1588. Activity of Imipenem/Relebactam Against Clinical Isolates of P. aeruginosa and K. pneumoniae Collected in Asia/Pacific Countries – SMART 2016-2018

Abstract Background Relebactam (REL) inhibits class A and C β-lactamases and was approved in the USA in combination with imipenem (IMI) and cilastatin for the treatment of complicated intraabdominal and urinary tract infections. We evaluated the activity of IMI/REL against clinical isolates collected in Asia/Pacific as part of the global SMART surveillance program. Methods In 2016-2018, 56 clinical laboratories each collected up to 250 consecutive, aerobic and facultative gram-negative pathogens from various infection sources per year. Susceptibility was determined using CLSI broth microdilution and CLSI breakpoints. IMI-nonsusceptible isolates (except from India) were screened for β-lactamase genes. Results Among 5501 K. pneumoniae and 4362 P. aeruginosa isolates, 46.6% and 65.3%, respectively, were collected from patients with lower respiratory tract infections, 25.6% and 17.1% from intraabdominal infections, 19.9% and 13.9% from urinary tract infections, and 7.2 and 2.9% from bloodstream infections. No infection source was specified for 0.7% of isolates from either species. 90.7% of collected K. pneumoniae isolates were IMI/REL-susceptible, ranging from 56.8% in India and ~80% in Thailand and Vietnam (~16% MBL-positive) to ≥97% in 7 countries (0-2% MBL-positive). 28.6% (202/707) of IMI-nonsusceptible K. pneumoniae were IMI/REL-susceptible. Of the 425 molecularly characterized IMI-nonsusceptible K. pneumoniae, 187 (44.0%) were MBL/OXA-48-like negative and 83.4% of these (156/187) were IMI/REL-susceptible; 82 isolates (19.3%) were KPC-positive and 91.5% of these (75/82) were IMI/REL-susceptible. The table shows percent susceptible and percent MBL-positive among all collected P. aeruginosa isolates. 74.3% of IMI-nonsusceptible P. aeruginosa (n=1236) were IMI/REL-susceptible. Table Conclusion IMI/REL was active against 91% of K. pneumoniae and 89% of P. aeruginosa isolates collected in Asia/Pacific overall, with higher activity in countries with lower MBL-positive rates. IMI/REL promises to be an important treatment option for IMI-nonsusceptible MBL-negative isolates, including KPC-producing K. pneumoniae. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Wei-Ting Chen, MD, Merck, Sharp & Dohme, Taiwan (Employee) Tsz Kin Khan, PhD, Merck, Sharp & Dohme, Hong Kong (Employee) 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)

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1583. In Vitro Activity of Imipenem/Relebactam against Klebsiella pneumoniae and Pseudomonas aeruginosa from Patients in ICUs in the Asia/Pacific region – SMART 2015-2018

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1763 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S789-S789

Author(s):

Sibylle Lob ◽

Meredith Hackel ◽

Wei-Ting Chen ◽

Yivonne Khoo ◽

Kanchan Balwani ◽

...

Keyword(s):

Hong Kong ◽

Urinary Tract ◽

Antimicrobial Susceptibility ◽

Bloodstream Infections ◽

Asia Pacific ◽

Surveillance Program ◽

Independent Contractor ◽

Icu Patients ◽

Tract Infections

Abstract Background Relebactam (REL) is an inhibitor of class A and C β-lactamases approved in the USA in combination with imipenem (IMI) and cilastatin for the treatment of complicated intraabdominal and urinary tract infections. Elevated antimicrobial resistance rates have been reported in ICUs. Using isolates collected in Asia/Pacific for the SMART surveillance program, we evaluated the activity of IMI/REL and comparators against K. pneumoniae (KP) and P. aeruginosa (PA) from ICU patients. Methods In 2015-2018, 51 clinical laboratories in Australia, Hong Kong, Malaysia, New Zealand, Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam each collected up to 250 consecutive aerobic gram-negative pathogens per year. Susceptibility was determined using CLSI broth microdilution and CLSI and FDA (IMI/REL) breakpoints. IMI-nonsusceptible KP and PA were screened for β-lactamase genes. Results Analyzing only the 6322 isolates from ICU patients, the 3 most common species collected were KP (21.4%), E. coli (20.5%), and PA (19.7%). Tables 1 and 2 show % susceptible and % MBL- and/or OXA-48-like-positive for the most common Enterobacterales species (KP; 70.6% from lower respiratory tract, 17.6% from intraabdominal, 7.1% from urinary tract, and 4.1% from bloodstream infections) and the most common non-Enterobacterales species (PA; 83.6%, 9.9%, 4.3%, and 1.9%, respectively). % IMI/REL-susceptible ranged from 66-79% in Thailand and Vietnam (where 13-36% of isolates carried MBL and/or OXA-48-like carbapenemases, which REL does not inhibit) to ≥95% in 6 countries (0-3% MBL- and/or OXA-48-like-positive). Among 103 IMI/REL-nonsusceptible KP isolates, 66.0% carried MBL, 20.4% OXA-48-like carbapenemases, 2.9% KPC, 2.9% acquired AmpC and/or ESBL, and in 7.8% no acquired β-lactamases were detected. Among 145 IMI/REL- nonsusceptible PA, 54.5% carried MBL, 1.4% GES carbapenemases, 4.1% only ESBL, and 40.0% no acquired β-lactamases. Table 1. Antimicrobial susceptibility of K. pneumoniae collected from ICU patients Table 2. Antimicrobial susceptibility of P. aeruginosa collected from ICU patients Conclusion IMI/REL was active against 92% of KP and 88% of PA from ICU patients in Asia/Pacific overall, with higher activity in countries with lower prevalence of MBL or OXA-48-like carbapenemases. IMI/REL provides a potential treatment option for ICU patients in Asia/Pacific with infections caused by KP and PA. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Wei-Ting Chen, MD, Merck, Sharp & Dohme, Taiwan (Employee) Yivonne Khoo, PhD, Merck, Sharp & Dohme, Malaysia (Employee) Kanchan Balwani, MBBS, MS, Merck, Sharp & Dohme, Hong Kong (Employee) 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)

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1617. Mecillinam susceptibility against Enterobacterales isolated from urinary tract infections from US patients in 2018

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1797 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S801-S802

Author(s):

Stephen Hawser ◽

Ian Morrissey ◽

Cedric Charrier ◽

Cyntia De Piano ◽

Morton Alexander ◽

...

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Clinical Development ◽

Penicillin Binding Protein ◽

Beta Lactams ◽

Independent Contractor ◽

Susceptibility Data ◽

First Line Therapy ◽

The Usa ◽

Tract Infections

Abstract Background Mecillinam is a unique amidinopenicillin antibiotic, being the first and the only compound in its class. In contrast to other beta-lactams, it has a unique mechanism of action whereby it exerts its antibacterial activity through binding to penicillin binding protein 2. Pivmecillinam is the oral-prodrug of mecillinam and recommended as a first line therapy in the IDSA guidelines for uncomplicated urinary tract infections (uUTI), despite not yet being available in the USA. To support the clinical development of mecillinam and pivmecillinam in the USA for the treatment of both complicated UTI and uUTI this study investigated the activity of mecillinam against Enterobacterales isolates from the USA during 2018. Methods A total of 1,090 isolates from urinary tract infections from patients in the USA were tested. Activity of antibiotics was tested by CLSI methodology and susceptibility interpreted according to CLSI guidelines. Results Susceptibility and activity of each antibiotic are shown in the Table. Mecillinam MIC50 and MIC90 were 0.25 and 4 µg/mL, respectively and 94.5% of isolates were susceptible. Fosfomycin MIC50 and MIC90 were 2 and 32 µg/mL, respectively and 95.7% of isolates were susceptible. The other four comparator antibiotics showed MIC90 values >8 µg/mL and a 70.5 – 79.9% susceptible isolates. The highest MIC90 against all isolates combined was 64 µg/mL for nitrofurantoin and the highest percentage of resistance was obtained with trimethoprim-sulfamethoxazole with 29.5%. Resistance towards ceftriaxone and ciprofloxacin was 19.6% and 26.1%, respectively. Table Conclusion Overall, mecillinam showed the lowest MIC90 and a comparable susceptibility profile (94.5 % susceptible and 4.0 % resistant) to fosfomycin (i.e. 95.7% and 2.0% resistant) susceptible isolates). Resistance to ceftriaxone, ciprofloxacin and trimethoprim/sulfamethoxazole around or above 20% is concerning for their clinical usage to treat urinary tract infections. These encouraging susceptibility data warrant further studies to support the clinical development of mecillinam/pivmecillinam for the treatment of UTI in the USA. Disclosures Stephen Hawser, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator) Cedric Charrier, PhD, IHMA (Employee)Utility Therapeutics (Independent Contractor) Cyntia De Piano, PhD, IHMA (Employee)Utility Therapeutics (Independent Contractor) Morton Alexander, PhD, Utility Therapeutics (Employee, Shareholder) Anne Santerre Henriksen, MS, Maxel Consulting ApS (Employee)Utility Therapeutics (Independent Contractor)

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Single Clinical Isolates from Acute Uncomplicated Urinary Tract Infections Are Representative of Dominant In Situ Populations

mBio ◽

10.1128/mbio.01064-13 ◽

2014 ◽

Vol 5 (2) ◽

Cited By ~ 18

Author(s):

Dana Willner ◽

Serene Low ◽

Jason A. Steen ◽

Narelle George ◽

Graeme R. Nimmo ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Clinical Isolates ◽

Content Type ◽

E Coli ◽

Strain Diversity ◽

Amplicon Pyrosequencing ◽

Culture Independent ◽

Tract Infections

ABSTRACTUrinary tract infections (UTIs) are one of the most commonly acquired bacterial infections in humans, and uropathogenicEscherichia colistrains are responsible for over 80% of all cases. The standard method for identification of uropathogens in clinical laboratories is cultivation, primarily using solid growth media under aerobic conditions, coupled with morphological and biochemical tests of typically a single isolate colony. However, these methods detect only culturable microorganisms, and characterization is phenotypic in nature. Here, we explored the genotypic identity of communities in acute uncomplicated UTIs from 50 individuals by using culture-independent amplicon pyrosequencing and whole-genome and metagenomic shotgun sequencing. Genus-level characterization of the UTI communities was achieved using the 16S rRNA gene (V8 region). Overall UTI community richness was very low in comparison to other human microbiomes. We strain-typedEscherichia-dominated UTIs using amplicon pyrosequencing of the fimbrial adhesin gene,fimH. There were nine highly abundantfimHtypes, and each UTI sample was dominated by a single type. Molecular analysis of the corresponding clinical isolates revealed that in the majority of cases the isolate was representative of the dominant taxon in the community at both the genus and the strain level. Shotgun sequencing was performed on a subset of eightE. coliurine UTI and isolate pairs. The majority of UTI microbial metagenomic sequences mapped to isolate genomes, confirming the results obtained using phylogenetic markers. We conclude that for the majority of acute uncomplicatedE. coli-mediated UTIs, single cultured isolates are diagnostic of the infection.IMPORTANCEIn clinical practice, the diagnosis and treatment of acute uncomplicated urinary tract infection (UTI) are based on analysis of a single bacterial isolate cultured from urine, and it is assumed that this isolate represents the dominant UTI pathogen. However, these methods detect only culturable bacteria, and the existence of multiple pathogens as well as strain diversity within a single infection is not examined. Here, we explored bacteria present in acute uncomplicated UTIs using culture-independent sequence-based methods.Escherichia coliwas the most common organism identified, and analysis ofE. colidominant UTI samples and their paired clinical isolates revealed that in the majority of infections the cultured isolate was representative of the dominant taxon at both the genus and the strain level. Our data demonstrate that in most cases single cultured isolates are diagnostic of UTI and are consistent with the notion of bottlenecks that limit strain diversity during UTI pathogenesis.

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1582. In Vitro Activity of Ceftolozane/Tazobactam against Enterobacterales and Pseudomonas aeruginosa Isolates from Geriatric Patients in the Asia/Pacific region – SMART 2016-2018

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1762 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S788-S789

Author(s):

Sibylle Lob ◽

Meredith Hackel ◽

Wei-Ting Chen ◽

Yivonne Khoo ◽

Kanchan Balwani ◽

...

Keyword(s):

Hong Kong ◽

Urinary Tract ◽

Length Of Hospital Stay ◽

Asia Pacific ◽

Surveillance Program ◽

Independent Contractor ◽

In Vitro Susceptibility ◽

Specimen Collection ◽

Genes Encoding

Abstract Background Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor approved by FDA and EMA for complicated urinary tract and intraabdominal infections, and hospital-acquired and ventilator-associated bacterial pneumonia. We evaluated the activity of C/T against isolates collected from patients ≥65 years old as part of the SMART surveillance program in Asia/Pacific. Methods In 2016-2018, 49 clinical laboratories in Australia, Hong Kong, Malaysia, New Zealand, Philippines, Singapore, Korea, Taiwan, Thailand, and Vietnam each collected up to 250 consecutive gram-negative pathogens per year. Susceptibility was determined using CLSI broth microdilution and breakpoints. C/T-nonsusceptible (NS) Enterobacterales (ENT) and P. aeruginosa (PA) isolates were screened by PCR and sequenced for genes encoding β-lactamases (except ENT from 1 site in Taiwan). Results 2082 PA (68.3% lower respiratory tract, 12.7% intraabdominal, 15.1% urinary tract, and 3.0% bloodstream infection isolates) and 8181 ENT isolates (29.8%, 27.8%, 32.5%, and 9.2%, respectively) were collected from patients ≥65 years old. In vitro susceptibility of PA and ENT stratified by length of hospital stay at time of specimen collection (LOS) is shown (Table). C/T maintained activity against 75.5% of 518 P/T-NS, 67.9% of 395 cefepime-NS, and 71.6% of 377 meropenem-NS PA isolates. Among 136 C/T-NS PA isolates, 44.9% carried metallo-β-lactamases (MBL), 0.7% KPC, 1.5% GES carbapenemases, 5.9% only ESBL, and in 47.1% no acquired β-lactamases were detected. Among 878 characterized C/T-NS ENT, 14.1% carried MBL, 5.2% KPC, 3.3% OXA-48-like carbapenemases, and 53.5% AmpC and/or ESBL; no acquired β-lactamases were detected in 23.8% of isolates, of which 89.5% were species with intrinsic AmpC. Table Conclusion Susceptibility of PA and ENT to all studied agents was lower for isolates collected ≥48 than < 48 hours post-admission. C/T was active against >92% of PA in both strata, 7-29 percentage points higher than the studied comparators except amikacin, and against >84% of ENT, 4-30% higher than the comparators except meropenem and amikacin. C/T is a potential new treatment option for older patients with infections caused by ENT and PA in Asia/Pacific. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Wei-Ting Chen, MD, Merck, Sharp & Dohme, Taiwan (Employee) Yivonne Khoo, PhD, Merck, Sharp & Dohme, Malaysia (Employee) Kanchan Balwani, MBBS, MS, Merck, Sharp & Dohme, Hong Kong (Employee) 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)

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Low pH reduces the activity of ceftolozane/tazobactam in human urine, but confirms current breakpoints for urinary tract infections

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz488 ◽

2019 ◽

Vol 75 (3) ◽

pp. 593-599 ◽

Cited By ~ 1

Author(s):

Alina Karoline Nussbaumer-Pröll ◽

Sabine Eberl ◽

Birgit Reiter ◽

Thomas Stimpfl ◽

Christoph Dorn ◽

...

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Human Urine ◽

Negative Impact ◽

Low Ph ◽

Antibiotic Activity ◽

Clinical Isolates ◽

Acidic Ph ◽

Bacterial Strains ◽

Tract Infections

Abstract Background Acidic pH has been shown to impact the antibiotic activity of non-β-lactams in urine. Objectives To investigate the in vitro activity of ceftolozane/tazobactam compared with meropenem at different pH settings in urine. Methods We determined the MICs for 30 clinical isolates of Escherichia coli, 25 clinical isolates of Klebsiella pneumoniae and 24 clinical isolates of Proteus mirabilis in pooled human urine and standard growth medium at pH 5 and 7. Time–kill curves were produced for one representative clinical isolate of tested bacterial strains in urine at pH 5, 6 and 7 for both antibiotics at concentrations above and below the MIC. HPLC analysis of the stability of ceftolozane/tazobactam and meropenem was performed at different pH values. Results The median MICs of both antibiotics were up to 8-fold higher at pH 5 than at pH 7. Bacterial growth of E. coli was not impacted by pH, while for K. pneumoniae and P. mirabilis low pH slightly reduced growth. Compared with pH 7, pH 5 resulted in a significant decrease in antibiotic activity with a delta of up to 3 log10 bacterial counts after 24 h. Impact of acidic pH was lowest for P. mirabilis; however, this strain metabolically increased the pH during experiments. Stability was not impacted by low pH. Conclusions Acidic pH had a significant negative impact on the activity of ceftolozane/tazobactam and meropenem in urine. Considering concentrations achieved in urine, our results confirm existing breakpoints and do not advocate increasing ceftolozane/tazobactam breakpoints for urinary tract infections.

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