Global Surveillance Program Research Articles

In vitro activity of ceftazidime/avibactam against isolates of Enterobacteriaceae collected in European countries: INFORM global surveillance 2012–15

The activity of ceftazidime/avibactam was assessed against 24 750 isolates of Enterobacteriaceae collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistant phenotypes and β-lactamase content. Antimicrobial susceptibility testing was performed using broth microdilution and the presence of β-lactamase genes in isolates of interest was determined using PCR and sequencing. Ceftazidime/avibactam was the most active agent, compared with all other tested comparator agents, against the overall collection of Enterobacteriaceae isolates (99.4% susceptible) and against subsets of ceftazidime-non-susceptible (97.7% susceptible), colistin-resistant (98.2% susceptible), MDR (96.7% susceptible) and meropenem-non-susceptible, MBL-negative (98.5% susceptible) isolates. At the country level, susceptibility to ceftazidime/avibactam ranged from 96.3% to 100% among Enterobacteriaceae isolates, with decreased susceptibilities only observed in countries where MBLs were more frequently encountered (e.g. Greece and Romania). Ceftazidime/avibactam was active against 99.7% of Enterobacteriaceae isolates that carried serine β-lactamases, including ESBLs, AmpC cephalosporinases and carbapenemases (KPC, GES and OXA-48-like) in all combinations. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs. The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of Enterobacteriaceae collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes.

In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012-15.

The activity of ceftazidime/avibactam was assessed against 5716 Pseudomonas aeruginosa isolates collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistance phenotypes and β-lactamase content. Antimicrobial susceptibility testing was performed by broth microdilution and β-lactamase genes were detected by PCR screening and sequencing. Ceftazidime/avibactam was highly active in vitro against the overall collection of P. aeruginosa isolates and colistin-resistant isolates (92.4% and 92.9% susceptible, respectively). Although activity was slightly reduced against MBL-negative subsets of ceftazidime-non-susceptible (79.6% susceptible), meropenem-non-susceptible (85.1% susceptible) and MDR (81.6% susceptible) P. aeruginosa, ceftazidime/avibactam remained the second most active entity, after colistin, compared with all other comparator agents tested. At the country level, susceptibility to ceftazidime/avibactam ranged from 74.6% to 99.6%, with decreased susceptibilities only observed in countries where MBLs are more frequently encountered, such as the Czech Republic, Greece, Romania and Russia. Ceftazidime/avibactam was also active in vitro against 87.6% of meropenem-non-susceptible isolates in which no acquired β-lactamases were detected by molecular methods; these isolates were assumed to hyperproduce the chromosomally encoded AmpC in combination with alterations in OprD or drug efflux. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs. The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of P. aeruginosa collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes.

Dried Blood Spots for Global Health Diagnostics and Surveillance: Opportunities and Challenges.

.There is increasing interest in using dried blood spot (DBS) cards to extend the reach of global health and disease surveillance programs to hard-to-reach populations. Conceptually, DBS offers a cost-effective solution for multiple use cases by simplifying logistics for collecting, preserving, and transporting blood specimens in settings with minimal infrastructure. This review describes methods to determine both the reliability of DBS-based bioanalysis for a defined use case and the optimal conditions that minimize pre-analytical sources of data variability. Examples by the newborn screening, drug development, and global health communities are provided in this review of published literature. Sources of variability are linked in most cases, emphasizing the importance of field-to-laboratory standard operating procedures that are evidence based and consider both stability and efficiency of recovery for a specified analyte in defining the type of DBS card, accessories, handling procedures, and storage conditions. Also included in this review are reports where DBS was determined to not be feasible because of technology limitations or physiological properties of a targeted analyte.

In Vitro Activity of Imipenem-Relebactam against Clinical Isolates of Gram-Negative Bacilli Isolated in Hospital Laboratories in the United States as Part of the SMART 2016 Program.

Relebactam is a non-β-lactam, bicyclic diazabicyclooctane β-lactamase inhibitor of class A and class C β-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs). It is in phase 3 clinical development in combination with imipenem/cilastatin. The in vitro activities of imipenem-relebactam, imipenem, and comparators were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method for isolates of Enterobacteriaceae (n = 3,419) and Pseudomonas aeruginosa (n = 896) collected in 2016 by 21 U.S. hospital laboratories participating in the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 μg/ml. Imipenem-relebactam MICs were interpreted using CLSI breakpoints for imipenem. Rates of susceptibility to imipenem-relebactam and imipenem for non-ProteeaeEnterobacteriaceae (n = 3,143) and P. aeruginosa were 99.1% (3,115/3,143) and 95.9% (3,013/3,143) and were 94.4% (846/896) and 74.7% (669/896), respectively. Relebactam restored imipenem susceptibility to 78.5% (102/130) of imipenem-nonsusceptible non-ProteeaeEnterobacteriaceae and to 78.0% (177/227) of imipenem-nonsusceptible P. aeruginosa isolates. Susceptibility to imipenem-relebactam was 98.2% (444/452) and 82.2% (217/264) for multidrug-resistant (MDR) non-ProteeaeEnterobacteriaceae and MDR P. aeruginosa, respectively. Given the ability of relebactam to restore susceptibility to imipenem in nonsusceptible isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa and to demonstrate potent activity against current MDR isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa, further development of imipenem-relebactam appears warranted.

In Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia-Pacific Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015.

The in vitro activities of ceftazidime-avibactam and comparators against 9,149 isolates of Enterobacteriaceae and 2,038 isolates of Pseudomonas aeruginosa collected by 42 medical centers in nine countries in the Asia-Pacific region from 2012 to 2015 were determined as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. Antimicrobial susceptibility testing was conducted by Clinical and Laboratory Standards Institute (CLSI) broth microdilution, and isolate subset analysis was performed on the basis of the resistant phenotypes and β-lactamase content. Ceftazidime-avibactam demonstrated potent in vitro activity (MIC, ≤8 μg/ml) against all Enterobacteriaceae tested (99.0% susceptible) and was the most active against isolates that were metallo-β-lactamase (MBL) negative (99.8% susceptible). Against P. aeruginosa, 92.6% of all isolates and 96.1% of MBL-negative isolates were susceptible to ceftazidime-avibactam (MIC, ≤8 μg/ml). The rates of susceptibility to ceftazidime-avibactam ranged from 97.0% (Philippines) to 100% (Hong Kong, South Korea) for Enterobacteriaceae and from 83.1% (Thailand) to 100% (Hong Kong) among P. aeruginosa isolates, with lower susceptibilities being observed in countries where MBLs were more frequently encountered (Philippines, Thailand). Ceftazidime-avibactam inhibited 97.2 to 100% of Enterobacteriaceae isolates, per country, that carried serine β-lactamases, including extended-spectrum β-lactamases, AmpC cephalosporinases, and carbapenemases (KPC, GES, OXA-48-like). It also inhibited 91.3% of P. aeruginosa isolates that were carbapenem nonsusceptible in which no acquired β-lactamase was detected. Among MBL-negative Enterobacteriaceae isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 96.1, 87.7, 100, and 98.8% of isolates, respectively, and among MBL-negative P. aeruginosa isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 79.6, 83.6, 83.3, and 68.2% of isolates, respectively. Overall, clinical isolates of Enterobacteriaceae and P. aeruginosa collected in nine Asia-Pacific countries from 2012 to 2015 were highly susceptible to ceftazidime-avibactam.

In vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens isolated in 17 European countries: 2015 SMART surveillance programme.

Relebactam is an inhibitor of class A β-lactamases, including KPC β-lactamases, and class C β-lactamases, and is currently under clinical development in combination with imipenem. The objective of the current study was to evaluate the in vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) submitted by clinical laboratories in 17 European countries to the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme in 2015. MICs were determined using the CLSI standard broth microdilution method and interpreted using EUCAST clinical breakpoints. Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using breakpoints for imipenem. Rates of susceptibility to imipenem and imipenem/relebactam for isolates of P. aeruginosa (n = 1705), K. pneumoniae (n = 1591) and Enterobacter spp. (n = 772) were 72.0/94.7%, 88.7/94.8% and 95.6/96.8%, respectively. Relebactam restored imipenem susceptibility to 81.1%, 54.2% and 26.5% of imipenem-non-susceptible isolates of P. aeruginosa (n = 477), K. pneumoniae (n = 179) and Enterobacter spp. (n = 34). Most imipenem/relebactam-non-susceptible isolates carried MBLs, OXA-48 or GES carbapenemases. Relebactam did not increase the number of isolates of A. baumannii (n = 486) susceptible to imipenem. Relebactam restored susceptibility to imipenem for the majority of imipenem-non-susceptible isolates of P. aeruginosa and K. pneumoniae tested as well as some isolates of imipenem-non-susceptible Enterobacter spp. Based on our results, imipenem/relebactam appears to be a promising therapeutic option for treating patients with infections caused by antimicrobial-resistant Gram-negative bacilli.

Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program.

A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014–2016 were screened for the presence of the plasmid-borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations. Genes from the mcr-3 family were found in isolates from Thailand, including mcr-3.1 (n = 3) and mcr-3.2 (n = 1). An E. coli isolated from a patient with a urinary tract infection in Colombia contained the recently discovered mcr-5. The full colistin-resistant collection was tested against a panel of antimicrobial agents with ceftazidime-avibactam and tigecycline exhibiting the highest activity.

Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014)

Omadacycline is an aminomethylcycline with in vitro activity against many gram-negative pathogens. Omadacycline and comparators were tested against Enterobacteriaceae from urinary tract infections (UTIs) selected from a 2014 global surveillance program and compared to results of isolates from 2010 surveillance. The omadacycline MIC50/90 for Enterobacteriaceae collected during 2014 was 2/≥8 μg/mL (1/4 μg/mL minus Proteus, Providencia, and Morganella spp.). The MIC50/90 for E. coli was 1/2 μg/mL, similar to that in 2010 (MIC50/90, 0.5/2 μg/mL). The MICs for 91.7% of Klebsiella spp. isolates in 2014 (89.7%, 2010) were ≤4 μg/mL. In 2010 and 2014, a total of 100.0% and 95.8% of ESBL screen-positive (SP) phenotype E. coli and 73.9% and 75.0% of ESBL SP Klebsiella spp., respectively, exhibited MIC values at ≤4 μg/mL. Omadacycline was active against UTI-causing Enterobacteriaceae isolates from NA and EU. Further study of omadacycline to treat UTIs caused by Enterobacteriaceae may be indicated.

Antimicrobial Resistance: Its Surveillance, Impact, and Alternative Management Strategies in Dairy Animals.

Antimicrobial resistance (AMR), one among the most common priority areas identified by both national and international agencies, is mushrooming as a silent pandemic. The advancement in public health care through introduction of antibiotics against infectious agents is now being threatened by global development of multidrug-resistant strains. These strains are product of both continuous evolution and un-checked antimicrobial usage (AMU). Though antibiotic application in livestock has largely contributed toward health and productivity, it has also played significant role in evolution of resistant strains. Although, a significant emphasis has been given to AMR in humans, trends in animals, on other hand, are not much emphasized. Dairy farming involves surplus use of antibiotics as prophylactic and growth promoting agents. This non-therapeutic application of antibiotics, their dosage, and withdrawal period needs to be re-evaluated and rationally defined. A dairy animal also poses a serious risk of transmission of resistant strains to humans and environment. Outlining the scope of the problem is necessary for formulating and monitoring an active response to AMR. Effective and commendably connected surveillance programs at multidisciplinary level can contribute to better understand and minimize the emergence of resistance. Besides, it requires a renewed emphasis on investments into research for finding alternate, safe, cost effective, and innovative strategies, parallel to discovery of new antibiotics. Nevertheless, numerous direct or indirect novel approaches based on host–microbial interaction and molecular mechanisms of pathogens are also being developed and corroborated by researchers to combat the threat of resistance. This review places a concerted effort to club the current outline of AMU and AMR in dairy animals; ongoing global surveillance and monitoring programs; its impact at animal human interface; and strategies for combating resistance with an extensive overview on possible alternates to current day antibiotics that could be implemented in livestock sector.

In Vitro Activity of the Novel Lactone Ketolide Nafithromycin (WCK 4873) against Contemporary Clinical Bacteria from a Global Surveillance Program.

Nafithromycin (WCK 4873), a novel antimicrobial agent of the lactone ketolide class, is currently in phase 2 development for treatment of community-acquired bacterial pneumonia (CABP). A total of 4,739 nonduplicate isolates were selected from a 2014 global surveillance program at medical institutions located in 43 countries within the United States, Europe, Latin America, and the Asia-Pacific region. Nafithromycin and comparator agents were used for susceptibility testing by reference broth microdilution methods. Nafithromycin was active against Staphylococcus aureus (MIC50/90, 0.06/>2 μg/ml), including erythromycin-resistant strains exhibiting an inducible clindamycin resistance phenotype (MIC50/90, 0.06/0.06 μg/ml) and telithromycin-susceptible strains (MIC50/90, 0.06/0.06 μg/ml), but it exhibited limited activity against most telithromycin-resistant and clindamycin-resistant isolates that were constitutively resistant to macrolides (MIC50/90, >2/>2 μg/ml). Nafithromycin was very active (MIC50/90, 0.015/0.06 μg/ml) against 1,911 Streptococcus pneumoniae strains, inhibiting all strains, with MIC values of ≤0.25 μg/ml. Telithromycin susceptibility was 99.9% for Streptococcus pneumoniae strains, and nafithromycin was up to 8-fold more potent than telithromycin. Overall, 37.9% of S. pneumoniae strains were resistant to erythromycin, and 19.7% were resistant to clindamycin. Nafithromycin was highly active against 606 Streptococcus pyogenes strains (MIC50/90, 0.015/0.015 μg/ml), inhibiting 100.0% of isolates at ≤0.5 μg/ml, and MIC50/90 values (0.015/0.015 to 0.03 μg/ml) were similar for the 4 geographic regions. Nafithromycin and telithromycin demonstrated comparable in vitro activities against 1,002 Haemophilus influenzae isolates and 504 Moraxella catarrhalis isolates. Overall, nafithromycin showed potent in vitro activity against a broad range of contemporary (2014) global pathogens. These results support the continued clinical development of nafithromycin for treatment of CABP.

Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014)

The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC50/90 for S. pneumoniae (2014) was 0.06/0.06μg/mL, similar to 2010 (MIC50/90, 0.06/0.12μg/mL). The omadacycline MIC90 (0.06–0.12μg/mL) was similar for the penicillin-susceptible, -intermediate, -resistant, multidrug-resistance (MDR; ≥3 classes), and ceftriaxone nonsusceptible subgroups. Omadacycline MIC90 values were 0.06–0.12μg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern.

Activity of Ceftazidime–Avibactam Against Respiratory Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia/Pacific as part of the INFORM Global Surveillance Program, 2014–2016

BackgroundAvibactam (AVI) is a non-β-lactam β-lactamase inhibitor that restores the in vitro activity of ceftazidime (CAZ) against class A, class C, and some class D β-lactamases, including extended-spectrum β-lactamases, serine carbapenemases, and the chromosomal AmpC of Pseudomonas aeruginosa (Pae). This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacteriaceae (Eba) and Pae collected from patients with lower respiratory tract infections (LRTI) in Asia/Pacific in 2014–2016 as part of the INFORM surveillance program.MethodsNon-duplicate isolates from patients with LRTI were collected from 28 medical centers in Australia, Hong Kong, Japan, Malaysia, Philippines, South Korea, Taiwan, and Thailand. Susceptibility (S) testing was performed by broth microdilution and interpreted using FDA breakpoints for CAZ-AVI and CLSI breakpoints for comparators. AVI was tested at a fixed concentration of 4 µg/mL with doubling dilutions of CAZ. Multidrug resistance (MDR) phenotype was defined as resistant by CLSI breakpoints to sentinel agents from ≥3 drug classes.ResultsCAZ-AVI showed potent in vitro activity against the overall population of Eba (MIC90, 0.5 µg/mL; 98.0% S) and against ceftazidime-nonsusceptible (CAZ-NS), colistin-resistant (CST-R), and MDR isolates, with >91% of these resistant subsets testing as susceptible (MIC ≤8 µg/mL). Reduced activity against meropenem-nonsusceptible (MEM-NS) Eba was attributable to the presence of class B metallo-β-lactamases (MBL); 95.7% of MEM-NS, MBL-negative isolates were susceptible to CAZ-AVI. CAZ-AVI also showed good activity against most Pae isolates (MIC90, 8 µg/mL; 92.5% S), as well as CST-R isolates (MIC90, 8 µg/mL; 100% S). Activity of CAZ-AVI was reduced against CAZ-NS, MEM-NS, MEM-NS MBL-negative, and MDR Pae subsets (46.9–82.3% S) but exceeded the activity of CAZ and MEM.ConclusionCAZ-AVI is a potential therapeutic option for treating respiratory infections in the Asia/Pacific region caused by Eba and Pae isolates resistant to commonly used and last-in-line agents.Disclosures G. G. Stone, Pfizer: Employee, Salary AstraZeneca: Shareholder, Capital Gains

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

BackgroundOmadacycline (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.MethodsA 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.ResultsOMC 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.ConclusionOMC 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

Activity of Ceftolozane-Tazobactam and Comparators When Tested against Bacterial Surveillance Isolates Collected from Pediatric Patients in the US during 2012–2016 as Part of a Global Surveillance Program

BackgroundCeftolozane-tazobactam (C-T) is an antibacterial combination of a novel antipseudomonal cephalosporin and a β-lactamase inhibitor. C-T was approved by the US Food and Drug Administration in 2014 and by the European Medicine Agency in 2015 to treat complicated urinary tract infections, acute pyelonephritis, and complicated intra-abdominal infections in adults. The Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) monitors C-T resistance to gram-negative (GN) isolates worldwide.MethodsA total of 4121 GN isolates were collected during 2012–2016 from pediatric patients (<18 years old) in 31 US hospitals and tested for C-T susceptibility (S) by CLSI broth microdilution method in a central monitoring laboratory (JMI Laboratories). Other antibiotics tested were amikacin (AMK), cefepime (FEP), ceftazidime (CAZ), colistin (COL), levofloxacin (LVX), meropenem (MER), and piperacillin-tazobactam (TZP). Antibiotic-resistant phenotypes identified using CLSI (2017) clinical breakpoints included: carbapenem-resistant Enterobacteriaceae (CRE), non-CRE extended-spectrum β-lactamase screen positive (ESBL, non-CRE), ceftazidime-nonsusceptible (CAZ-NS), and meropenem-NS (MER-NS). EUCAST (2017) COL clinical breakpoints were used for Enterobacteriaceae (ENT).ResultsThe most common infection type in hospitalized pediatric patients was pneumonia (n = 1,488) followed by urinary tract infection (n = 1,143) and bloodstream infection (n = 767). A total of 2,969 ENT and 1,152 non-enterics were isolated. The 5 most common species were Escherichia coli (EC: 1,311), Pseudomonas aeruginosa (PSA: 821 isolates), Klebsiella pneumoniae (KPN: 429), Enterobacter cloacae complex (ECC: 360), and Serratia marcescens (SM: 264). Susceptibilities of C-T and comparators for the main species and resistant phenotypes are shown in the Table. Only 7 isolates were CRE in this study.Conclusion C-T demonstrated good activity against pediatric ENT isolates (96.1%S), EC (99.2%S), and KPN (97.9%S). For ENT, all agents but COL had >90% S. For PSA, C-T demonstrated potent activity (99.5%S) and was the most potent antibiotic tested with activity similar to COL.Disclosures D. Shortridge, Merck: Research Contractor, Research grant; L. R. Duncan, Merck: Research Contractor, Research grant; M. A. Pfaller, Merck: Research Contractor, Research grant; R. K. Flamm, Merck: Research Contractor, Research grant

Activity of Ceftazidime–Avibactam Against Respiratory Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin America as Part of the INFORM Global Surveillance Program, 2014–2016

BackgroundThe β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) is active in vitro against isolates producing class A, C, and some class D β-lactamases, including extended-spectrum β-lactamases, stably derepressed AmpC, and serine carbapenemases. This study evaluated the in vitro activity of CAZ-AVI and comparators against respiratory isolates of Enterobacteriaceae (Eba) and Pseudomonas aeruginosa (Pae) collected in Latin America from 2014–2016 as part of the INFORM surveillance program.MethodsNon-duplicate isolates from hospitalized patients with lower respiratory tract infections were collected from 24 medical centers in Argentina, Brazil, Chile, Colombia, Mexico, and Venezuela. Susceptibility (S) testing was performed by broth microdilution and interpreted using CLSI breakpoints except for CAZ-AVI (U.S. FDA) and colistin (EUCAST; Ebaonly). AVI was tested at a fixed concentration of 4 µg/mL with doubling dilutions of CAZ. Multidrug resistance (MDR) phenotype was defined as resistant by CLSI breakpoints to sentinel agents from ≥3 drug classes. Isolates were screened for β-lactamase genes by PCR and sequencing.ResultsCAZ-AVI showed potent in vitro activity against Eba isolates (MIC90, 0.5 µg/mL; 99.3% S) and against CAZ-non-susceptible (CAZ-NS), colistin-resistant (CST-R) and MDR subsets (>93% S). CAZ-AVI activity against meropenem-non-susceptible (MEM-NS) Eba (89.7% S) was reduced due to production of metallo-β-lactamases (MBL); MEM-NS MBL-negative isolates were 100% S. CAZ-AVI showed greater in vitro activity against Pae isolates (MIC90, 32 µg/mL; 85.4% S) than CAZ (69.2% S) or MEM (59.9% S). CAZ-AVI activity against CAZ-NS, CST-R, MEM-NS, MEM-NS MBL-negative, and MDR Paeisolates (50.4–92.6% S) also exceeded that of CAZ and MEM against these resistant subsets.ConclusionCAZ-AVI is a potential treatment option for respiratory infections in Latin America that are caused by Eba and Pae resistant to commonly used and last-in-line agents. Funding: This study was sponsored by AstraZeneca. The AstraZeneca product ceftazidime-avibactam was acquired by Pfizer in December 2016.Disclosures G. G. Stone, Pfizer: Employee, Salary AstraZeneca: Shareholder, Capital Gains

Activity of Delafloxacin When Tested Against Bacterial Surveillance Isolates Collected in the US and Europe During 2014–2016 as Part of a Global Surveillance Program

BackgroundDelafloxacin (DLX) is an investigational anionic fluoroquinolone with an NDA that is under US FDA review to treat acute bacterial skin and skin structure infections and is undergoing Phase 3 studies to treat community-acquired bacterial pneumonia.MethodsA total of 36,683 Gram-positive (GP) and -negative (GN) bacteria isolated during 2014–2016 were selected from medical centers in the US and Europe. Susceptibility testing (S) was performed by frozen-form broth microdilution methods for DLX and comparators.ResultsDLX was very active against Staphylococcus aureus (SA, n = 9,355; MIC50/90, 0.008/0.5 mg/L) while the levofloxacin (LEV) MIC50/90 was 0.25/>4 mg/L (67.9%S). The MIC50/90 for methicillin-resistant SA (MRSA) was 0.12/1 mg/L. For MRSA, all isolates were S to vancomycin and daptomycin (DAP), linezolid and tigecycline (TGC) S was ≥99.9%. Decreased rates of S were noted for LEV (29.8%), clindamycin (72.9%), and erythromycin (17.3/17.8%; CLSI/EUCAST). Minocycline (MIC50/90, 0.12/0.25 mg/L), ceftaroline (MIC50/90, 0.25/0.5 mg/L), DAP (MIC50/90, 0.5/0.5 mg/L), and DLX (MIC50/90, 0.015/0.5 mg/L) were the most active agents tested against coagulase-negative staphylococci. Against Streptococcus pneumoniae (SPN), the MIC50/90 for DLX (0.015/0.03 mg/L) and TGC (0.03/0.06 mg/L) were the lowest among the agents tested. The DLX MIC50/90 values did not vary among the penicillin-S, -intermediate, and -R subgroups of SPN. The MIC50/90 values for DLX against S. pyogenes and S. agalactiae were 0.015/0.03 mg/L. DLX was highly active against Haemophilus influenzae. The DLX MIC50/90 (≤0.001/0.004 mg/L) was the same for β-lactamase positive and negative H. influenzae. Against Enterobacteriaceae, 76.0% of DLX MIC values were ≤1 mg/L. Susceptibility to LEV was 80.8%, and S to ceftriaxone, ceftazidime (CAZ), and cefepime ranged from 78.5–86.3%. A total of 72.6% of Pseudomonas aeruginosa isolates exhibited DLX MIC values ≤1 mg/L, while LEV S was 73.2% and CAZ was 81.6%. The MIC50/90 for both DLX and LEV were 0.5/>4 mg/L, respectively.ConclusionDLX was active against a broad range of GP and GN bacteria, including MRSA and multidrug-resistant SPN. DLX merits further study as therapy in infections in which these organisms may occur.Disclosures R. K. Flamm, Melinta Therapeutics: Research Contractor, Research grant D. Shortridge, Melinta Therapeutics: Research Contractor, Research grant M. D. Huband, Melinta Therapeutics: Research Contractor, Research grant S. McCurdy, Melinta Therapeutics: Employee, Salary M. A. Pfaller, Melinta Therapeutics: Research Contractor, Research grant

Global invasive Cochliobolus species: cohort of destroyers with implications in food losses and insecurity in the twenty-first century.

Matching the global food demand by 2050 and to ensure the stability of food security in over than 99 countries, it is necessary to scale up the production of food such as sorghum, wheat, rice, maize and sugarcane which are however natural hosts of Cochliobolus species. Cochliobolus species major epidemics such as the Great Bengal famine, Southern corn leaf blight, and Northern leaf spot blight were associated with substantial economic losses in the past decades. Thus, there is an urgent need to establish a specific coordinated global surveillance program for the migration of invasive Cochliobolus species, planning contextual control programs engaging all agricultural stakeholders and information sharing in real time for prevention of disastrous Cochliobolus disease outbreak effects. We discuss pertinent outcome of interactions of cash crops with Cochliobolus species having devastating impact on the livelihood of farmers and food security. While post-genomic era elucidated prominent differences among Cochliobolus heterostrophus, C. carbonum, C. victoriae, C. lunatus and C. miyabeanus, their destructive potentials and implications in food losses remained unearthed. Intriguingly, the annual colossal losses caused by Cochliobolus species in the production perspective of sorghum, wheat, rice, maize, cassava and soybean is estimated over 10 billion USD worldwide. This paper provides a comprehensive analysis of the invasive Cochliobolus species distribution and diversity, evolving pathogenicity, persistent diseases, threats and epidemics, consequences on food crops production and increasing global food insecurity issues.

Antimicrobial-resistant Gram-negative infections in neonates: burden of disease and challenges in treatment.

This review summarizes the main challenges of antimicrobial resistance (AMR) in the neonatal population with a special focus on multidrug-resistant (MDR) Gram-negative pathogens. MDR-Gram-negative bacteria are a great concern in the neonatal population, with a worldwide rise in the reported incidence and with very limited therapeutic options. Extended-spectrum β-lactamase and carbapenem-resistant Enterobacteriaceae (CRE) have been reported as responsible for neonatal ICU outbreaks. Hospital data from low/middle-income countries show high proportions of isolates from neonates resistant to the WHO first-line and second-line recommended treatments. The spread of CRE has resulted in old antibiotics, such as colistin and fosfomycin, to be considered as alternative treatment options, despite the paucity of available data on safety and appropriate dosage. Improved global neonatal AMR surveillance programmes including both epidemiology and clinical outcomes are critical for defining the burden and designing interventions. The optimal empiric treatment for neonatal sepsis in settings of high rates of AMR is currently unknown. Both strategic trials of older antibiotics and regulatory trials of new antibiotics are required to improve clinical outcomes in MDR-Gram-negative neonatal sepsis.

In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program)

Relebactam (formerly MK-7655) is an inhibitor of class A and C β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the in vitro activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens (including Klebsiella pneumoniae, n = 689; Acinetobacter baumannii, n = 72; Pseudomonas aeruginosa, n = 845; and Enterobacter spp., n = 399) submitted by 21 clinical laboratories in the United States in 2015 as part of the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 μg/ml in combination with doubling dilutions of imipenem. Imipenem-relebactam MICs were interpreted using CLSI imipenem breakpoints. The respective rates of susceptibility to imipenem-relebactam and imipenem were 94.2% (796/845) and 70.3% (594/845) for P. aeruginosa, 99.0% (682/689) and 96.1% (662/689) for K. pneumoniae, and 100% (399/399) and 98.0% (391/399) for Enterobacter spp. Relebactam restored imipenem susceptibility to 80.5% (202/251), 74.1% (20/27), and 100% (8/8) of isolates of imipenem-nonsusceptible P. aeruginosa, K. pneumoniae, and Enterobacter spp. Relebactam did not increase the number of isolates of Acinetobacter spp. susceptible to imipenem, and the rates of resistance to all of the agents tested against this pathogen were >30%. Further development of imipenem-relebactam is warranted given the demonstrated ability of relebactam to restore the activity of imipenem against current clinical isolates of Enterobacteriaceae and P. aeruginosa that are nonsusceptible to carbapenems and its potential as a therapy for treating patients with antimicrobial-resistant Gram-negative infections.

Resistance among Gram-negative ESKAPE pathogens isolated from hospitalized patients with intra-abdominal and urinary tract infections in Latin American countries: SMART 2013–2015

Gram-negative ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are important etiologic agents of nosocomial infection that are frequently resistant to broad-spectrum antimicrobial agents. Gram-negative ESKAPE pathogens were collected from hospitalized patients in 11 Latin American countries from 2013 to 2015 as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program. In total, 2113 isolates from intra-abdominal infections (IAI) and 970 isolates from urinary tract infections (UTI) were tested against antimicrobial agents using standardized CLSI broth microdilution methodology. Of the agents tested, amikacin demonstrated the highest rates of susceptibility (%) for K. pneumoniae (92.2, 92.3), Enterobacter spp. (97.5, 92.1), and P. aeruginosa (85.3, 75.2) isolates from both IAI and UTI, respectively. Ertapenem (68.5, 62.6) and imipenem (79.2, 75.9) showed substantially higher rates of susceptibility (%) than other β-lactams, including piperacillin-tazobactam (35.9, 37.4) against ESBL-positive isolates of K. pneumoniae from IAI and UTI, respectively. Rates of susceptibility to all agents tested against A. baumannii were ≤30.9%. Gram-negative ESKAPE pathogens isolated from Latin America demonstrated compromised in vitro susceptibility to commonly prescribed broad-spectrum, parenteral antimicrobial agents. Continued surveillance is warranted. New antimicrobial agents with potent activity against Gram-negative ESKAPE pathogens are urgently needed.