Daniel F. Sahm

Ibero American University

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James A. Karlowsky

University of Manitoba

106

Mary Motyl

Merck & Co., Inc., Rahway, NJ, USA (United States)

Katherine Young

Merck & Co., Inc., Rahway, NJ, USA (United States)

Sibylle Lob

Merck & Co., Inc., Rahway, NJ, USA (United States)

Meredith Hackel

Pearl River Community College

Clyde Thornsberry

Eurofins (United States)

Krystyna M. Kazmierczak

Indiana University Bloomington

Mark G. Wise

U.S. National Poultry Research Center

Mark E. Jones

Basilea Pharmaceutica (Switzerland)

Gregory G. Stone

Pfizer (United States)

Cooperative Institutions

Ibero American University

Pfizer (United States)

Merck & Co., Inc., Rahway, NJ, USA (United States)

Harvard University

Shionogi (Japan)

AstraZeneca (United States)

Futaba (Japan)

Janssen (United States)

Centers for Disease Control and Prevention

Johnson & Johnson (United States)

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P-1520. Addition of Relebactam Increases Susceptibility to Imipenem Among Imipenem-Intermediate Pseudomonas aeruginosa: Asia/Pacific SMART 2018-2022

Open Forum Infectious Diseases (2025)

Mark G. Wise C Andrew DeRyke Wei‐Ting Chen Fakhar Siddiqui Katherine Young

Abstract Background Imipenem/relebactam (IMR) combines imipenem with the β-lactamase inhibitor relebactam, an inhibitor of class A and C β-lactamases. We assessed the activity of IMR and comparators against Pseudomonas aeruginosa collected in 9 countries in the Asia/Pacific region as part of the global SMART surveillance program, with a focus on the increased antimicrobial activity brought by the addition of relebactam to imipenem for those organisms interpreted as “intermediate” by 2024 CLSI criteria (MIC = 4 µg/mL) to imipenem alone. Methods From 2018-2022, 50 clinical laboratories in nine countries in Asia/Pacific (Australia, Hong Kong, Malaysia, New Zealand, Philippines, South Korea, Taiwan, Thailand, and Vietnam) each collected up to 250 consecutive, aerobic or facultative, Gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with 2024 CLSI breakpoints. Most isolates that were imipenem or ceftolozane/tazobactam-nonsusceptible (NS) were screened for β-lactamases. Results IMR demonstrated excellent antimicrobial activity against isolates from most countries, inhibiting >80% of the isolates from each country except Vietnam (63.2% susceptible; Table). Ceftolozane/tazobactam and amikacin showed similar levels of activity. Limiting the analysis to isolates that tested “intermediate” to imipenem (MIC = 4 µg/mL) revealed that the addition of relebactam rendered >96% of the organisms from each country susceptible, ranging from 100% (Australia, New Zealand and South Korea) to 96.3% (Vietnam). Most imipenem-I P. aeruginosa examined molecularly (727/740; 98.2%) did not carry an acquired β-lactamase. As relebactam itself does not possess antibacterial activity, this suggests that the increased antimicrobial activity attributable to its addition is likely a result of its inhibitory activity on the intrinsic AmpC (blaPDC) in this species. Conclusion IMR showed potent activity against clinical P. aeruginosa collected in Asia/Pacific. The addition of relebactam to imipenem was responsible for the inhibition of >96% of isolates that were “intermediate” to imipenem alone. Disclosures Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Asia-Pacific

10.1093/ofid/ofae631.1689

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Citations (0)

ANTIMICROBIAL SUSCEPTIBILITIES OF ENTEROBACTERIACEAE (EB) AND PSEUDOMONAS AERUGINOSA (PA) FROM INPATIENT INFECTIONS IN THE U.S.: 1999-2002 TRUST SURVEILLANCE

Critical Care Medicine (2002)

Daniel F. Sahm Renee Blosser Clyde Thornsberry Ian A. Critchley James A. Karlowsky

SOCIETY OF CRITICAL CARE MEDICINE 32ND CRITICAL CARE CONGRESS SAN ANTONIO, TEXAS, USA JANUARY 28-FEBRUARY 2, 2003: ORAL/SANDWICH PRESENTATIONS: Poster Presentation: Clinical Science: Sepsis Pneumonia: PDF Only

Antimicrobial Stewardship

10.1097/00003246-200212001-00401

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Citations (2)

Emerging Trends in Antimicrobial Resistance: A Laboratory Perspective

Springer eBooks (1995)

Daniel F. Sahm

Clinical Microbiology

10.1007/978-1-4757-9203-4_12

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Citations (0)

1584. In Vitro Activity of Imipenem/Relebactam against Gram-Negative Pathogens from Patients with Bloodstream Infections in the United States and Canada – SMART 2018

Open Forum Infectious Diseases (2020)

Sibylle Lob Meredith Hackel Katherine Young Mary Motyl Daniel F. Sahm

Abstract Background Relebactam (REL) inhibits class A and C β-lactamases, including KPC, and was approved in the United States combined with imipenem (IMI) and cilastatin for complicated urinary tract and intraabdominal infections. We evaluated the activity of IMI/REL against non-Morganellaceae (NME) and P. aeruginosa collected as part of the global SMART surveillance program from patients with bloodstream infections (BSI) in the US and Canada. Methods In 2018, 24 US and 8 Canadian hospitals each collected up to 50 consecutive aerobic or facultative gram-negative pathogens from patients with BSI. MICs were determined using CLSI broth microdilution and interpreted with 2020 CLSI breakpoints. Multidrug-resistance (MDR) was defined as resistance to ≥3 of the following sentinel drugs: amikacin, aztreonam, cefepime, ceftazidime (NME only), ciprofloxacin, colistin, imipenem, and piperacillin/tazobactam. Results The 5 most common species among 1463 collected BSI isolates were E. coli (46.9%), K. pneumoniae (16.0%), P. aeruginosa (8.5%), P. mirabilis (4.8%), and E. cloacae (4.3%). Susceptibility to IMI/REL and comparators of selected species and subsets of resistant phenotypes is shown in the table. IMI/REL was active against 99.8% of NME isolates; only meropenem, ceftazidime/avibactam, and amikacin showed comparable activity. Per 2020 CLSI guidelines, Enterobacterales and P. aeruginosa isolates are no longer considered susceptible to colistin. IMI/REL maintained activity against 89-100% of NME isolates that were nonsusceptible (NS) to β-lactams or MDR. Among P. aeruginosa, IMI/REL was active against 94.4% of isolates; a susceptibility rate only exceeded by amikacin. The addition of relebactam lowered the MIC90 for P. aeruginosa from 16 µg/mL to 1 µg/mL. IMI/REL maintained activity against 40-77% of P. aeruginosa isolates NS to β-lactams or MDR; susceptibility rates only exceeded by amikacin. Susceptibility to IMI/REL was similar in the US (99.8% of NME [n=846]; 93.8% of P. aeruginosa [n=96]) and Canada (99.7% of NME [n=339]; 96.4% of P. aeruginosa [n=28]). Table Conclusion In the US and Canada, IMI/REL could provide an important treatment option for patients with BSI caused by resistant gram-negative organisms. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)

Broth microdilution

Colistin

Amikacin

Cefepime

Aztreonam

10.1093/ofid/ofaa439.1764

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Citations (1)

Clinical and Public Health Implications of Macrolide-ResistantStreptococcus pneumoniae

Journal of Chemotherapy (2002)

Robert C. Moellering William A. Craig Michael B. Edmond David J. Farrell Mary Jane Ferraro

SummaryMacrolide resistance among Streptococcus pneumoniae is a growing global concern, although its specific impact on public health is not currently well defined. A Consensus Working Group was convened in March 2001 to address whether credible, scientific data substantiate macrolide resistance in S. pneumoniae as: (i) producing significant morbidity; (ii) creating attendant health and economic burdens; (iii) constituting a public health threat; and (iv) warranting intervention, including development of new antibiotics with efficacy against these strains. Despite the limitations of available clinical data, concern about the possibility of treatment failure with macrolides is being expressed in clinical practice and in formal treatment guidelines, threatening the important role of these agents in the treatment of respiratory tract infections. Further studies are required to monitor and control macrolide resistance and evaluate settings in which macrolide treatment failures are occurring, and new therapeutic interventions are needed.

10.1080/1120009x.2002.11782351

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Citations (13)

Susceptibilities to Levofloxacin in Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis Clinical Isolates from Children: Results from 2000-2001 and 2001-2002 TRUST Studies in the United States

Antimicrobial Agents and Chemotherapy (2003)

James A. Karlowsky Clyde Thornsberry Ian A. Critchley Mark E. Jones Alan T. Evangelista

Among respiratory tract isolates of Streptococcus pneumoniae from children, resistance to penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole (SXT) increases on an annual basis. Pediatric patients who do not respond to conventional therapy for respiratory tract infections someday may be treated with fluoroquinolones. In this study, MICs of beta-lactams, azithromycin, SXT, and levofloxacin were determined and interpreted by using NCCLS guidelines for isolates of S. pneumoniae (2,834 from children and 10,966 from adults), Haemophilus influenzae (629 from children and 2,281 from adults), and Moraxella catarrhalis (389 from children and 1,357 from adults) collected during the 2000-2001 and 2001-2002 respiratory illness seasons in the United States as part of the ongoing TRUST surveillance studies. Rates of resistance to penicillin, azithromycin, and SXT were > or = 7.5% higher among patients < or = 4 years old than among patients 5 to 10, 11 to 17, and > or = 18 years old in both the 2000-2001 and the 2001-2002 respiratory illness seasons. Levofloxacin resistance was detected in 2 of 2,834 isolates (0.07%) from patients <18 years old. Levofloxacin MICs of 0.25 to 1 micro g/ml accounted for 99.6, 99.5, 99.3, 99.7, 98.4, and 98.0% of isolates from patients < 2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and > 64 years old. Multidrug resistance was twice as common among patients < or = 4 years old (25.3%) as among patients 5 to 10 years old (13.7%), 11 to 17 years old (11.9%), 18 to 64 years old (12.1%), and > 64 years old (12.4%). The most common multidrug resistance phenotype in S. pneumoniae isolates for all age groups was resistance to penicillin, azithromycin, and SXT (70.3 to 76.6%). For H. influenzae and M. catarrhalis isolates from patients < 2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and > 64 years old, levofloxacin MICs at which 90% of the isolates were inhibited were 0.015 and 0.03 to 0.06 microg/ml, respectively, in the 2000-2001 and 2001-2002 respiratory illness seasons. In the 2000-2001 and 2001-2002 respiratory illness season surveillance studies in the United States, 99.9% of pediatric isolates of S. pneumoniae were susceptible to levofloxacin. If fluoroquinolones become a treatment option for pediatric patients, careful monitoring of fluoroquinolone susceptibilities will be increasingly important in future surveillance studies.

Wheeze

Sulfamethoxazole

Moraxella (Branhamella) catarrhalis

Trimethoprim

10.1128/aac.47.6.1790-1797.2003

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Citations (49)

Epidemiology and Antimicrobial Susceptibility of Gram-Negative Pathogens Causing Intra-abdominal Infections in Pediatric Patients in Europe—SMART 2011–2014

Journal of the Pediatric Infectious Diseases Society (2016)

Sibylle Lob Robert E. Badal Meredith Hackel Daniel F. Sahm

In this study, susceptibility varied among European Gram-negative isolates from pediatric intra-abdominal infections. Resistance, rates of extended-spectrum β-lactamase-positive isolates, and multidrug-resistance rates were substantially higher in isolates from hospital-associated infections than in those from community-associated infections and were higher in ICUs than in general wards, which suggests that different empiric therapy strategies are needed in different settings. The most common type of intra-abdominal infection (IAI) is appendicitis, which occurs most frequently in children and young adults. Yet, few studies on the microbiology of pediatric IAI are available, which is problematic because antimicrobial therapy for IAI usually needs to be initiated before microbiological culture results are available. With this study, we aimed to assess whether resistance patterns in pediatric IAI in Europe that would help clinicians select empiric therapy can be identified. Gram-negative pathogens (n = 1259) were collected from pediatric patients as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) in 16 European countries from 2011 to 2014. Minimal inhibitory concentrations (MICs) and extended-spectrum β-lactamase (ESBL) phenotype were determined by broth microdilution according to Clinical and Laboratory Standards Institute guidelines, and susceptibility was interpreted according to European Committee on Antimicrobial Susceptibility Testing guidelines. An IAI was defined as hospital- or community-associated if cultured ≥48 or <48 hours after admission, respectively. Overall, only imipenem and amikacin exceeded 90% susceptibility when all Gram-negative pathogens were combined, and ertapenem, cefepime, ceftazidime, piperacillin-tazobactam, and levofloxacin reached at least 85%. However, resistance, ESBL-positive, and multidrug-resistance (MDR) rates were substantially higher in isolates from patients with hospital-associated IAI than from those with community-associated IAI (eg, 14.1% vs 5.1% MDR isolates, respectively, among all Gram-negative pathogens), higher in isolates from intensive care units than in those from general wards, and higher in isolates from infants than in those from children ≥1 year of age. In addition, MDR rates varied markedly within Europe. These results indicate that empiric therapy of pediatric IAI in Europe should reflect not only regional and local resistance patterns but also higher resistance rates in hospital-associated infections, intensive care units, and infants.

Cefepime

Ertapenem

Amikacin

Empiric therapy

Tazobactam

Broth microdilution

10.1093/jpids/piv109

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Citations (22)

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 (2003)

Ian A. Critchley Renée S. Blosser-Middleton Mark E. Jones Clyde Thornsberry Daniel F. Sahm

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 (MIC(90)s) 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 MIC(90) of 0.12 micro g/ml for both penicillin-susceptible and -resistant isolates of S. pneumoniae. Against oxacillin-resistant S. aureus daptomycin had a MIC(90) of 0.5 micro g/ml, and it had a MIC(90) of 4 micro g/ml against both vancomycin-susceptible and -resistant E. faecium. The MIC(90)s 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.

Daptomycin

Linezolid

Enterococcus faecium

Dalfopristin

Quinupristin

10.1128/aac.47.5.1689-1693.2003

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Citations (78)

Global Dissemination of bla _KPC into Bacterial Species beyond Klebsiella pneumoniae and In Vitro Susceptibility to Ceftazidime-Avibactam and Aztreonam-Avibactam

Antimicrobial Agents and Chemotherapy (2016)

Krystyna M. Kazmierczak Douglas J. Biedenbach Meredith Hackel Sharon Rabine Boudewijn L. M. de Jonge

The Klebsiella pneumoniae carbapenemase (KPC), first described in the United States in 1996, is now a widespread global problem in several Gram-negative species. A worldwide surveillance study collected Gram-negative pathogens from 202 global sites in 40 countries during 2012 to 2014 and determined susceptibility to β-lactams and other class agents by broth microdilution testing. Molecular mechanisms of β-lactam resistance among carbapenem-nonsusceptible Enterobacteriaceae and Pseudomonas aeruginosa were determined using PCR and sequencing. Genes encoding KPC enzymes were found in 586 isolates from 22 countries (76 medical centers), including countries in the Asia-Pacific region (32 isolates), Europe (264 isolates), Latin America (210 isolates), and the Middle East (19 isolates, Israel only) and the United States (61 isolates). The majority of isolates were K. pneumoniae (83.4%); however, KPC was detected in 13 additional species. KPC-2 (69.6%) was more common than KPC-3 (29.5%), with regional variation observed. A novel KPC variant, KPC-18 (KPC-3[V8I]), was identified during the study. Few antimicrobial agents tested remained effective in vitro against KPC-producing isolates, with ceftazidime-avibactam (MIC90, 4 μg/ml), aztreonam-avibactam (MIC90, 0.5 μg/ml), and tigecycline (MIC90, 2 μg/ml) retaining the greatest activity against Enterobacteriaceae cocarrying KPC and other β-lactamases, whereas colistin (MIC90, 2 μg/ml) demonstrated the greatest in vitro activity against KPC-positive P. aeruginosa This analysis of surveillance data demonstrated that KPC is widely disseminated. KPC was found in multiple species of Enterobacteriaceae and P. aeruginosa and has now become a global problem.

Broth microdilution

Ceftazidime/avibactam

Tigecycline

Colistin

Avibactam

Aztreonam

10.1128/aac.00107-16

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Citations (88)

Multiple-Drug Resistant Enterococci: The Nature of the Problem and an Agenda for the Future

Emerging infectious diseases (1998)

Mark M. Huycke Daniel F. Sahm Michael S. Gilmore

Enterococci, leading causes of nosocomial bacteremia, surgical wound infection, and urinary tract infection, are becoming resistant to many and sometimes all standard therapies. New rapid surveillance methods are highlighting the importance of examining enterococcal isolates at the species level. Most enterococcal infections are caused by Enterococcus faecalis, which are more likely to express traits related to overt virulence but--for the moment--also more likely to retain sensitivity to at least one effective antibiotic. The remaining infections are mostly caused by E. faecium, a species virtually devoid of known overt pathogenic traits but more likely to be resistant to even antibiotics of last resort. Effective control of multiple-drug resistant enterococci will require 1) better understanding of the interaction between enterococci, the hospital environment, and humans, 2) prudent antibiotic use, 3) better contact isolation in hospitals and other patient care environments, and 4) improved surveillance. Equally important is renewed vigor in the search for additional drugs, accompanied by the evolution of new therapeutic paradigms less vulnerable to the cycle of drug introduction and drug resistance.

Enterococcus faecalis

Isolation

Enterococcus faecium

Bacteremia

10.3201/eid0402.980211

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Citations (735)