Abstract
Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, ≥8 μg/ml), 18 (0.09%) to daptomycin (MIC, ≥2 μg/ml), and 369 (1.9%) to vancomycin (MIC, ≥2 μg/ml; 368 isolates at 2 μg/ml and 1 at 4 μg/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, ≥8 μg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, ≥2 μg/ml). Ceftaroline was very active against S. aureus overall (MIC50/90, 0.5/1 μg/ml; 98.5% susceptible), including MRSA (MIC50/90, 0.5/1 μg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of ≥2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤1 μg/ml), including methicillin-resistant (MIC50/90, 0.25/0.5 μg/ml), linezolid-resistant (MIC50/90, 0.5/0.5 μg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 μg/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.
INTRODUCTION
Staphylococcus aureus continues to be a major cause of both community-acquired and health care-associated infections, including skin and skin structure infections, pneumonia, bacteremia, endocarditis, osteomyelitis, prosthetic joint infections, and catheter-related infections (1). The prevalence of nosocomial infections caused by methicillin-resistant S. aureus (MRSA) has remained markedly high in the United States in the last decade (2). Furthermore, since its appearance in the 1990s, community-acquired MRSA (CA-MRSA) strains have increasingly caused community-onset infections as well as hospital- and health care-associated disease in various U.S. regions (3).
Prompt and appropriate antimicrobial therapy plays an important role in the management of MRSA infections (4). Vancomycin has been used for treatment of MRSA infections for more than 50 years, and although susceptibility rates remain high (>99%) in the United States and worldwide, there have been increasing reports of treatment failure in recent years, which appears to be related to increased vancomycin MICs that occur within the susceptibility range (2 μg/ml) (5). Linezolid and daptomycin have been increasingly used worldwide in the last decade, and resistance to these two compounds is still very uncommon among S. aureus strains isolated in U.S. hospitals (2, 6).
Ceftaroline fosamil is approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) (7, 8), and by the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTI) and community-acquired pneumonia (CAP) (9). The active metabolite, ceftaroline, is a cephalosporin with potent bactericidal activity against resistant Gram-positive organisms, including MRSA, and common Gram-negative organisms (10). We report here the activity of ceftaroline tested against a large collection of staphylococci, including strains with reduced susceptibility to vancomycin, linezolid, or daptomycin.
MATERIALS AND METHODS
Organism collection.
A total of 19,350 S. aureus isolates (51.0% MRSA) and 3,270 coagulase-negative staphylococci (CoNS; 69.4% were oxacillin resistant) were collected from 82 U.S. medical centers from January 2008 to December 2011 as part of the SENTRY and Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programs. Organisms were consecutively collected from clinical infections, and target numbers of strains for each of the requested bacterial species/genera were predetermined in the study protocol. Strain selection was not based on any antimicrobial susceptibility pattern. The isolates were collected primarily from ABSSSI and respiratory tract and bloodstream infections in hospitalized patients according to a common surveillance design. Isolates were sent to the coordinator laboratory (JMI Laboratories, North Liberty, IA) for reference susceptibility testing. Only one strain per patient infection episode was included in the surveillance sample.
Susceptibility testing.
Ceftaroline and various comparator agents were tested by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods in validated panels manufactured by ThermoFisher Scientific Inc. (formerly TREK Diagnostics Systems, Cleveland, OH) (11). The test medium was Mueller-Hinton broth adjusted to contain physiological levels of calcium (50 mg/liter) when testing daptomycin. CLSI interpretive criteria were used to categorize the isolates as susceptible, intermediate, and resistant (12). A ceftaroline susceptibility breakpoint of ≤1 μg/ml was established by the CLSI, U.S. FDA, and EUCAST for S. aureus and applied in this study. Furthermore, ceftaroline-resistant breakpoints of ≥4 and ≥2 μg/ml were also established for S. aureus by CLSI and EUCAST, respectively (8, 12, 13). The S. aureus ATCC 29213 quality control strain was tested concurrently, and all results were within published ranges (11).
RESULTS
Among almost 20,000 S. aureus isolates tested from the 2008-2011 period, 14 (0.07%), 18 (0.09%), and 369 (1.9%) strains exhibited decreased susceptibility to linezolid (MIC, ≥8 μg/ml), daptomycin (MIC, ≥2 μg/ml), and vancomycin (MIC, ≥2 μg/ml; 368 isolates at 2 μg/ml and 1 isolate at 4 μg/ml), respectively, whereas among 3,270 CoNS isolates evaluated, 51 (1.6%) strains were linezolid resistant and four (0.12%) were daptomycin nonsusceptible. The MIC distributions for ceftaroline against the entire collection of organisms, as well as the resistant subsets, are summarized in Table 1.
Table 1.
Summary of ceftaroline tested against S. aureus and CoNS from U.S. hospitals (2008 to 2011), including strains with reduced susceptibility to linezolid, daptomycin, or vancomycin
| Organism (no. tested) | No. of strains (cumulative %) inhibited at ceftaroline MIC (μg/ml) of: |
|||||
|---|---|---|---|---|---|---|
| ≤0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | |
| S. aureus | ||||||
| All strains (19,350) | 63 (0.3) | 1,027 (5.6) | 8,122 (47.6) | 5,853 (77.8) | 4,004 (98.5) | 281 (100.0) |
| MSSA (9,475) | 61 (0.6) | 1,020 (11.4) | 7,928 (95.1) | 460 (99.9) | 6 (100.0) | |
| MRSA (9,875) | 2 (0.2) | 7 (0.9) | 194 (2.1) | 5,393 (56.7) | 3,998 (97.2) | 281 (100.0) |
| Linezolid resistant (14) | 1 (7.1) | 5 (42.9) | 6 (85.7) | 2 (100.0) | ||
| Daptomycin nonsusceptible (18) | 1 (5.6) | 0 (5.6) | 2 (16.7) | 7 (55.6) | 8 (100.0) | |
| Vancomycin MIC of ≥2 μg/ml (369) | 5 (1.4) | 10 (4.1) | 89 (28.2) | 92 (53.1) | 143 (91.9) | 30 (100.0) |
| CoNS | ||||||
| All strains (3,270) | 689 (21.1) | 467 (35.3) | 1,086 (68.5) | 882 (95.5) | 118 (99.1) | 28 (100.0) |
| Oxacillin susceptible (1,002) | 631 (63.0) | 293 (92.2) | 74 (99.6) | 2 (99.8) | 2 (100.0) | |
| Oxacillin resistant (2,268) | 58 (2.6) | 174 (10.2) | 1,012 (54.8) | 880 (93.6) | 116 (98.7) | 28 (100.0) |
| Linezolid resistant (51) | 1 (2.0) | 3 (7.8) | 7 (21.6) | 37 (94.1) | 1 (96.1) | 2 (100.0) |
| Daptomycin nonsusceptible (4) | 2 (50.0) | 2 (100.0) | ||||
Ceftaroline exhibited potent in vitro activity against S. aureus isolates (MIC50/90, 0.5/1 μg/ml; 98.5% susceptible and highest MIC of 2 μg/ml), including MRSA strains (9,875 strains tested; MIC50/90, 0.5/1 μg/ml; 97.1% susceptible), for which the highest MIC observed was 2 μg/ml. MRSA strains showed low susceptibility to erythromycin (8.9 to 9.0%), levofloxacin (29.5%), and clindamycin (67.5 to 67.9%) (Table 2). Ceftaroline remained very active against daptomycin-nonsusceptible (MIC50/90, 0.5/1 μg/ml; 100.0% susceptible) and linezolid-resistant (MIC50/90, 1/2 μg/ml; 85.7% susceptible [14 strains tested]) strains of S. aureus (Tables 1 and 2). Among S. aureus strains with vancomycin MICs of ≥2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively, and ceftaroline and daptomycin (MIC50/90, 0.5/1 μg/ml for both) were 2-fold more active than linezolid (MIC50/90, 1/2 μg/ml) (Table 2).
Table 2.
Activity of ceftaroline and comparator antimicrobial agents when tested against 19,350 Staphylococcus aureus and 3,270 CoNS isolates from U.S. hospitals
| Organism (no. tested) and antimicrobial agent | MIC (μg/ml) |
% S/% R (CLSI)a | |
|---|---|---|---|
| MIC50 | MIC90 | ||
| Staphylococcus aureus (19,350) | |||
| Ceftaroline | 0.5 | 1 | 98.5/0.0 |
| Ceftriaxone | 8 | >8 | 49.0/51.0 |
| Oxacillin | >2 | >2 | 49.0/51.0 |
| Clindamycin | ≤0.25 | >2 | 80.9/18.9 |
| Levofloxacin | ≤0.5 | >4 | 58.4/40.1 |
| TMP-SMXb | ≤0.5 | ≤0.5 | 98.4/1.6 |
| Tetracycline | ≤2 | ≤2 | 95.5/3.9 |
| Linezolid | 1 | 2 | 99.9/0.1 |
| Vancomycin | 1 | 1 | >99.9/0.0 |
| Daptomycin | 0.25 | 0.5 | 99.9/— |
| MRSA (9,875) | |||
| Ceftaroline | 0.5 | 1 | 97.2/0.0 |
| Clindamycin | ≤0.25 | >2 | 67.9/31.8 |
| Levofloxacin | 4 | >4 | 29.5/68.4 |
| TMP-SMX | ≤0.5 | ≤0.5 | 98.0/2.0 |
| Tetracycline | ≤2 | ≤2 | 95.0/4.6 |
| Linezolid | 1 | 2 | 99.9/0.1 |
| Vancomycin | 1 | 1 | >99.9/0.0 |
| Daptomycin | 0.25 | 0.5 | 99.8/— |
| Linezolid resistant (MIC, ≥8 μg/ml; 14) | |||
| Ceftaroline | 1 | 2 | 85.7/0.0 |
| Ceftriaxone | >8 | >8 | 0.0/100.0 |
| Oxacillin | >2 | >2 | 0.0/100.0 |
| Clindamycin | >2 | >2 | 21.4/71.4 |
| Levofloxacin | >4 | >4 | 14.3/85.7 |
| TMP-SMX | ≤0.5 | ≤0.5 | 92.9/7.1 |
| Tetracycline | ≤2 | >8 | 78.6/21.4 |
| Vancomycin | 1 | 2 | 100.0/0.0 |
| Daptomycin | 0.5 | 0.5 | 100.0/— |
| Daptomycin nonsusceptible (MIC, ≥2 μg/ml; 18) | |||
| Ceftaroline | 0.5 | 1 | 100.0/0.0 |
| Ceftriaxone | >8 | >8 | 5.6/94.4 |
| Oxacillin | >2 | >2 | 5.6/94.4 |
| Clindamycin | >2 | >2 | 33.3/66.7 |
| Levofloxacin | >4 | >4 | 27.8/72.2 |
| TMP-SMX | ≤0.5 | ≤0.5 | 100.0/0.0 |
| Tetracycline | ≤2 | ≤2 | 100.0/0.0 |
| Linezolid | 1 | 2 | 100.0/0.0 |
| Vancomycin | 2 | 2 | 100.0/0.0 |
| Vancomycin MIC of ≥2 μg/ml (369) | |||
| Ceftaroline | 0.5 | 1 | 91.9/0.0 |
| Ceftriaxone | >8 | >8 | 29.8/70.2 |
| Oxacillin | >2 | >2 | 29.8/70.2 |
| Clindamycin | ≤0.25 | >2 | 57.5/42.5 |
| Levofloxacin | >4 | >4 | 37.7/61.2 |
| TMP-SMX | ≤0.5 | ≤0.5 | 96.7/3.3 |
| Tetracycline | ≤2 | ≤2 | 95.7/4.1 |
| Linezolid | 1 | 2 | 98.9/1.1 |
| Vancomycin | 2 | 2 | 99.7/0.0 |
| Daptomycin | 0.5 | 1 | 96.2/— |
| CoNSc (all strains; 3,270) | |||
| Ceftaroline | 0.25 | 0.5 | —/— |
| Ceftriaxone | 8 | >8 | 30.6/69.4 |
| Oxacillin | 2 | >2 | 30.6/69.4 |
| Clindamycin | ≤0.25 | >2 | 68.5/29.3 |
| Levofloxacin | 4 | >4 | 47.9/50.5 |
| TMP-SMX | ≤0.5 | >2 | 61.8/38.2 |
| Tetracycline | ≤2 | >8 | 85.6/13.6 |
| Linezolid | 0.5 | 1 | 98.4/1.6 |
| Vancomycin | 1 | 2 | 100.0/0.0 |
| Daptomycin | 0.25 | 0.5 | 99.9/— |
| Methicillin resistant (2,268) | |||
| Ceftaroline | 0.25 | 0.5 | —/— |
| Clindamycin | ≤0.25 | >2 | 59.8/37.8 |
| Levofloxacin | >4 | >4 | 34.3/63.8 |
| TMP-SMX | 2 | >2 | 52.7/47.3 |
| Tetracycline | ≤2 | >8 | 84.1/15.5 |
| Linezolid | 0.5 | 1 | 97.9/2.1 |
| Vancomycin | 2 | 2 | 100.0/0.0 |
| Daptomycin | 0.25 | 0.5 | 99.9/— |
| Linezolid resistant (MIC, ≥8 μg/ml; 51) | |||
| Ceftaroline | 0.5 | 0.5 | —/— |
| Ceftriaxone | >8 | >8 | 5.9/94.1 |
| Oxacillin | >2 | >2 | 5.9/94.1 |
| Clindamycin | 1 | >2 | 39.2/19.6 |
| Levofloxacin | >4 | >4 | 2.0/98.0 |
| TMP-SMX | >2 | >2 | 9.8/90.2 |
| Tetracycline | ≤2 | ≤2 | 96.1/3.9 |
| Vancomycin | 2 | 2 | 100.0/0.0 |
| Daptomycin | 0.5 | 0.5 | 100.0/— |
| Daptomycin nonsusceptible (MIC, ≥2 μg/ml; 4) | |||
| Ceftaroline | 0.06 | —/— | |
| Ceftriaxone | 4 | 50.0/50.0 | |
| Oxacillin | ≤0.25 | 50.0/50.0 | |
| Clindamycin | ≤0.25 | 75.0/25.0 | |
| Levofloxacin | ≤0.5 | 100.0/0.0 | |
| TMP-SMX | ≤0.5 | 100.0/0.0 | |
| Tetracycline | ≤2 | 100.0/0.0 | |
| Linezolid | 0.5 | 100.0/0.0 | |
| Vancomycin | 2 | 100.0/0.0 | |
Criteria as published by the CLSI (12) and EUCAST (13); β-lactam susceptibility should be directed by the oxacillin test results. S, susceptible; R, resistant. —, no breakpoint has been established.
TMP-SMX, trimethoprim-sulfamethoxazole.
Among the included strains were Staphylococcus auricularis (18 strains), S. capitis (65 strains), S. carnosus (1 strain), S. cohnii (2 strains), S. epidermidis (924 strains), S. haemolyticus (66 strains), S. hominis (119 strains), S. intermedius (5 strains), S. lentus (1 strain), S. lugdunensis (87 strains), S. saccharolyticus (1 strain), S. saprophyticus (26 strains), S. sciuri (5 strains), S. simulans (6 strains), S. succinus (1 strain), S. warneri (38 strains), S. xylosus (2 strains), and unspeciated CoNS (1,903 strains).
Ceftaroline demonstrated potent activity against CoNS isolates, with a MIC50/90 of 0.25/0.5 μg/ml, and 99.1% of strains were inhibited at ≤1 μg/ml, which is the susceptible breakpoint established by CLSI for S. aureus (12). Among CoNS, 69.4% of strains were resistant to oxacillin, and ceftaroline remained active against these oxacillin-resistant isolates (MIC50/90, 0.25/0.5 μg/ml) (Tables 1 and 2). CoNS exhibited high rates of resistance for erythromycin (63.5 to 64.1%), levofloxacin (50.5%), trimethoprim-sulfamethoxazole (28.7 to 38.2%), and clindamycin (29.3 to 31.5%) (Table 2). Ceftaroline showed potent activity against linezolid-resistant (MIC50/90, 0.5/0.5 μg/ml; 96.1% inhibited at ≤1 μg/ml) and daptomycin-nonsusceptible (MIC range, 0.03 to 0.12 μg/ml) strains of CoNS (Tables 1 and 2).
DISCUSSION
The treatment of S. aureus infections continues to represent a great concern to clinicians. MRSA, which until recently has been regarded as almost exclusively a hospital-associated pathogen, is increasingly identified as a cause of community-onset infections (14). Although the initial community-acquired MRSA strains were more susceptible to antimicrobial agents than traditional health care-associated MRSA strains, the occurrence of USA300 variants with multidrug resistance patterns has increased recently (3, 15). Furthermore, accumulating evidence indicates that MRSA infections are associated with a poorer prognosis than methicillin-susceptible S. aureus (MSSA) infections (16), and inappropriate initial antimicrobial therapy can have an important impact on the clinical outcome of MRSA infections (17). Thus, therapeutic options against these organisms need constant investigation.
Vancomycin remains widely used to treat MRSA infections. Although reports of vancomycin-intermediate (VISA) or -resistant S. aureus (VRSA) remain relatively rare, an increasing number of studies suggest an association between poor clinical outcome and infections with MRSA isolates for which vancomycin MICs are increased yet are still within the susceptible range (e.g., ≥1.5 or 2 μg/ml) (5, 18). In the present study, ceftaroline demonstrated good activity against S. aureus strains with reduced susceptibility to vancomycin, with a MIC50/90 of 0.5/1 μg/ml (91.9% susceptible and 0.0% resistant according to CLSI breakpoint criteria). Although some older compounds, such as tetracycline and sulfamethoxazole-trimethoprim, also exhibited good activity against MRSA, including multidrug-resistant strains, the lack of robust clinical efficacy data and concerns regarding toxicity prevent the use of these compounds for the treatment of severe invasive staphylococcal infections (19).
Antimicrobial resistance has always been an important problem in the treatment of CoNS infections as well. CoNS species associated with human infections usually are resistant to oxacillin and other antimicrobials commonly used for the treatment of staphylococcal infections, leading to the frequent use of glycopeptides (20). The results presented here indicate that ceftaroline possesses potent activity (MIC50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤1 μg/ml) and a spectrum that includes all species of CoNS tested, including isolates with reduced susceptibility to the antimicrobial agents commonly used to treat CoNS infections.
In summary, we tested a large surveillance collection of clinical staphylococcal strains by reference broth microdilution methods, and our results indicated that ceftaroline possesses potent in vitro activity against contemporary strains of S. aureus and CoNS from U.S. hospitals. In addition, ceftaroline retained significant activity against staphylococci with reduced susceptibility to linezolid, daptomycin, and vancomycin, and it may represent a valuable treatment option, alone or in combination, for serious infections caused by these multidrug-resistant staphylococci in the United States (21, 22).
ACKNOWLEDGMENTS
We thank S. Benning, J. Streit, and M. Stilwell for the preparation of the manuscript and the JMI staff members for scientific assistance in performing this study.
This study was funded by educational/research grants from Cerexa, Inc. (Oakland, CA), a wholly owned subsidiary of Forest Laboratories, Inc. (New York, NY). Cerexa, Inc., was involved in the study design and decision to present these results. Cerexa, Inc., had no involvement in the collection, analysis, or interpretation of data. Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc.
JMI Laboratories, Inc., received research and educational grants in 2010 to 2012 from Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Bayer, bioMérieux, Cempra, Cerexa, Contrafect, Cubist, Dipexium, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences, Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, ThermoFisher Scientific, and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, J&J, and Theravance.
We have no speaker bureaus or stock options to declare.
Footnotes
Published ahead of print 29 April 2013
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