LEADER Program Results for 2009: an Activity and Spectrum Analysis of Linezolid Using 6,414 Clinical Isolates from 56 Medical Centers in the United States

ABSTRACTThe LEADER Program monitors thein vitroactivity of linezolid in sampled U.S. medical centers using reference broth microdilution methods with supporting molecular investigations in a central laboratory design. This report summarizes data obtained in 2009, the 6th consecutive year of this longitudinal study. A total of 6,414 isolates from 56 medical centers in all nine Census regions across the United States participated in 2009. For the six leading species/groups, the following linezolid MIC90values were observed:Staphylococcus aureus, 2 μg/ml; coagulase-negative staphylococci (CoNS), 1 μg/ml;Enterococcusspp., 2 μg/ml;Streptococcus pneumoniae, 1 μg/ml; viridans group streptococci, 1 μg/ml; and beta-hemolytic streptococci, 1 μg/ml. Linezolid resistance was only 0.34% overall, with no evidence of significant increase in the LEADER Program since 2006. The predominant linezolid resistant mechanism found was a G2576T mutation in the 23S rRNA. L3/L4 riboprotein mutations were also found. The mobile multidrug-resistantcfrgene was found in four strains (twoS. aureusstrains and one strain each ofS. epidermidisandS. capitis) from four different states, suggesting persistence but a lack of dissemination. Linezolid continues to exhibit excellent activity and spectrum, and this study documents the need for continued monitoring of emerging mechanisms of resistance over a wide geographic area.

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129. Antimicrobial Activity of Ceftazidime–avibactam and Comparator Agents Tested against Gram-Negative Organisms Isolated from Patients with Bloodstream Infections in United States Medical Centers (2017–2018)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.204 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S93-S94

Author(s):

Cecilia G Carvalhaes ◽

Mariana Castanheira ◽

Rodrigo E Mendes ◽

Helio S Sader

Keyword(s):

United States ◽

New York ◽

Bloodstream Infections ◽

The United States ◽

Multidrug Resistant ◽

Medical Centers ◽

Carbapenem Resistant ◽

Gram Negative Organisms ◽

Esbl Producers

Abstract Background We evaluated the antimicrobial susceptibility of Enterobacterales (ENT) and P. aeruginosa (PSA) causing bloodstream infections (BSIs) in the United States (US) hospitals. Methods A total of 3,317 ENT and 331 PSA isolates were consecutively collected (1/patient) from patients with BSI in 68 US medical centers in 2017–2018 and tested for susceptibility (S) by reference broth microdilution methods in a central laboratory as part of the International Network for Optimal Resistance Monitoring (INFORM) Program. β-Lactamase screening was performed by whole-genome sequencing on ENT with decreased S to broad-spectrum cephalosporins (ESBL phenotype). Results The most common ENT species isolated from BSI were E. coli (EC; 41.9% of ENT), K. pneumoniae (KPN; 24.4%), and E. cloacae (ECL; 8.7%), and the most active agents against ENT were ceftazidime–avibactam (CAZ-AVI; 99.9%S), amikacin (AMK; 99.6%S) and meropenem (MEM; 99.3%S). CAZ-AVI was active against all EC and KPN isolates (100.0%S). Only 2 ENT isolates (0.06%) were CAZ-AVI resistant, 2 NDM-1-producing ECL isolated in the New York City area. Ceftolozane–tazobactam (C-T) and piperacillin–tazobactam (PIP-TAZ) showed good activity against EC and KPN (92.2–98.9%S; Table), with limited activity against ECL (81.9–83.7%S). The most common ESBLs were CTX-M-type, which was observed in 93% of ESBL producers (mainly CTX-M-15 [64% of ESBL producers] and CTX-M-27 [13%]), and OXA-1/OXA-30 (42%); 42% of ESBL producers (n = 333, excluding carbapenemase producers) displayed ≥2 ESBL genes, mainly CTX-M-15 and OXA-1/OXA-30 (40% of ESBL producers). The most active agents against ESBL producers were CAZ-AVI (100.0%S), imipenem (99.4%S), and colistin (COL; 99.1%S). Only CAZ-AVI (99.4%S), AMK (96.2%S) and MEM (92.8%S) were active against >90% of multidrug-resistant (MDR) ENT. Among 19 carbapenem-resistant ENT (CRE; 0.6% of ENT), 9 produced a KPC-like, 2 an NDM-1, and 2 an NMC-A; carbapenemase genes were not found in 6 CRE isolates. COL (100.0%S), CAZ-AVI (98.5%S), AMK (98.5%S), C-T (98.1%S), and tobramycin (97.0%S) were very active against PSA. Conclusion CAZ-AVI exhibited potent in vitro activity and great spectrum against ENT (99.9%S) and PSA (98.5%) isolated from patients with BSI from US hospitals. Disclosures All authors: No reported disclosures.

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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)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00609-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 36

Author(s):

Michael A. Pfaller ◽

Rodrigo E. Mendes ◽

Jennifer M. Streit ◽

Patricia A. Hogan ◽

Robert K. Flamm

Keyword(s):

United States ◽

Staphylococcus Aureus ◽

The United States ◽

Resistance Mechanisms ◽

23S Rrna ◽

Rrna Gene ◽

Gram Positive ◽

Content Type ◽

Linezolid Resistance

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.

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Mechanisms of Linezolid Resistance among Coagulase-Negative Staphylococci Determined by Whole-Genome Sequencing

mBio ◽

10.1128/mbio.00894-14 ◽

2014 ◽

Vol 5 (3) ◽

Cited By ~ 22

Author(s):

Ryan Tewhey ◽

Bing Gu ◽

Theodoros Kelesidis ◽

Carmen Charlton ◽

April Bobenchik ◽

...

Keyword(s):

United States ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

The United States ◽

23S Rrna ◽

Whole Genome ◽

Coagulase Negative Staphylococci ◽

Content Type ◽

Linezolid Resistance ◽

Methylase Gene

ABSTRACT Linezolid resistance is uncommon among staphylococci, but approximately 2% of clinical isolates of coagulase-negative staphylococci (CoNS) may exhibit resistance to linezolid (MIC, ≥8 µg/ml). We performed whole-genome sequencing (WGS) to characterize the resistance mechanisms and genetic backgrounds of 28 linezolid-resistant CoNS (21 Staphylococcus epidermidis isolates and 7 Staphylococcus haemolyticus isolates) obtained from blood cultures at a large teaching health system in California between 2007 and 2012. The following well-characterized mutations associated with linezolid resistance were identified in the 23S rRNA: G2576U, G2447U, and U2504A, along with the mutation C2534U. Mutations in the L3 and L4 riboproteins, at sites previously associated with linezolid resistance, were also identified in 20 isolates. The majority of isolates harbored more than one mutation in the 23S rRNA and L3 and L4 genes. In addition, the cfr methylase gene was found in almost half (48%) of S. epidermidis isolates. cfr had been only rarely identified in staphylococci in the United States prior to this study. Isolates of the same sequence type were identified with unique mutations associated with linezolid resistance, suggesting independent acquisition of linezolid resistance in each isolate. IMPORTANCE Linezolid is one of a limited number of antimicrobials available to treat drug-resistant Gram-positive bacteria, but resistance has begun to emerge. We evaluated the genomes of 28 linezolid-resistant staphylococci isolated from patients. Multiple mutations in the rRNA and associated proteins previously associated with linezolid resistance were found in the isolates investigated, underscoring the multifocal nature of resistance to linezolid in Staphylococcus. Importantly, almost half the S. epidermidis isolates studied harbored a plasmid-borne cfr RNA methylase gene, suggesting that the incidence of cfr may be higher in the United States than previously documented. This finding has important implications for infection control practices in the United States. Further, cfr is commonly detected in bacteria isolated from livestock, where the use of phenicols, lincosamides, and pleuromutilins in veterinary medicine may provide selective pressure and lead to maintenance of this gene in animal bacteria.

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Evaluation of In Vitro Activity of Ceftaroline Tested against Streptococcus pneumoniae Isolates from United States Hospitals: Results from 7 Years of the AWARE Surveillance Program (2010–2016)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.935 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S378-S378

Author(s):

Michael A Pfaller ◽

Rodrigo E Mendes ◽

Leonard R Duncan ◽

Robert K Flamm ◽

Helio S Sader

Keyword(s):

United States ◽

The United States ◽

Multidrug Resistant ◽

Vitro Activity ◽

Surveillance Program ◽

In Vitro Activity ◽

Amoxicillin Clavulanate ◽

Infection Types ◽

Research Grant

Abstract Background Ceftaroline (CPT) is a broad-spectrum cephalosporin with activity against S. pneumoniae (SPN), including multidrug-resistant (MDR) strains. CPT fosamil is approved for clinical use in the United States (US) to treat community-acquired bacterial pneumonia (CABP). The AWARE Program monitors the in vitro activity of CPT against clinical bacteria from various infection types. We evaluated the activity of CPT against isolated SPN clinical isolates from US hospitals collected in 2010 through 2016. Methods A total of 8,768 isolates were consecutively collected (1 per patient) from 47 medical centers in 2010–2016 and tested for susceptibility (S) to CPT and comparator agents using CLSI broth microdilution methods. Resistant subgroups included isolates that were nonsusceptible (NS) to penicillin (PCN), ceftriaxone (CRO), amoxicillin-clavulanate (AMC), erythromycin (ERY), clindamycin (CM), and levofloxacin (LEV) as well as MDR (NS to ≥3 classes of agents) and extensively drug resistant (XDR; NS to ≥5 classes). Results CPT inhibited 99.99% of SPN isolates at ≤0.5 mg/L (only 1 isolate had a CPT MIC of 1 mg/L) and remained active against all SPN-resistant (R) subgroups, including PCN-NS (8.7% at ≥4 mg/L), CRO-NS (6.9% at ≥2 mg/L), MDR (21.7%), and XDR (8.4%) strains. CPT activity remained stable against all R subgroups each year. MDR and XDR frequency decreased from 25.0% and 14.1% in 2011 to 17.8% and 3.2% in 2015, respectively; and S to PCN, CRO, AMC, CM, trimethoprim-sulfamethoxazole (TMX), and tetracycline (TET) increased in the same period (Table). The CPT-NS isolate had multiple substitutions in the penicillin binding proteins (PBP), mainly PBP2x, when compared with reference sequences, and showed 31 amino acid alterations in MurM. For MDR isolates, CPT (99.9%S), tigecycline (99.9%S), linezolid (100.0%S), and vancomycin (100.0%S) were the most active agents. Conclusion CPT demonstrated potent and consistent (2010–2016) activity against SPN, including several R phenotypes and the less S serotypes. SPN S to many antibiotics increased from 2011 to 2015, but remained stable in 2015–2016. Increases in S rates could be related to the anti-pneumococcal vaccine PVC-13 introduced in 2010. Disclosures M. A. Pfaller, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; L. R. Duncan, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant; H. S. Sader, Allergan: Research Contractor, Research grant

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Arbekacin Activity against Contemporary Clinical Bacteria Isolated from Patients Hospitalized with Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04839-14 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3263-3270 ◽

Cited By ~ 17

Author(s):

Helio S. Sader ◽

Paul R. Rhomberg ◽

David J. Farrell ◽

Ronald N. Jones

Keyword(s):

The United States ◽

Multidrug Resistant ◽

Surveillance Program ◽

Content Type ◽

Microdilution Method ◽

Medical Centers ◽

Broth Microdilution Method ◽

Mrsa Strains ◽

Infection Types

ABSTRACTArbekacin is a broad-spectrum aminoglycoside licensed for systemic use in Japan and under clinical development as an inhalation solution in the United States. We evaluated the occurrence of organisms isolated from pneumonias in U.S. hospitalized patients (PHP), including ventilator-associated pneumonia (VAP), and thein vitroactivity of arbekacin. Organism frequency was evaluated from a collection of 2,203 bacterial isolates (339 from VAP) consecutively collected from 25 medical centers in 2012 through the SENTRY Antimicrobial Surveillance Program. Arbekacin activity was tested against 904 isolates from PHP collected in 2012 from 62 U.S. medical centers and 303 multidrug-resistant (MDR) organisms collected worldwide in 2009 and 2010 from various infection types. Susceptibility to arbekacin and comparator agents was evaluated by the reference broth microdilution method. The four most common organisms from PHP wereStaphylococcus aureus,Pseudomonas aeruginosa,Klebsiellaspp., andEnterobacterspp. The highest arbekacin MIC amongS. aureusisolates from PHP (43% methicillin-resistantS. aureus[MRSA]) was 4 μg/ml. AmongP. aeruginosaisolates from PHP, only one had an arbekacin MIC of >16 μg/ml (MIC50and MIC90, 1 and 4 μg/ml), and susceptibility rates for gentamicin, tobramycin, and amikacin were 88.0, 90.0, and 98.0%, respectively. Arbekacin (MIC50, 2 μg/ml) and tobramycin (MIC50, 4 μg/ml) were the most potent aminoglycosides tested againstAcinetobacter baumannii. AgainstEnterobacteriaceaefrom PHP, arbekacin and gentamicin (MIC50and MIC90, 0.25 to 1 and 1 to 8 μg/ml for both compounds) were generally more potent than tobramycin (MIC50and MIC90, 0.25 to 2 and 1 to 32 μg/ml) and amikacin (MIC50and MIC90, 1 to 2 and 2 to 32 μg/ml). Arbekacin also demonstrated potentin vitroactivity against a worldwide collection of well-characterized MDR Gram-negative and MRSA strains.

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Activity of Ceftaroline and Epidemiologic Trends in Staphylococcus aureus Isolates Collected from 43 Medical Centers in the United States in 2009

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00315-11 ◽

2011 ◽

Vol 55 (9) ◽

pp. 4154-4160 ◽

Cited By ~ 51

Author(s):

Sandra S. Richter ◽

Kristopher P. Heilmann ◽

Cassie L. Dohrn ◽

Fathollah Riahi ◽

Andrew J. Costello ◽

...

Keyword(s):

United States ◽

Staphylococcus Aureus ◽

The United States ◽

Surveillance Program ◽

Content Type ◽

Type Iv ◽

Medical Centers ◽

High Level ◽

Resistance Rates

ABSTRACTAStaphylococcus aureussurveillance program was initiated in the United States to examine thein vitroactivity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 from 43 medical centers. All isolates were screened formecAby PCR and evaluated by pulsed-field gel electrophoresis. Methicillin-resistantS. aureus(MRSA) were analyzed for Panton-Valentine leukocidin (PVL) genes and the staphylococcal cassette chromosomemec(SCCmec) type. All isolates had ceftaroline MICs of ≤2 μg/ml with an MIC50of 0.5 and an MIC90of 1 μg/ml. The overall resistance rates, expressed as the percentages of isolates that were intermediate and resistant (or nonsusceptible), were as follows: ceftaroline, 1.0%; clindamycin, 30.2% (17.4% MIC ≥ 4 μg/ml; 12.8% inducible); daptomycin, 0.2%; erythromycin, 65.5%; levofloxacin, 39.9%; linezolid, 0.02%; oxacillin, 53.4%; tetracycline, 4.4%; tigecycline, 0%; trimethoprim-sulfamethoxazole, 1.6%; vancomycin, 0%; and high-level mupirocin, 2.2%. ThemecAPCR was positive for 53.4% of the isolates. The ceftaroline MIC90s were 0.25 μg/ml for methicillin-susceptibleS. aureusand 1 μg/ml for MRSA. Among the 2,247 MRSA isolates, 51% were USA300 (96.9% PVL positive, 99.7% SCCmectype IV) and 17% were USA100 (93.4% SCCmectype II). The resistance rates for the 1,137 USA300 MRSA isolates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6% (6.2% MIC ≥ 4 μg/ml; 1.4% inducible); tetracycline, 3.3%; trimethoprim-sulfamethoxazole, 0.8%; high-level mupirocin, 2.7%; daptomycin, 0.4%; and ceftaroline and linezolid, 0%. USA300 is the dominant clone causing MRSA infections in the United States. Ceftaroline demonstrated potentin vitroactivity against recentS. aureusclinical isolates, including MRSA, daptomycin-nonsusceptible, and linezolid-resistant strains.

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Benchmarking the In Vitro Activities of Moxifloxacin and Comparator Agents against Recent Respiratory Isolates from 377 Medical Centers throughout the United States

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.10.2645-2652.2000 ◽

2000 ◽

Vol 44 (10) ◽

pp. 2645-2652 ◽

Cited By ~ 36

Author(s):

Mark E. Jones ◽

Angela M. Staples ◽

Ian Critchley ◽

Clyde Thornsberry ◽

Paul Heinze ◽

...

Keyword(s):

Moraxella Catarrhalis ◽

The United States ◽

Multidrug Resistant ◽

Pulsed Field Gel Electrophoresis ◽

In Vitro Activity ◽

Resistant Clone ◽

Future Studies ◽

Medical Centers ◽

Drug Classes

ABSTRACT To benchmark the activity of moxifloxacin (a newer fluoroquinolone), a U.S. study comprising 16,141 contemporary isolates of Streptococcus pneumoniae (5,640), Haemophilus influenzae (6,583), and Moraxella catarrhalis (3,648) referred from 377 institutions during 1998 is described. For S. pneumoniae the modal MIC and MIC at which 90% of the isolates were inhibited (MIC90) for moxifloxacin were 0.12 and 0.25 μg/ml, respectively, independent of susceptibility to other drug classes, geography, or site of infection. Eleven isolates were intermediate or resistant to levofloxacin and grepafloxacin; of these isolates, 1 remained susceptible to sparfloxacin, 2 remained susceptible to moxifloxacin, and 4 remained susceptible to trovafloxacin. All 11 isolates possessed classic mutations ingyrA and/or parC known to confer reduced susceptibility to fluoroquinolones. Four isolates (originating from four separate states) belonging to a multidrug-resistant, fluoroquinolone-resistant clone were identified by pulsed-field gel electrophoresis. For moxifloxacin and trovafloxacin, at least 87% of isolates demonstrated MICs ≥3 twofold concentrations below the susceptibility breakpoints, in contrast to no more than 15% for levofloxacin, grepafloxacin, and sparfloxacin. Of the isolates that were multidrug resistant (7.4%), >98% remained susceptible to moxifloxacin. The modal MIC and MIC90 for M. catarrhalis (both 0.06 μg/ml) and for H. influenzae(both 0.03 μg/ml) were independent of β-lactamase production. These data demonstrate the in vitro activity of moxifloxacin and establish a baseline for future studies.

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Summary of Ceftaroline Activity against Pathogens in the United States, 2010: Report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance Program

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00330-12 ◽

2012 ◽

Vol 56 (6) ◽

pp. 2933-2940 ◽

Cited By ~ 52

Author(s):

Robert K. Flamm ◽

Helio S. Sader ◽

David J. Farrell ◽

Ronald N. Jones

Keyword(s):

United States ◽

Bloodstream Infections ◽

The United States ◽

Surveillance Program ◽

Coagulase Negative Staphylococci ◽

Methicillin Resistant ◽

Content Type ◽

Medical Centers ◽

Therapeutic Decision Making ◽

Tract Infections

ABSTRACTTheAssessingWorldwideAntimicrobialResistanceEvaluation (AWARE) surveillance program is a sentinel resistance monitoring system designed to track the activity of ceftaroline and comparator agents. In the United States, a total of 8,434 isolates were collected during the 2010 surveillance program from 65 medical centers distributed across the nine census regions (5 to 10 medical centers per region). All organisms were isolated from documented infections, including 3,055 (36.2%) bloodstream infections, 2,282 (27.1%) respiratory tract infections, 1,965 (23.3%) acute bacterial skin and skin structure infections, 665 (7.9%) urinary tract infections, and 467 (5.5%) miscellaneous other infection sites. Ceftaroline was the most potent β-lactam agent tested against staphylococci. The MIC90values were 1 μg/ml for methicillin-resistantStaphylococcus aureus(MRSA; 98.4% susceptible) and 0.5 μg/ml for methicillin-resistant coagulase-negative staphylococci (CoNS). Ceftaroline was 16- to 32-fold more potent than ceftriaxone against methicillin-susceptible staphylococcal strains. All staphylococcus isolates (S. aureusand CoNS) were inhibited at ceftaroline MIC values of ≤2 μg/ml. Ceftaroline also displayed potent activity against streptococci (MIC90, 0.015 μg/ml for beta-hemolytic streptococci; MIC90, 0.25 μg/ml for penicillin-resistantStreptococcus pneumoniae). Potent activity was also shown against Gram-negative pathogens (Haemophilus influenzae,Haemophilus parainfluenzae, andMoraxella catarrhalis). Furthermore, wild-type strains ofEnterobacteriaceae(non-extended-spectrum β-lactamase [ESBL]-producing strains and non-AmpC-hyperproducing strains) were often susceptible to ceftaroline. Continued monitoring through surveillance networks will allow for the assessment of the evolution of resistance as this new cephalosporin is used more broadly to provide clinicians with up-to-date information to assist in antibiotic stewardship and therapeutic decision making.

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1353. In Vitro Activity of Lefamulin (LEF) Against Bacterial Pathogens Commonly Causing Community-Acquired Bacterial Pneumonia (CABP): 2016 SENTRY Data From the United States

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1184 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S414-S414 ◽

Cited By ~ 1

Author(s):

Susanne Paukner ◽

Robert K Flamm ◽

Steven P Gelone ◽

Helio S Sader

Keyword(s):

United States ◽

Ribosomal Subunit ◽

The United States ◽

Vitro Activity ◽

Surveillance Program ◽

Respiratory Pathogens ◽

In Vitro Activity ◽

Medical Centers ◽

Tract Infections

Abstract Background LEF, the first pleuromutilin antibiotic for IV and oral use in humans, is in Phase 3 clinical trials for the treatment of CABP in adults. In the first of these to be completed, LEF demonstrated noninferiority to moxifloxacin ± linezolid. LEF inhibits bacterial translation by binding the 50S ribosomal subunit at the A- and P-sites in the peptidyl transferase center. CABP is a leading cause of infectious diseases in the United States and increasing antibacterial resistance complicates its treatment. This study investigated the in vitro activity of LEF and comparators against a contemporary set of bacterial respiratory pathogens collected in the United States. Methods Isolates (n = 1674, 1/patient) were collected from 32 medical centers in the United States as part of the SENTRY Surveillance Program. LEF and comparators were tested by CLSI broth microdilution methods, and susceptibility was determined using the CLSI (2018) breakpoints. Results LEF was the most active compound against Streptococcus pneumoniae (MIC50/90 of 0.12/0.12 µg/mL), and its activity was not affected by resistance to other antibiotic classes. S. pneumoniae isolates were susceptible to levofloxacin (99.1%) and ceftriaxone (97.7%), whereas only 53.9%, 63.9%, and 80.4% of isolates were susceptible to macrolides, penicillin (oral), and tetracycline, respectively. LEF also showed potent activity against Staphylococcus aureus (MIC50/90 of 0.06/0.12 µg/mL), including methicillin-resistant (MRSA) isolates (MIC50/90 of 0.06/0.12 µg/mL, 87.1% resistant to erythromycin), Haemophilus influenzae, (MIC50/90 of 0.5/1 µg/mL, 26.9% β-lactamase producing), and Moraxella catarrhalis (MIC50/90 0.06/0.06 µg/mL, 96.5% β-lactamase positive) (figure). Conclusion LEF displayed potent in vitro activity against a contemporary collection of respiratory pathogens from the United States. LEF was active regardless of resistance phenotype to other antibiotic classes including β-lactams, tetracyclines, or macrolides. These results further support the clinical development of lefamulin for the treatment of CABP or other respiratory tract infections. Disclosures S. Paukner, Nabriva: Employee and Shareholder, Salary. R. K. Flamm, Nabriva: Research Contractor, Research grant. S. P. Gelone, Nabriva Therapeutics: Employee, Equity, Shareholder and Salary. Achaogen: Shareholder, Equity, Shareholder. H. S. Sader, Nabriva Therapeutics: Research Contractor, Research support.

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Baseline Study To Determine In Vitro Activities of Daptomycin against Gram-Positive Pathogens Isolated in the United States in 2000-2001

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.5.1689-1693.2003 ◽

2003 ◽

Vol 47 (5) ◽

pp. 1689-1693 ◽

Cited By ~ 59

Author(s):

Ian A. Critchley ◽

Renée S. Blosser-Middleton ◽

Mark E. Jones ◽

Clyde Thornsberry ◽

Daniel F. Sahm ◽

...

Keyword(s):

United States ◽

Outpatient Care ◽

Antimicrobial Agents ◽

The United States ◽

Multidrug Resistant ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Oxacillin Resistance ◽

Positive Spectrum

ABSTRACT The activity of daptomycin was assessed by using 6,973 gram-positive bacteria isolated at 50 United States hospitals in 2000 and 2001. Among the isolates of Streptococcus pneumoniae (n = 1,163) collected, the rate of penicillin resistance was 16.1%; rates of oxacillin resistance among Staphylococcus aureus isolates (n = 1,018) and vancomycin resistance among Enterococcus faecium isolates (n = 368) were 30.0 and 59.5%, respectively. Multidrug-resistant (MDR) phenotypes (isolates resistant to three or more different chemical classes of antimicrobial agents) accounted for 14.2% of S. pneumoniae isolates, 27.1% of S. aureus isolates, and 58.4% of E. faecium isolates. For all gram-positive species tested, MICs at which 90% of the isolates tested were inhibited (MIC90s) and MIC ranges for directed-spectrum agents (daptomycin, quinupristin-dalfopristin, and linezolid) were identical or highly similar for isolates susceptible or resistant to other agents or MDR. Daptomycin had a MIC90 of 0.12 μg/ml for both penicillin-susceptible and -resistant isolates of S. pneumoniae. Against oxacillin-resistant S. aureus daptomycin had a MIC90 of 0.5 μg/ml, and it had a MIC90 of 4 μg/ml against both vancomycin-susceptible and -resistant E. faecium. The MIC90s for daptomycin and other directed-spectrum agents were unaffected by the regional or anatomical origin of isolates or patient demographic parameters (patient age, gender, and inpatient or outpatient care). Our results confirm the gram-positive spectrum of activity of daptomycin and that its activity is independent of susceptibility or resistance to commonly prescribed and tested antimicrobial agents. This study may serve as a baseline to monitor future changes in the susceptibility of gram-positive species to daptomycin following its introduction into clinical use.

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