Jennifer M. Streit

Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014)

ABSTRACT The LEADER surveillance program monitors the in vitro activity of linezolid and comparator agents against Gram-positive bacteria in the United States. In its eighth consecutive year (2011), a total of 60 medical centers from the United States, including seven medical centers specializing in childrens health care contributed a total of 7,303 Gram-positive pathogens. The MIC90 value for Staphylococcus aureus was 2 μg/ml, and for coagulase-negative staphylococci, enterococci, Streptococcus pneumoniae, β-hemolytic streptococci, and viridans group streptococci, the MIC90 was 1 μg/ml. The “all organism” linezolid-resistant and nonsusceptible rate was only 0.19%.

Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) Program: report of linezolid activity over 9 years (2004–12)

OBJECTIVES To summarize the activity and spectrum of linezolid and comparators tested against 7972 Gram-positive clinical isolates as part of the Zyvox(®) Annual Appraisal of Potency and Spectrum (ZAAPS) Program for 2012. Moreover, to provide molecular characterization for associated resistance mechanisms and epidemiological typing. METHODS A total of 7972 isolates were collected from 73 medical centres (33 countries) on five continents. Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A9 document. MIC interpretations were based on CLSI and EUCAST criteria. RESULTS Linezolid showed MIC50 and MIC90 results of 1 and 2 mg/L, respectively, when tested against Staphylococcus aureus. These isolates were inhibited by linezolid at ≤2 mg/L, except for four S. aureus exhibiting higher MIC values (4-8 mg/L), which had cfr and/or target site mutations, including a first detection of cfr in an isolate from Brazil. Coagulase-negative staphylococci (CoNS) were susceptible to linezolid (MIC50/90, 0.5/1 mg/L), with only eight isolates exhibiting high MIC results (16-32 mg/L). These CoNS had cfr and/or single or multiple target site alterations in 23S rRNA and/or ribosomal proteins (L3, L4). The same species of linezolid-resistant CoNS collected from the same hospital were clonally related to those observed in previously surveyed years. Linezolid exhibited stable modal MIC and MIC50 results when tested against enterococci, regardless of the species or vancomycin resistance phenotype; in addition, linezolid inhibited all streptococci at ≤2 mg/L. CONCLUSIONS This surveillance report documents stable linezolid activity and susceptibility rates against a large and longitudinal collection of clinical isolates worldwide.

Update of the telavancin activity in vitro tested against a worldwide collection of Gram-positive clinical isolates (2013), when applying the revised susceptibility testing method

A revised broth microdilution susceptibility testing method for telavancin was approved by the Food and Drug Administration (FDA). Telavancin activity was assessed against Gram-positive pathogens collected worldwide (2013) using the revised method. A total of 12,346 isolates from 90 sites were included as part of the Telavancin International Surveillance Program for the Americas, Europe, and Asia-Pacific. Telavancin had MIC50 and MIC90 values of 0.03 and 0.06 μg/mL, respectively, against staphylococci, regardless of methicillin susceptibility, and inhibited all Staphylococcus aureus at ≤0.12 μg/mL (revised FDA breakpoint). Telavancin was 8-fold more active than daptomycin (MIC50/90, 0.25/0.5 μg/mL) and 16- to 32-fold more active than vancomycin (MIC50/90, 1/1 μg/mL) and linezolid (MIC50/90, 1/1 μg/mL) against methicillin-resistant S. aureus. All 692 vancomycin-susceptible Enterococcus faecalis were inhibited by telavancin (MIC50/90, 0.12/0.12 μg/mL) at ≤0.25 μg/mL (FDA breakpoint), except for 1 strain (MIC, 0.5 μg/mL). All Enterococcus faecium and E. faecalis with telavancin MIC values of ≥0.5 and ≥1 μg/mL, respectively, had a VanA phenotype. A comparison data analysis based on the MIC90 demonstrated that telavancin was at least 8-fold more potent than comparators against vancomycin-susceptible enterococci. Streptococci showed telavancin MIC50 values of ≤0.015 μg/mL, except for Streptococcus agalactiae (MIC50, 0.03 μg/mL). These in vitro results obtained by the recently approved susceptibility testing method establish a new benchmark of telavancin activity worldwide.

Ceftaroline Activity against Bacterial Pathogens Frequently Isolated in U.S. Medical Centers: Results from Five Years of the AWARE Surveillance Program

ABSTRACT A total of 84,704 isolates were collected from 191 medical centers in 2009 to 2013 and tested for susceptibility to ceftaroline and comparator agents by broth microdilution methods. Ceftaroline inhibited all Staphylococcus aureus isolates at ≤2 μg/ml and was very active against methicillin-resistant strains (MIC at which 90% of the isolates tested are inhibited [MIC90], 1 μg/ml; 97.6% susceptible). Among Streptococcus pneumoniae isolates, the highest ceftaroline MIC was 0.5 μg/ml, and ceftaroline activity against the most common Enterobacteriaceae species (MIC50, 0.12 μg/ml; 78.9% susceptible) was similar to that of ceftriaxone (MIC50, ≤0.25 μg/ml; 86.8% susceptible).

Update on Linezolid In Vitro Activity through the Zyvox Annual Appraisal of Potency and Spectrum Program, 2013

ABSTRACT Linezolid showed MIC50s and MIC90s of 1 μg/ml (for both) against Staphylococcus aureus. Two S. aureus strains exhibited higher MICs (4 to 8 μg/ml) caused by cfr and/or target site mutations, including the first detection of cfr in Poland. Linezolid (MIC50 and MIC90, 0.5 and 1 μg/ml) had potent MICs against coagulase-negative staphylococci (CoNS). Four CoNS had MICs of 16 to 128 μg/ml due to alterations in 23S rRNA and/or L3/L4. Linezolid inhibited all enterococci and streptococci at ≤2 μg/ml, except for one Enterococcus faecium strain (MIC, 8 μg/ml; G2576T [Escherichia coli numbering] mutation).

Five-Year Summary of In Vitro Activity and Resistance Mechanisms of Linezolid against Clinically Important Gram-Positive Cocci in the United States from the LEADER Surveillance Program (2011 to 2015)

ABSTRACT This report describes linezolid susceptibility testing results for 6,741 Gram-positive pathogens from 60 U.S. sites collected during 2015 for the LEADER Program. In addition, the report summarizes linezolid in vitro activity, resistance mechanisms, and molecular typing obtained for 2011 to 2015. During 2015, linezolid showed potent activity in testing against Staphylococcus aureus, inhibiting >99.9% of 3,031 isolates at ≤2 µg/ml. Similarly, linezolid showed coverage against 99.2% of coagulase-negative staphylococci, 99.7% of enterococci, and 100.0% of Streptococcus pneumoniae, virdans group, and beta-hemolytic streptococcus isolates tested. The overall linezolid resistance rate remained a modest <1% from 2011 to 2015. Staphylococci, especially Staphylococcus epidermidis, showed a range of linezolid resistance mechanisms. Increased annual trends for the presence of cfr among Staphylococcus aureus isolates were not observed, but 64.3% (9/14) of the isolates with decreased susceptibility (MIC, ≥4 µg/ml) to linezolid carried this transferrable gene (2011 to 2015). The cfr gene was detected in 21.9% (7/32) of linezolid-resistant staphylococci other than S. aureus from 2011 to 2015. The optrA gene was noted in half (2/4) of the population of linezolid-nonsusceptible Enterococcus faecalis isolates from 2011 to 2015, while linezolid-nonsusceptible Enterococcus faecium isolates showed alterations predominantly (16/16) in the 23S rRNA gene (G2576T). This report confirms a long record of linezolid activity against Gram-positive isolates in the United States since regulatory approval in 2000 and reports the oxazolidinones evolving resistance mechanisms.

Antimicrobial activity of ceftaroline and comparator agents when tested against numerous species of coagulase-negative Staphylococcus causing infection in US hospitals.

A total of 1593 coagulase-negative staphylococci (CoNS) considered clinically significant were collected from 71 US medical centers in 2013-2014 and tested for susceptibility by CLSI broth microdilution methods. Species identification was performed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Overall, 59.7% of isolates were oxacillin resistant (MRCoNS). Ceftaroline (MIC50/90, 0.25/0.5μg/mL) inhibited 99.2% of CoNS at ≤1μg/mL (susceptible breakpoint for Staphylococcus aureus), including 98.7% of MRCoNS, and the highest ceftaroline MIC value was 2μg/mL (13 isolates). Staphylococcus epidermidis represented 60.3% of the CoNS collection and was highly susceptible to ceftaroline (MIC50/90, 0.25/0.5μg/mL, 99.9% inhibited at ≤1μg/mL). All isolates of Staphylococcus capitis, Staphylococcus caprae, Staphylococcus hominis, Staphylococcus lugdunensis, Staphylococcus pettenkoferi, Staphylococcus simulans, and Staphylococcus warneri (MIC50/90, 0.06-0.25/0.25-0.5μg/mL) were inhibited at ceftaroline MIC of ≤1μg/mL. Staphylococcus haemolyticus represented only 4.8%, was atypically less susceptible to ceftaroline (MIC50/90, 0.5/2μg/mL, 87.0% inhibited at ≤1μg/mL), and accounted for 76.9% (10/13) of isolates with ceftaroline MIC >1μg/mL.

ZAAPS programme results for 2016: an activity and spectrum analysis of linezolid using clinical isolates from medical centres in 42 countries

Objectives To report the linezolid in vitro activity obtained during the 2015 ZAAPS Program. Methods In total, 7587 organisms causing documented infections were consecutively collected in 65 centres in 32 ex-USA countries. Broth microdilution susceptibility testing was performed. Isolates displaying linezolid MIC results of ≥ 4 mg/L were molecularly characterized. Results Linezolid inhibited >99.9% of Staphylococcus aureus at ≤ 2 mg/L, with MIC50 results of 1 mg/L, regardless of methicillin resistance. A similar linezolid MIC50 result (0.5 mg/L) was observed for CoNS, with the vast majority of isolates (99.7%) also inhibited at ≤ 2 mg/L. Three CoNS (linezolid MIC, 16-64 mg/L) from Italy were found to contain alterations in the 23S rRNA and/or L3/L4 ribosomal proteins. One isolate also harboured cfr. Linezolid exhibited consistent modal MIC and MIC50 results (1 mg/L) for enterococci regardless of species or vancomycin resistance. One Enterococcus faecalis (linezolid MIC, 8 mg/L) from Galway, Ireland, carried optrA. One Enterococcus faecium (linezolid MIC, 16 mg/L) from Italy contained a G2576T mutation in the 23S rRNA. All Streptococcus pneumoniae, viridans group streptococci and β-haemolytic streptococci were inhibited by linezolid at ≤ 2, ≤ 2 and ≤ 1 mg/L, respectively, with equivalent MIC90 results (1 mg/L for all groups). Conclusions These results document the continued long-term and stable in vitro potency of linezolid and a limited number of isolates with decreased susceptibility to linezolid (MIC, ≥4 mg/L). The latter isolates showed primarily mutations in the 23S rRNA gene and/or L3/L4 proteins, with plasmid-mediated resistance (cfr and optrA) also present, albeit at a low prevalence.

Antimicrobial Susceptibility Trends among Staphylococcus aureus Isolates from U.S. Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program, 2010 to 2016

ABSTRACT We evaluated trends in Staphylococcus aureus antimicrobial susceptibility in U.S. hospitals in the 2010–2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. Methicillin-resistant S. aureus (MRSA) rates decreased from 50.0% (in 2010) to 42.2% (in 2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against methicillin-susceptible S. aureus (MSSA) and MRSA (97.2% susceptible) with no marked variations.

Surveillance of tigecycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Pacific) collection (2016)

Tigecycline and comparators were tested by the reference broth microdilution method against 33 348 non-duplicate bacterial isolates collected prospectively in 2016 from medical centres in the Asia-Pacific (3443 isolates), Europe (13 530 isolates), Latin America (3327 isolates) and the USA (13 048 isolates). Among 7098 Staphylococcus aureus isolates tested, >99.9% were inhibited by ≤0.5 mg/L tigecycline (MIC50/90, 0.06/0.12 mg/L), including >99.9% of methicillin-resistant S. aureus and 100.0% of methicillin-susceptible S. aureus. Tigecycline was slightly more active against Enterococcus faecium (MIC50/90, 0.03/0.06 mg/L) compared with Enterococcus faecalis (MIC50/90, 0.06/0.12 mg/L) and its activity was not adversely affected by vancomycin resistance when tested against these organisms. Tigecycline potency was comparable for Streptococcus pneumoniae (MIC50/90, 0.03/0.06 mg/L), viridans group streptococci (MIC50/90, 0.03/0.06 mg/L) and β-haemolytic streptococci (MIC50/90, 0.06/0.06 mg/L) regardless of species and penicillin susceptibility. Tigecycline was active against Enterobacteriaceae (MIC50/90, 0.25/1 mg/L; 97.8% inhibited at ≤2 mg/L) but was slightly less active against Enterobacteriaceae isolates expressing resistant phenotypes: carbapenem-resistant Enterobacteriaceae (MIC50/90, 0.5/2 mg/L; 98.0% susceptible); multidrug-resistant (MIC50/90, 0.5/2 mg/L; 93.1% susceptible); and extensively drug-resistant (MIC50/90, 0.5/4 mg/L; 87.8% susceptible). Tigecycline inhibited 74.4% of 888 Acinetobacter baumannii isolates at ≤2 mg/L (MIC50/90, 2/4 mg/L) and demonstrated good in vitro activity against Stenotrophomonas maltophilia (MIC50/90, 1/2 mg/L; 90.6% inhibited at ≤2 mg/L) Tigecycline was active against Haemophilus influenzae (MIC50/90, 0.12/0.25 mg/L) regardless of β-lactamase status. Tigecycline represents an important treatment option for resistant Gram-negative and Gram-positive bacterial infections.