In Vitro Activity of Lefamulin against S. aureus Collected Worldwide from Hospitalized Patients with Bacterial Pneumonia

Abstract Background S. aureus (SA) is a well-recognized cause of pneumonia from both the community and hospital settings. The clinical management of SA pneumonia is complicated by the invasive infection it can cause and the high prevalence of methicillin-resistance (MR). Lefamulin (LEF) is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans. LEF is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans and it specifically inhibits bacterial protein synthesis. LEF is currently in Phase 3 trials for the treatment of community-acquired bacterial pneumonia (CABP). This study investigated the in vitro activity of LEF and comparators against SA strains collected from patients hospitalized with pneumonia in 2015. Methods 1273 unique SA isolates were collected from hospitalized patients with pneumonia worldwide in 28 countries (33 sites) in 2015 as part of the SENTRY surveillance program. Isolates included 401 hospital-acquired (HA) SA (259 from ICU, 152 from ventilator associated pneumonia, VAP). Susceptibility testing was conducted using the CLSI broth microdilution method and susceptibility was interpreted per CLSI 2017 breakpoint criteria. Results LEF was the most potent compound tested, with 99.7% of all SA isolates being inhibited at a concentration of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L) and irrespective of the collection source (ICU/non-ICU, VAP/non-VAP). 31.6% of isolates (n = 402) were MRSA of which 99.3% were inhibited at a LEF concentration of ≤0.25 µg/mL (MIC50/90, 0.06/0.12 mg/L). Susceptibility rates for all SA isolates were >90% for ceftaroline, vancomycin, linezolid and doxycycline. Susceptibility to azithromycin, levofloxacin and clindamycin was limited, particularly among MRSA (see Table). Conclusion SA strains collected from patients hospitalized with pneumonia including HAP and VAP were highly susceptible to LEF regardless of the resistance phenotype to the other antibiotics tested. Due to its potent activity against resistant SA and the most prevalent typical and atypical respiratory pathogens, as well as the availability of IV and oral formulations, LEF has the potential to play a role in the empiric treatment of CABP and supports evaluation in HAP and VAP caused by SA. Disclosures S. Paukner, Nabriva Therapeutics: Employee and Shareholder, Salary; R. K. Flamm, Nabriva Therapeutics: Research Contractor, Research grant; J. Schuchert, Nabriva Therapeutics: Research Contractor, Research grant; S. P. Gelone, Nabriva Therapeutics: Employee and Shareholder, Salary; H. S. Sader, The Medicines Company: Research Contractor, Research grant

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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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Cefepime-Zidebactam (WCK 5222) Activity Tested against Gram-negative Organisms Causing Bloodstream Infections Worldwide

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.922 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S374-S375 ◽

Cited By ~ 1

Author(s):

Helio S Sader ◽

Mariana Castanheira ◽

Jennifer M Streit ◽

Leonard R Duncan ◽

Robert K Flamm

Keyword(s):

Bloodstream Infections ◽

Multidrug Resistant ◽

Vitro Activity ◽

Asia Pacific ◽

In Vitro Activity ◽

Gram Negative ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Research Grant

Abstract Background Zidebactam (ZID), a bicyclo-acyl hydrazide, is a β-lactam enhancer with a dual mechanism of action involving selective and high binding affinity to Gram-negative (GN) PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime (FEP) combined with ZID against GN organisms causing bloodstream infections (BSI) in hospitals worldwide. Methods A total of 2,094 isolates from 105 medical centers were evaluated. Isolates were collected from Europe (1,050), USA (331), Latin America (LA; 200) and the Asia-Pacific region (AP; 393) in 2015, and China (120) in 2013 by the SENTRY Program. Susceptibility (S) testing was performed by reference broth microdilution method against FEP-ZID (1:1 ratio) and comparators. The collection included 1,809 Enterobacteriaceae (ENT), 170 P. aeruginosa (PSA) and 115 Acinetobacter spp. (ASP). Results FEP-ZID was very active against ENT (MIC50/90 of ≤0.03/0.12 μg/mL) with 99.9 and 100.0% of isolates inhibited at ≤4/4 and ≤8/8 μg/mL, respectively, and retained potent activity against carbapenem-resistant (CRE; n = 44; MIC50/90, 1/4 μg/mL), multidrug-resistant (MDR), and extensively drug-resistant (XDR) isolates (Table). Amikacin (AMK; MIC50/90, 2/4 μg/mL; 97.7% S) was also very active against ENT, and colistin (COL; MIC50/90, 0.12/>8 μg/mL) inhibited only 87.3% of isolates at ≤2 μg/mL. FEP-ZID was highly active against PSA, including isolates resistant to other antipseudomonal β-lactams, MDR (MIC50/90, 4/8 μg/mL) and XDR (MIC50/90, 4/8 μg/mL) isolates. Among the comparators, COL (MIC50/90 of ≤0.5/1 μg/mL; 100.0% S) and AMK (MIC50/90, 4/16 μg/mL; 91.2% S) were the most active agents against PSA. FEP-ZID (MIC50/90, 16/32 μg/mL) was 4-fold more active than FEP against ASP. Conclusion FEP-ZID (WCK 5222) exhibited potent in vitro activity against a large worldwide collection of GN isolates from BSI, including MDR and XDR isolates. These results support further clinical development of WCK 5222 for treating BSI. Disclosures H. S. Sader, Wockhardt Bio Ag: Research Contractor, Research grant; M. Castanheira, Wockhardt Bio Ag: Research Contractor, Research grant; J. M. Streit, Wockhardt Bio Ag: Research Contractor, Research grant; L. R. Duncan, Wockhardt Bio Ag: Research Contractor, Research grant; R. K. Flamm, Wock: Research Contractor, Research support

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In Vitro Activity of Omadacycline and Comparator Compounds Against Gram-positive Isolates Collected in the USA During 2016 as Part of a Global Surveillance Program

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.919 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S374-S374

Author(s):

Michael D Huband ◽

Michael a Pfaller ◽

Helio S Sader ◽

Robert K Flamm

Keyword(s):

Resistance Mechanisms ◽

Vitro Activity ◽

Surveillance Program ◽

Ionization Mass ◽

In Vitro Activity ◽

Coagulase Negative Staphylococci ◽

Gram Positive ◽

Resistant Strains ◽

Research Grant

Abstract Background Omadacycline (OMC) is a broad spectrum aminomethylcycline antibacterial in late stage clinical development (PO and IV formulations) for treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). OMC has potent in vitro activity against gram-positive (GP) pathogens expressing common resistance mechanisms to penicillins, tetracyclines, fluoroquinolones and macrolides. Methods A total of 4,122 GP isolates were collected in 2016 from 30 USA medical centers and included 2,366 staphylococci, 1,252 streptococci and 504 enterococci. A single isolate/patient/infection episode was included. Identifications were confirmed by matrix-assisted laser desorption/ionization mass spectrometry and susceptibility (S) testing was performed using reference broth microdilution methods. Results OMC was equally active against methicillin-susceptible (55.1% MSSA) and -resistant (44.9% MRSA) Staphylococcus aureus (SA; MIC50/90, 0.12/0.25 µg/mL). All SA were S to daptomycin (DAP), linezolid (LZD) and vancomycin (VAN). In MRSA, S was lower for levofloxacin (LEV; 28.2%), clindamycin (CLI; 69.9%), and erythromycin (ERY; 10.9%). OMC (MIC50/90, 0.12/0.5 µg/mL) and tigecycline (TGC; MIC50/90, 0.06/12 µg/mL) were the most active agents against coagulase-negative staphylococci (CoNS) and methicillin-R CoNS. S. pneumoniae (including penicillin- [12.8% resistant], ceftriaxone- and ERY-resistant strains), viridans group streptococci (VGS) and β-hemolytic streptococci (including ERY and tetracycline resistant strains) were inhibited by low levels of OMC (MIC50/90 0.06/0.06–0.12 µg/mL) and TGC (MIC50/90 0.03–0.06/0.06–0.12 µg/mL). OMC was highly potent against enterococci (MIC50/90 0.12/0.25 µg/mL) including vancomycin-R isolates. Vancomycin resistance rates were 4.3% and 66.5% in E. faecalis and E. faecium, respectively. Conclusion OMC demonstrated potent activity against susceptible and resistant GP pathogens often associated with ABSSSI and CABP including staphylococci, S. pneumoniae, β-hemolytic streptococci, VGS and enterococci. These data support further omadacycline clinical studies, especially in infections where resistant GP isolates occur. Disclosures M. D. Huband, Paratek Pharma, LLC: Research Contractor, Research grant; M. A. Pfaller, Paratek Pharma, LLC: Research Contractor, Research grant; H. S. Sader, Paratek Pharma, LLC: Research Contractor, Research grant R. K. Flamm, Paratek Pharma, LLC: Research Contractor, Research grant

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Analysis of Oritavancin Activity against Gram-Positive Clinical Isolates Responsible for Bacterial Endocarditis in United States and European Hospitals (2008–2016)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.903 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S369-S369 ◽

Cited By ~ 1

Author(s):

Michael A Pfaller ◽

Helio S Sader ◽

Dee Shortridge ◽

Robert K Flamm ◽

Rodrigo E Mendes

Keyword(s):

United States ◽

Active Agent ◽

Bacterial Endocarditis ◽

Vitro Activity ◽

Surveillance Program ◽

In Vitro Activity ◽

Coagulase Negative Staphylococci ◽

Gram Positive ◽

Research Grant

Abstract Background Oritavancin (ORI) has documented in vitro activity against gram-positive (GP) isolates. This study analyzed ORI tested against organisms causing endocarditis in United States (US) and European (EU) sites. Methods A total of 424 organisms recovered from patients with a diagnosis of bacterial endocarditis at US and EU sites during the SENTRY Antimicrobial Surveillance Program (2008–2016) were included (see Table). Isolates were identified by standard biochemical algorithms and MALDI-TOF. Susceptibility (S) testing was performed by CLSI methods, and MICs were interpreted per CLSI and/or EUCAST criteria. Results Among the 424 isolates, 212 (50.0%) were S. aureus (SA; 31.6% methicillin-resistant [MRSA]), 47 (11.1%) were coagulase-negative staphylococci (CoNS), 81 (19.1%) were E. faecalis (EFC), 21 (5.0%) were E. faecium (EFM), 24 (5.7%) were BHS, and 39 (9.2%) were viridans group streptococci (VGS). ORI had similar MIC90 values (0.06 µg/mL) against SA and CoNS, inhibiting 98.8% of these isolates at ≤0.12 µg/mL. ORI MIC50 values were 8- to 32-fold lower than those for vancomycin (VAN), daptomycin (DAP), and ceftaroline (CPT) against staphylococci. ORI showed MICs against EFM (MIC50/90, 0.008/0.03 µg/mL) that were 2-fold lower than against EFC (MIC50/90, 0.015/0.03 µg/mL; 97.5%S against all or 100%S against indicated VAN-S isolates). ORI inhibited 98.0% of all enterococci, including VAN-resistant isolates at ≤0.12 µg/mL. VAN, DAP, ampicillin (MIC50/90, ≤1/2 µg/mL), and linezolid (LZD) (MIC50/90, 1/2 µg/mL) were similarly active against EFC, while DAP and LZD had coverage (100.0%S) against EFM. Overall, BHS were highly S to all agents tested, except for erythromycin (70.8%S) and tetracycline (43.5%S). ORI was the most active agent (MIC90, 0.12 µg/mL) tested against VGS. Conclusion ORI showed potent in vitro activity against isolates recovered from patients with endocarditis in US and EU sites. The data presented here warrant further investigations to determine whether ORI has a role for treating endocarditis. Disclosures M. A. Pfaller, The Medicines Company: Research Contractor, Research grant; H. S. Sader, The Medicines Company: Research Contractor, Research grant; D. Shortridge, The Medicines Company: Research Contractor, Research grant; R. K. Flamm, The Medicines Company: Research Contractor, Research grant; R. E. Mendes, The Medicines Company: Research Contractor, Research grant

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1054. Activity of a Anti-staphylococcal Lysin, LSVT-1701: In vitro Susceptibility of Staphylococcus aureus and Coagulase-Negative Staphylococci (CoNS) Global Clinical Isolates (2002 to 2019)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1248 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S618-S619

Author(s):

David Huang ◽

Helio S Sader ◽

Paul R Rhomberg ◽

Katyna Borroto-Esoda ◽

Eric Gaukel

Keyword(s):

The United States ◽

Vitro Activity ◽

Clinical Isolates ◽

Asia Pacific ◽

In Vitro Activity ◽

Coagulase Negative Staphylococci ◽

Medical Centers ◽

Broth Microdilution Method ◽

Research Grant

Abstract Background LSVT-1701, formerly SAL200, is a novel, recombinantly-produced, bacteriophage-encoded lysin that specifically targets staphylococci via cell wall enzymatic hydrolysis. We reported the in vitro activity of LSVT-1701 against clinical isolates of S. aureus and coagulase-negative staphylococci (CoNS) collected worldwide. Methods LSVT-1701 and comparators were tested against 415 S. aureus (n=315) and CoNS (n=100) clinical isolates expressing various resistance phenotypes. The isolates were collected in 2002-2019 from medical centers located in the United States (50 medical centers; 174 isolates; 41.9% overall), Europe (37 medical centers; 140 isolates; 33.7% overall), Asia-Pacific region (15 medical centers; 55 isolates; 13.3% overall), and Latin America (12 medical centers; 46 isolates; 11.1% overall). These isolates originated mostly from the year 2019 (n=323).The isolates were susceptibility tested by the CLSI broth microdilution method. MIC interpretations were based on CLSI and EUCAST criteria where available. Results LSVT-1701 was highly active against S. aureus and CoNS isolates with MIC90 values of 2 mg/L for all S. aureus, methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and CoNS (Table). The highest LSVT-1701 MIC values were 4 and 8 mg/L among S. aureus and CoNS, respectively. LSVT-1701 retained potent activity against S. aureus isolates showing resistance or decreased susceptibility to oxacillin, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, or lefamulin; MIC50 values ranged from 0.5 to 1 mg/L and MIC90 values ranged from 1 to 4 mg/L among S. aureus resistant subsets. Summary of LSVT-1701 activity against S. aureus, CoNS and resistant subsets Conclusion LSVT-1701 demonstrated potent in vitro activity against contemporary clinical isolates of S. aureus and CoNS collected from medical centers worldwide and against resistant S. aureus isolates with uncommon resistance phenotypes. The results of this study support further clinical development of LSVT-1701 to treat staphylococcal infections. Disclosures David Huang, MD, PhD, Lysovant (Consultant) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Paul R Rhomberg, Cidara Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support) Katyna Borroto-Esoda, PhD, Lysovant (Consultant) Eric Gaukel, BS, Lysovant (Employee)

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1044. In vitro Activity of Tebipenem Against Relevant Clinical Isolates in the Presence of Pulmonary Surfactant

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1238 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S614-S614

Author(s):

S J Ryan Arends ◽

Abby L Klauer ◽

Nicole Cotroneo ◽

Ian A Critchley ◽

Rodrigo E Mendes

Keyword(s):

Pulmonary Surfactant ◽

Positive Control ◽

Vitro Activity ◽

Clinical Isolates ◽

In Vitro Activity ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Tract Infections ◽

Research Grant

Abstract Background Tebipenem (TBP) is an orally administered broad-spectrum carbapenem antibiotic under development for the treatment of acute pyelonephritis and complicated urinary tract infections. This study evaluated the effect of bovine pulmonary surfactant (BPS) on the in vitro activity of TBP and ertapenem (ETP) against a recent collection of clinical isolates. Methods A total of 10 isolates recovered from patients with infections in 2018 were tested for antimicrobial susceptibility to TBP and ETP in the absence or presence of 1%, 5%, or 10% BPS (Infasurf; ONY Biotech). These isolates included the following species: C. freundii, E. cloacae, E. coli, H. influenzae, H. parainfluenzae, K. pneumoniae, methicillin-susceptible S. aureus, M. catarrhalis, S. pneumoniae, and S. pyogenes. Isolates were tested with the appropriate broth microdilution method for each organism as specified by CLSI. For most organisms, MICs were determined in cation-adjusted Mueller-Hinton broth (CAMHB). CAMHB was supplemented with 2.5-5% lysed horse blood for streptococci and Haemophilus Test Medium broth for Haemophilus spp. Daptomycin (DAP) was tested against S. aureus ATCC 29213 as a positive control. Results All isolates displayed TBP MIC values ranging from ≤0.004 to 0.06 mg/L in media without BPS. There were no observed MIC increases >2-fold in the presence of BPS. 4 of the 10 isolates displayed slightly higher (≥4-fold) ETP than TBP MIC values. The ETP MIC values ranged from 0.015-0.25 mg/L in media without BPS. Similarly, there were no observed instances of a >2-fold shift toward lower potency in the presence of BPS. For both TBP and ETP, MIC endpoint values were easily determined, except for in the case of the 2 Haemophilus strains growing in the presence of 5% or 10% BPS. For these conditions, resazurin was added to establish an MIC value. The MIC values found with this method did not differ from the MIC values found in either HTM media or HTM media with 1% BPS. As expected, the addition of BPS shifted DAP S. aureus MIC values to >8 mg/L for all 3 BPS concentrations. Conclusion TBP displayed potent activity against all isolates tested, as all observed MIC values were ≤0.06 mg/L. The addition of BPS to the testing medium did not affect the in vitro MIC values of TBP or ETP against these species. Disclosures S J Ryan Arends, PhD, AbbVie (formerly Allergan) (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Abby L. Klauer, n/a, Cidara Therapeutics, Inc. (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Nicole Cotroneo, Spero Therapeutics (Employee, Shareholder) Ian A. Critchley, Ph.D., Spero Therapeutics (Employee, Shareholder) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

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1375. In vitro Activity of Cefiderocol and Comparator Agents against Gram-Negative Isolates from Cancer Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1206 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S421-S422 ◽

Cited By ~ 2

Author(s):

Kenneth V I Rolston ◽

Bahgat Gerges ◽

Issam Raad ◽

Samuel L Aitken ◽

Ruth Reitzel ◽

...

Keyword(s):

Cancer Patients ◽

Active Agent ◽

Vitro Activity ◽

Significant Activity ◽

In Vitro Activity ◽

Research Support ◽

Gram Negative ◽

E Coli ◽

Research Grant

Abstract Background Gram-negative bacilli (GNB) are now the predominant cause of bacterial infection in cancer patients (CP). Many GNB are problematic because they have become resistant to commonly used antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin, is active against a wide spectrum of GNB. We evaluated its in vitro activity and that of eleven comparator agents against GNB isolated from CP. Methods A total of 341 recent GNB blood isolates from CP were tested using CLSI approved methods for MIC determination by broth microdilution. Comparator agents were amikacin (A), aztreonam (AZ), ceftazidime (CZ), ceftazidime/avibactam (CAV), cefepime (CEF), ciprofloxacin (CIP), colistin (CL), meropenem (MR), ceftolozane/tazobactam (C/T), tigecycline (TG), and trimethoprim/sulfamethoxazole (T/S). Results CFDC MIC90s as mg/L were: S. maltophilia [50 isolates] 0.25, E. coli (ESBL−) [50 isolates] 0.5, E. coli (ESBL+) [51 isolates] 2.0, K. pneumoniae (ESBL− and +) [60 isolates] 0.5; K. pneumoniae (CRE) [22 isolates] 2.0; P. aeruginosa (MDR) [32 isolates] 1.0; E. cloacae [27 isolates] 4.0; Achromobacter spp. [15 isolates] 0.12. CFDC inhibited P. agglomerans, Burkholderia spp., Sphingomonas spp., Ochrobactrum spp. at ≤1 mg/L [23 total isolates] and Elizabethkingia spp. and R. radiobacter at ≤8 mg/L [11 total isolates]. Among comparator agents, only T/S had consistent activity against S. maltophilia. For E. coli (ESBL− and +) MR, TG, CAV, CL were most active. For K. pneumoniae (ESBL–and +) MR, CAV were most active. For K. pneumoniae (CRE) and P. aeruginosa (MDR), none of the comparators had significant activity. For E. cloacae, MR, A, CAV, TG were most active. Among the uncommon organisms, MR and TG had the greatest activity. Conclusion Although susceptibility breakpoints have yet to be determined, CFDC has significant activity (≤4 mg/L) against most problematic Gram-negative organisms causing infections in CP based on available pharmacokinetic/pharmacodynamic data. In particular, its activity against S. maltophilia was superior to the comparators. Also, it was the most active agent against P. aeruginosa (MDR) and K. pneumoniae (CRE). Based on our results, CFDC warrants clinical evaluation for the treatment of blood stream infections caused by GNB in CP. Disclosures K. V. I. Rolston, Merck: Investigator, Research grant; JMI Laboratories: Investigator, Research grant; Shionogi (Japan): Investigator, Research grant. B. Gerges, Shionogi: Collaborator, Research support. S. L. Aitken, Shionogi: Scientific Advisor, Consulting fee; Merck: Scientific Advisor, Consulting fee; Medicines Co: Scientific Advisor, Consulting fee; Achaogen: Scientific Advisor, Consulting fee; Zavante: Scientific Advisor, Consulting fee; R. Prince, Shionogi: Investigator, Research support. Merck: Investigator, Research support.

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1348. In vitro Activity of Plazomicin, a Next-Generation Aminoglycoside, Against Carbapenemase-Producing Klebsiella pneumoniae

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1179 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S412-S413

Author(s):

Michael R Jacobs ◽

Caryn E Good ◽

Ayman M Abdelhamed ◽

Daniel D Rhoads ◽

Kristine M Hujer ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Carbapenem Resistance ◽

Vitro Activity ◽

In Vitro Activity ◽

Next Generation ◽

Aminoglycoside Resistance ◽

Carbapenem Resistant ◽

Carbapenemase Gene ◽

Research Grant

Abstract Background Plazomicin is a next-generation aminoglycoside with in vitro activity against multidrug-resistant Gram-negative species, including carbapenem-resistant isolates. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a federally funded, prospective multicenter consortium of 20 hospitals from nine US healthcare systems to track carbapenem-resistant Enterobacteriaceae. Methods Minimum inhibitory concentrations (MICs) of plazomicin were determined by broth microdilution according to current CLSI guidelines against a collection of 697 carbapenem-resistant Klebsiella pneumoniae with defined carbapenem resistance mechanisms, including KPC and OXA carbapenemases. Isolates were submitted by participating CRACKLE centers. Results Carbapenemases present in study isolates included KPC-2 (n = 323), KPC-3 (n = 364), KPC-4 (n = 2), OXA-48 like (n = 7), and NDM (n = 1). Plazomicin MICs ranged from ≤0.12 to >32 mg/L, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively (figure). MICs of 689 (98.8%) isolates were ≤4 mg/L, while MICs of the remaining eight isolates were >32 mg/L. Plazomicin MICs were related to specific carbapenemases present in isolates: of eight isolates with MICs >32 mg/L, seven contained OXA-48 like and one contained KPC-3, suggesting that these isolates possess an aminoglycoside-resistance mechanism on the same plasmid as their carbapenemase gene, such as a 16S ribosomal RNA methyltransferase, against which plazomicin is not active. Conclusion Plazomicin has good in vitro potency against a collection of carbapenemase-producing K. pneumoniae, with MIC90 value of 1 mg/L and MICs of ≤4 mg/L for 98.9% of isolates. Disclosures M. R. Jacobs, Achaogen: Investigator, Research grant. Shionogi: Investigator, Research grant. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. M. Krause, Achaogen: Employee, Salary. S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant. D. Van Duin, achaogen: Scientific Advisor, Consulting fee. shionogi: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee.

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