015.10.012 0732-8893/© 2016 Elsevier Inc. All rights reserved.
A convenience sample of 97 S. aureus isolates (36%, oxacillin resistant) and 74 S. epidermidis isolates (74%, oxacillin resistant) collected from Mayo Clinic patients with PJI from 1999 to 2014 was studied. PJI was defined using Infectious Diseases Society of America guidelines, if at least 1 of the following was met: a sinus tract communicating with the prosthesis, purulence noted at the time of surgery, or acute inflammation on intraoperative frozen section histopathology (Osmon et al., 2013). 2.2. Susceptibility testing Ceftaroline and comparator agents listed below were tested using broth microdilution methods following Clinical and Laboratory Standard Institute (CLSI) guidelines (CLSI, 2012, 2015) or by gradient MIC testing. Broth microdilution testing was performed for cefazolin on methicillin-susceptible staphylococci only. Gradient MIC testing (Etest®; bioMérieux, Marcy L’Etoile, France) was performed for ceftriaxone, ceftaroline, daptomycin, levofloxacin, linezolid, minocycline, rifampin, trimethoprim-sulfamethoxazole (TMP-STX), and vancomycin. The ceftriaxone MIC for 56 of the 62 methicillin-susceptible S. aureus (MSSA) isolates has been reported elsewhere (Greenwood-Quaintance et al., 2015). Screening tests for methicillin resistance were performed using 30 μg cefoxitin disks. CLSI interpretive criteria were used, when available, to categorize isolates as susceptible, intermediate, or resistant (CLSI, 2012, 2015). A ceftaroline susceptibility breakpoint of ≤1 μg/mL,
142
K.-H. Park et al. / Diagnostic Microbiology and Infectious Disease 84 (2016) 141–143
Table 1 MIC90 and MIC50 (μg/mL) of study antimicrobial agents against methicillin-susceptible staphylococci isolated from patients with PJI. Antimicrobial agent
MSSA (n = 62) MIC90
MIC50
Cefazolin Ceftriaxone Ceftaroline Daptomycin Levofloxacin Linezolid Minocycline Rifampin TMP-STX Vancomycin
1.0 4 0.19 0.5 1.0 4 0.25 0.023 0.125 1.0
0.25 3 0.125 0.25 0.19 3 0.19 0.016 0.094 0.75
% Susceptiblea
MSSE (n = 19)
% Susceptiblea
Range
MIC90
MIC50
Range
≤0.125 to 1 1–4 0.047–0.38 0.064–1 0.04 to ≥32 0.38–4 0.047–16 0.004–0.032 0.047–0.19 0.38–2
100 100 94 100 97 100 100 100
0.5 4 0.094 0.38 ≥32 4 2 0.023 ≥32 3
0.25 2 0.047 0.19 0.19 3 0.38 0.012 0.19 2
≤0.125 to 4 0.05-4 0.016–0.094 0.032–0.5 0.094 to ≥32 0.25–4 0.064–2 0.002–0.023 0.047 to ≥32 0.38–3
100 84 100 100 100 79 100
a
CLSI interpretive criteria applied.
as established by the CLSI, United States Food and Drug Administration, and European Committee for Antimicrobial Susceptibility Testing (EUCAST), was applied to S. aureus (CLSI, 2015; EUCAST, 2015; Forest Pharmaceuticals, 2015). S. aureus ATCC 29213 was tested as a control on each test day of testing. Results were expressed as MIC90, MIC50, and MIC range. 3. Results Table 1 shows the MIC90 and MIC50 values for 62 MSSA and 19 methicillin-susceptible S. epidermidis (MSSE) isolates. Ceftaroline exhibited in vitro activity against MSSA (MIC90/50, 0.19/0.125; maximum MIC, 0.38 μg/mL) and MSSE (MIC90/50, 0.094/0.047; maximum MIC, 0.094 μg/mL) isolates. Ceftaroline had 2- to 4-fold greater activity than cefazolin and had 32-fold greater activity than ceftriaxone against MSSA and MSSE. Among methicillin-susceptible staphylococci, 6 isolates were resistant to levofloxacin, 4 (all MSSE) were resistant to TMP-STX, and 2 (both MSSA) were resistant to minocycline. Ceftaroline demonstrated in vitro activity against MRSA (n = 35) with an MIC90/50 of 0.5/0.38 μg/mL (maximum MIC, 0.5 μg/mL) and against methicillin-resistant S. epidermidis (MRSE, n = 55) with an MIC90/50 of 0.38/0.19 μg/mL (maximum MIC, 0.5 μg/mL) (Table 2). Although ceftaroline MIC values were 2- to 4-fold higher among methicillin-resistant than methicillin-susceptible staphylococci, the in vitro activity of ceftaroline was greater than that of daptomycin, linezolid, or vancomycin. As shown in Table 2, MRSE isolates exhibited high rates of resistance to levofloxacin (62%), TMP-STX (38%), and rifampin (13%). 4. Discussion We have shown that ceftaroline has in vitro activity against S. aureus and S. epidermidis isolated from patients with PJI, including both methicillin-susceptible and methicillin-resistant isolates. Ceftaroline activity was 4- to 32-fold greater than that of cefazolin and ceftriaxone against MSSA and MSSE. Ceftaroline MIC values for methicillin-resistant
staphylococci were generally 2- to 4-fold higher than they were for methicillin-susceptible staphylococci; nevertheless, all MRSA were susceptible to ceftaroline. These results are consistent with 2010 United States data from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance program (Flamm et al., 2012). The MIC90 values are within the predicted pharmacokinetic/pharmacodynamic target attainment using Monte Carlo simulation (Biek et al., 2010). The AWARE data showed that over 98.8% of S. aureus strains in the United States were susceptible to ceftaroline and that all staphylococcal isolates were inhibited at ceftaroline MIC values ≤2 μg/mL (Sader et al., 2015). However, the organisms tested in this surveillance program likely did not specifically originate from PJI. The in vitro ceftaroline susceptibility results presented here document potential clinical application to PJI. Options for treating methicillin-resistant staphylococcal PJI are limited (Osmon et al., 2013). Clinical activity of vancomycin against staphylococci is debated due to MIC values that may approach the susceptible breakpoint, heteroresistance, tolerance, challenges achieving adequate serum levels, and side effects, compounded by the occasional occurrence of vancomycin-intermediate staphylococci (Holmes et al., 2012). Linezolid is bacteriostatic and associated with toxicity, including thrombocytopenia and peripheral neuropathy (Osmon et al., 2013; Rouse et al., 2007). Recently, daptomycin-nonsusceptible S. aureus isolates have been reported (Mishra et al., 2013). Interestingly, ceftaroline has been shown by others to have more bactericidal activity than vancomycin in biofilm time-kill studies, and ceftaroline alone and in combination has been shown to decrease biofilm-embedded MRSA (Barber et al., 2014; Landini et al., 2015). An experimental animal study has shown that ceftaroline had the potential to be used as monotherapy or combination therapy in PJI (Gatin et al., 2014). There are case reports describing successful treatment of PJI, osteomyelitis, and endocarditis with ceftaroline (Jongsma et al., 2013; Lin et al., 2013). A recent retrospective evaluation of the clinical effectiveness of ceftaroline including off-label infections showed that 67 of 71 patients (94.4%) with bone and joint infection, mostly caused by staphylococci, had successful outcomes, although the 30-day readmission rates were higher in those with bone
Table 2 MIC90 and MIC50 (μg/mL) of study antimicrobial agents against methicillin-resistant staphylococci isolated from patients with PJI. Antimicrobial agent
Ceftaroline Daptomycin Levofloxacin Linezolid Minocycline Rifampin TMP-STX Vancomycin a
% Susceptiblea
MRSA (n = 35) MIC90
MIC50
Range
0.5 0.5 ≥32 4 0.5 0.016 0.19 1.5
0.38 0.38 ≥32 3 0.19 0.012 0.094 1.0
0.19–0.5 0.125–1 0.25 to ≥32 2–4 0.125–16 0.006–0.75 0.064–3 0.25–1.5
CLSI interpretive criteria applied.
100 100 86 100 97 100 97 100
% Susceptiblea
MRSE (n = 55) MIC90
MIC50
Range
0.38 1.0 ≥32 4 1.0 ≥32 ≥32 2
0.19 0.5 6 3 0.38 0.016 0.38 1.5
0.012–0.5 0.032–1 0.047 to ≥32 0.5–4 0.032 to ≥32 0.003 to ≥32 0.064 to ≥32 0.5–3
100 38 100 98 87 62 100
K.-H. Park et al. / Diagnostic Microbiology and Infectious Disease 84 (2016) 141–143
and joint compared to those with non–bone and joint infections (Casapao et al., 2014). To be considered as a therapeutic option for PJI, emergence of resistance and adverse events during prolonged therapy would need to be addressed, and more clinical data required. For MSSA, susceptibility to ceftaroline can be inferred based on oxacillin or cefoxitin susceptibility; ceftaroline may be tested directly if it is to be reported for MRSA (CLSI, 2015). Antimicrobial resistance is an important problem among isolates of S. epidermidis and MRSA. In our study, resistance rates for levofloxacin, rifampin, and TMP-STX in MRSE were numerically higher than in MRSA. Ceftaroline possessed activity against all MRSE isolates studied, regardless of their susceptibility to other agents. Currently, CLSI and EUCAST do not have ceftaroline susceptibility breakpoints for coagulase negative staphylococci, including S. epidermidis; the data presented suggest that a breakpoint similar to that of S. aureus may be appropriate for S. epidermidis. In summary, results of this study demonstrate that ceftaroline has in vitro activity against staphylococci associated with PJI, including methicillin-susceptible and methicillin-resistant S. aureus and S. epidermidis.
References Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med 2004;350:1422–9. Kurtz SM, Ong KL, Lau E, Bozic KJ. Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021. J Bone Joint Surg Am 2014;96:624–30. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med 2009;361:787–94. Flamm RK, Sader HS, Farrell DJ, Jones RN. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrob Agents Chemother 2012;56:2933–40. Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother 2010;65(Suppl. 4):iv9–iv16. File Jr TM, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 2012;55(Suppl. 3):S173–80. Forest Pharmaceuticals. Teflaro prescribing information, St. Louis, MO; 2015. Jacqueline C, Amador G, Caillon J, Le Mabecque V, Batard E, Miegeville AF, et al. Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-
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resistant Staphylococcus aureus acute osteomyelitis. J Antimicrob Chemother 2010; 65:1749–52. Gatin L, Saleh-Mghir A, Tasse J, Ghout I, Laurent F, Cremieux AC. Ceftaroline-fosamil efficacy against methicillin-resistant Staphylococcus aureus in a rabbit prosthetic joint infection model. Antimicrob Agents Chemother 2014;58:6496–500. Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2013;56:e1-25. Clinical and Laboratory Standards Institute (CLSI). M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. 9th ed. Wayne, PA: CLSI; 2012. abstr. Clinical and Laboratory Standards Institute (CLSI). M100-S25. Performance standards for antimicrobial susceptibility testing: 25th informational supplement. Wayne, PA: CLSI; 2015. Greenwood-Quaintance KE, Kohner P, Osmon DR, Virk A, Patel R. Ceftriaxone susceptibility of oxacillin-susceptible Staphylococcus aureus from patients with prosthetic joint infection. Diagn Microbiol Infect Dis 2015;82:177–8. EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. Version 5.0. Basel, Switzerland: European Society of Clinical Microbiology and Infectious Diseases; 2015. Sader HS, Flamm RK, Streit JM, Farrell DJ, Jones RN. Ceftaroline activity against bacterial pathogens frequently isolated in U.S. medical centers: results from five years of the AWARE surveillance program. Antimicrob Agents Chemother 2015;59:2458–61. Holmes NE, Johnson PD, Howden BP. Relationship between vancomycin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, high vancomycin MIC, and outcome in serious S. aureus infections. J Clin Microbiol 2012;50:2548–52. Rouse MS, Steckelberg JM, Patel R. In vitro activity of ceftobiprole, daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci associated with endocarditis and bone and joint infection. Diagn Microbiol Infect Dis 2007;58:363–5. Mishra NN, Yang SJ, Chen L, Muller C, Saleh-Mghir A, Kuhn S, et al. Emergence of daptomycin resistance in daptomycin-naive rabbits with methicillin-resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms. PLoS One 2013;8:e71151. Barber KE, Werth BJ, McRoberts JP, Rybak MJ. A novel approach utilizing biofilm time-kill curves to assess the bactericidal activity of ceftaroline combinations against biofilmproducing methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2014;58:2989–92. Landini G, Riccobono E, Giani T, Arena F, Rossolini GM, Pallecchi L. Bactericidal activity of ceftaroline against mature Staphylococcus aureus biofilms. Int J Antimicrob Agents 2015;45:551–3. Lin JC, Aung G, Thomas A, Jahng M, Johns S, Fierer J. The use of ceftaroline fosamil in methicillin-resistant Staphylococcus aureus endocarditis and deep-seated MRSA infections: a retrospective case series of 10 patients. J Infect Chemother 2013;19:42–9. Jongsma K, Joson J, Heidari A. Ceftaroline in the treatment of concomitant methicillinresistant and daptomycin-non-susceptible Staphylococcus aureus infective endocarditis and osteomyelitis: case report. J Antimicrob Chemother 2013;68:1444–5. Casapao AM, Davis SL, Barr VO, Klinker KP, Goff DA, Barber KE, et al. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother 2014;58:2541–6.
Contents lists available at ScienceDirect
Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio
In vitro activity of ceftaroline against staphylococci from prosthetic joint infection☆ Kyung-Hwa Park a,c, Kerryl E. Greenwood-Quaintance a, Robin Patel a,b,⁎ a b c
Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905 Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, South Korea
a r t i c l e
i n f o
Article history: Received 19 June 2015 Received in revised form 14 October 2015 Accepted 18 October 2015 Available online 21 October 2015 Keywords: Ceftaroline Prosthetic joint infection Staphylococcus aureus Staphylococcus epidermidis
a b s t r a c t We tested the in vitro activity of ceftaroline by Etest against staphylococci recovered from patients with prosthetic joint infection, including 97 Staphylococcus aureus isolates (36%, oxacillin resistant) and 74 Staphylococcus epidermidis isolates (74%, oxacillin resistant). Ceftaroline inhibited all staphylococci at ≤0.5 μg/mL. The ceftaroline MIC90/50 values for methicillin-susceptible S. aureus, methicillin-susceptible S. epidermidis, methicillin-resistant S. aureus, and methicillin-resistant S. epidermidis were 0.19/0.125, 0.094/0.047, 0.5/0.38, and 0.38/0.19 μg/mL, respectively. Based on these in vitro findings, ceftaroline should be further evaluated as a potential therapeutic option for the treatment of prosthetic joint infection caused by methicillin-susceptible and methicillinresistant S. aureus and S. epidermidis. © 2016 Elsevier Inc. All rights reserved.
1. Introduction
2. Materials and methods
Orthopedic joint replacement is an increasingly common surgical procedure worldwide, reflecting the aging population and increased acceptance of arthroplasty as a management strategy for osteoarthritic joints (Darouiche, 2004). With the increased number of prosthetic joint placements, there has been an increase in the number of cases of prosthetic joint infection (PJI) (Kurtz et al., 2014). Organisms associated with PJI attach to the implant, polymethylmethacrylate, and/or bone surfaces, where they grow in biofilms. Over half of PJI cases are caused by staphylococci, with Staphylococcus aureus and Staphylococcus epidermidis being most common (Del Pozo and Patel, 2009). These microorganisms are often resistant to many commonly used antibiotics. Moreover, bacteria growing in biofilms can be challenging to treat. Ceftaroline is a novel cephalosporin with high affinity for penicillinbinding protein 2a, conferring activity against both methicillinsusceptible and methicillin-resistant staphylococci (Biek et al., 2010; Flamm et al., 2012). Currently, ceftaroline is Food and Drug Administration approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia (File et al., 2012; Forest Pharmaceuticals, 2015). It was effective against methicillin-resistant S. aureus (MRSA) in rabbit models of acute osteomyelitis and PJI (Gatin et al., 2014; Jacqueline et al., 2010). We assessed the in vitro activity of ceftaroline against isolates of staphylococci associated with PJI.
2.1. Organism collection
☆ This study was supported by Actavis (Allergan). ⁎ Corresponding author. Tel.: +1-507-538-0579; fax: +1-507-284-4272. E-mail address: [email protected] (R. Patel). http://dx.doi.org/10.1016/j.diagmicrobio.2015.10.012 0732-8893/© 2016 Elsevier Inc. All rights reserved.
A convenience sample of 97 S. aureus isolates (36%, oxacillin resistant) and 74 S. epidermidis isolates (74%, oxacillin resistant) collected from Mayo Clinic patients with PJI from 1999 to 2014 was studied. PJI was defined using Infectious Diseases Society of America guidelines, if at least 1 of the following was met: a sinus tract communicating with the prosthesis, purulence noted at the time of surgery, or acute inflammation on intraoperative frozen section histopathology (Osmon et al., 2013). 2.2. Susceptibility testing Ceftaroline and comparator agents listed below were tested using broth microdilution methods following Clinical and Laboratory Standard Institute (CLSI) guidelines (CLSI, 2012, 2015) or by gradient MIC testing. Broth microdilution testing was performed for cefazolin on methicillin-susceptible staphylococci only. Gradient MIC testing (Etest®; bioMérieux, Marcy L’Etoile, France) was performed for ceftriaxone, ceftaroline, daptomycin, levofloxacin, linezolid, minocycline, rifampin, trimethoprim-sulfamethoxazole (TMP-STX), and vancomycin. The ceftriaxone MIC for 56 of the 62 methicillin-susceptible S. aureus (MSSA) isolates has been reported elsewhere (Greenwood-Quaintance et al., 2015). Screening tests for methicillin resistance were performed using 30 μg cefoxitin disks. CLSI interpretive criteria were used, when available, to categorize isolates as susceptible, intermediate, or resistant (CLSI, 2012, 2015). A ceftaroline susceptibility breakpoint of ≤1 μg/mL,
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K.-H. Park et al. / Diagnostic Microbiology and Infectious Disease 84 (2016) 141–143
Table 1 MIC90 and MIC50 (μg/mL) of study antimicrobial agents against methicillin-susceptible staphylococci isolated from patients with PJI. Antimicrobial agent
MSSA (n = 62) MIC90
MIC50
Cefazolin Ceftriaxone Ceftaroline Daptomycin Levofloxacin Linezolid Minocycline Rifampin TMP-STX Vancomycin
1.0 4 0.19 0.5 1.0 4 0.25 0.023 0.125 1.0
0.25 3 0.125 0.25 0.19 3 0.19 0.016 0.094 0.75
% Susceptiblea
MSSE (n = 19)
% Susceptiblea
Range
MIC90
MIC50
Range
≤0.125 to 1 1–4 0.047–0.38 0.064–1 0.04 to ≥32 0.38–4 0.047–16 0.004–0.032 0.047–0.19 0.38–2
100 100 94 100 97 100 100 100
0.5 4 0.094 0.38 ≥32 4 2 0.023 ≥32 3
0.25 2 0.047 0.19 0.19 3 0.38 0.012 0.19 2
≤0.125 to 4 0.05-4 0.016–0.094 0.032–0.5 0.094 to ≥32 0.25–4 0.064–2 0.002–0.023 0.047 to ≥32 0.38–3
100 84 100 100 100 79 100
a
CLSI interpretive criteria applied.
as established by the CLSI, United States Food and Drug Administration, and European Committee for Antimicrobial Susceptibility Testing (EUCAST), was applied to S. aureus (CLSI, 2015; EUCAST, 2015; Forest Pharmaceuticals, 2015). S. aureus ATCC 29213 was tested as a control on each test day of testing. Results were expressed as MIC90, MIC50, and MIC range. 3. Results Table 1 shows the MIC90 and MIC50 values for 62 MSSA and 19 methicillin-susceptible S. epidermidis (MSSE) isolates. Ceftaroline exhibited in vitro activity against MSSA (MIC90/50, 0.19/0.125; maximum MIC, 0.38 μg/mL) and MSSE (MIC90/50, 0.094/0.047; maximum MIC, 0.094 μg/mL) isolates. Ceftaroline had 2- to 4-fold greater activity than cefazolin and had 32-fold greater activity than ceftriaxone against MSSA and MSSE. Among methicillin-susceptible staphylococci, 6 isolates were resistant to levofloxacin, 4 (all MSSE) were resistant to TMP-STX, and 2 (both MSSA) were resistant to minocycline. Ceftaroline demonstrated in vitro activity against MRSA (n = 35) with an MIC90/50 of 0.5/0.38 μg/mL (maximum MIC, 0.5 μg/mL) and against methicillin-resistant S. epidermidis (MRSE, n = 55) with an MIC90/50 of 0.38/0.19 μg/mL (maximum MIC, 0.5 μg/mL) (Table 2). Although ceftaroline MIC values were 2- to 4-fold higher among methicillin-resistant than methicillin-susceptible staphylococci, the in vitro activity of ceftaroline was greater than that of daptomycin, linezolid, or vancomycin. As shown in Table 2, MRSE isolates exhibited high rates of resistance to levofloxacin (62%), TMP-STX (38%), and rifampin (13%). 4. Discussion We have shown that ceftaroline has in vitro activity against S. aureus and S. epidermidis isolated from patients with PJI, including both methicillin-susceptible and methicillin-resistant isolates. Ceftaroline activity was 4- to 32-fold greater than that of cefazolin and ceftriaxone against MSSA and MSSE. Ceftaroline MIC values for methicillin-resistant
staphylococci were generally 2- to 4-fold higher than they were for methicillin-susceptible staphylococci; nevertheless, all MRSA were susceptible to ceftaroline. These results are consistent with 2010 United States data from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance program (Flamm et al., 2012). The MIC90 values are within the predicted pharmacokinetic/pharmacodynamic target attainment using Monte Carlo simulation (Biek et al., 2010). The AWARE data showed that over 98.8% of S. aureus strains in the United States were susceptible to ceftaroline and that all staphylococcal isolates were inhibited at ceftaroline MIC values ≤2 μg/mL (Sader et al., 2015). However, the organisms tested in this surveillance program likely did not specifically originate from PJI. The in vitro ceftaroline susceptibility results presented here document potential clinical application to PJI. Options for treating methicillin-resistant staphylococcal PJI are limited (Osmon et al., 2013). Clinical activity of vancomycin against staphylococci is debated due to MIC values that may approach the susceptible breakpoint, heteroresistance, tolerance, challenges achieving adequate serum levels, and side effects, compounded by the occasional occurrence of vancomycin-intermediate staphylococci (Holmes et al., 2012). Linezolid is bacteriostatic and associated with toxicity, including thrombocytopenia and peripheral neuropathy (Osmon et al., 2013; Rouse et al., 2007). Recently, daptomycin-nonsusceptible S. aureus isolates have been reported (Mishra et al., 2013). Interestingly, ceftaroline has been shown by others to have more bactericidal activity than vancomycin in biofilm time-kill studies, and ceftaroline alone and in combination has been shown to decrease biofilm-embedded MRSA (Barber et al., 2014; Landini et al., 2015). An experimental animal study has shown that ceftaroline had the potential to be used as monotherapy or combination therapy in PJI (Gatin et al., 2014). There are case reports describing successful treatment of PJI, osteomyelitis, and endocarditis with ceftaroline (Jongsma et al., 2013; Lin et al., 2013). A recent retrospective evaluation of the clinical effectiveness of ceftaroline including off-label infections showed that 67 of 71 patients (94.4%) with bone and joint infection, mostly caused by staphylococci, had successful outcomes, although the 30-day readmission rates were higher in those with bone
Table 2 MIC90 and MIC50 (μg/mL) of study antimicrobial agents against methicillin-resistant staphylococci isolated from patients with PJI. Antimicrobial agent
Ceftaroline Daptomycin Levofloxacin Linezolid Minocycline Rifampin TMP-STX Vancomycin a
% Susceptiblea
MRSA (n = 35) MIC90
MIC50
Range
0.5 0.5 ≥32 4 0.5 0.016 0.19 1.5
0.38 0.38 ≥32 3 0.19 0.012 0.094 1.0
0.19–0.5 0.125–1 0.25 to ≥32 2–4 0.125–16 0.006–0.75 0.064–3 0.25–1.5
CLSI interpretive criteria applied.
100 100 86 100 97 100 97 100
% Susceptiblea
MRSE (n = 55) MIC90
MIC50
Range
0.38 1.0 ≥32 4 1.0 ≥32 ≥32 2
0.19 0.5 6 3 0.38 0.016 0.38 1.5
0.012–0.5 0.032–1 0.047 to ≥32 0.5–4 0.032 to ≥32 0.003 to ≥32 0.064 to ≥32 0.5–3
100 38 100 98 87 62 100
K.-H. Park et al. / Diagnostic Microbiology and Infectious Disease 84 (2016) 141–143
and joint compared to those with non–bone and joint infections (Casapao et al., 2014). To be considered as a therapeutic option for PJI, emergence of resistance and adverse events during prolonged therapy would need to be addressed, and more clinical data required. For MSSA, susceptibility to ceftaroline can be inferred based on oxacillin or cefoxitin susceptibility; ceftaroline may be tested directly if it is to be reported for MRSA (CLSI, 2015). Antimicrobial resistance is an important problem among isolates of S. epidermidis and MRSA. In our study, resistance rates for levofloxacin, rifampin, and TMP-STX in MRSE were numerically higher than in MRSA. Ceftaroline possessed activity against all MRSE isolates studied, regardless of their susceptibility to other agents. Currently, CLSI and EUCAST do not have ceftaroline susceptibility breakpoints for coagulase negative staphylococci, including S. epidermidis; the data presented suggest that a breakpoint similar to that of S. aureus may be appropriate for S. epidermidis. In summary, results of this study demonstrate that ceftaroline has in vitro activity against staphylococci associated with PJI, including methicillin-susceptible and methicillin-resistant S. aureus and S. epidermidis.
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