Lower Respiratory Tract Isolates Research Articles

1080. Relebactam Increases Imipenem Activity Against Imipenem-Nonsusceptible and -Susceptible Pseudomonas aeruginosa and Enterobacterales: Assessment of Isolates from RESTORE-IMI 2

BackgroundRelebactam (REL) inhibits class A and C β-lactamases (BLs) and is approved in the US in the combination imipenem/cilastatin/REL (IMI/REL) for hospital acquired bacterial pneumonia (HABP) and ventilator associated bacterial pneumonia (VABP), and also in patients with limited treatment options for complicated urinary tract infections and complicated intraabdominal infections. The objective of this study was to evaluate the potentiation of imipenem (IMI) by REL in baseline respiratory isolates from the recently completed Phase 3 RESTORE-IMI 2 study that demonstrated efficacy and safety of IMI/REL in the treatment of patients with HABP/VABP.MethodsBaseline lower respiratory tract (LRT) isolates were evaluated for IMI MICs in the presence and absence of REL using broth microdilution and CLSI interpretive criteria. All Pseudomonas aeruginosa and Enterobacterales for which IMI/REL is either indicated or the MIC90 is less than or equal to the susceptibility breakpoint were evaluated.ResultsSummary statistics and the MIC distribution for P. aeruginosa are shown in the figure. For P. aeruginosa, REL reduces the IMI mode MIC of IMI-nonsusceptible (IMI-NS) (MIC >2) isolates ≥8-fold (from 16-32 to 2 µg/mL) and that of IMI-susceptible (IMI-S) (MIC ≤2) isolates ≥2-fold (from 1 to ≤0.5 µg/mL). Among Enterobacterales, the IMI mode MIC of IMI-NS (MIC >1) isolates was reduced ≥4-fold (from 2 to ≤0.5 µg/mL). REL enhanced the activity of IMI among IMI-S isolates (MIC ≤1), most notably observed in Enterobacterales species that produce a chromosomal AmpC, increasing the proportion with MIC ≤0.5 µg/mL from 76% to 98%.MIC Distribution and Summary Statistics of RESTORE IMI-2 Isolates ConclusionAmong baseline LRT isolates from RESTORE-IMI 2 the potentiation of IMI by REL results in the restoration of susceptibility among IMI-NS P. aeruginosa and Enterobacterales and enhanced IMI activity among IMI-S isolates. This enhanced activity among IMI-S Enterobacterales is most notable among species with reported chromosomal expression of AmpC. This lowering of IMI MICs upon addition of REL contributes to the high probability of target attainment (≥90%) observed following administration of IMI/REL 1.25g every 6 hours, further supporting the IMI/REL efficacy data observed in RESTORE-IMI 2.Disclosures David W. Hilbert, PhD, Merck (Employee) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck (Employee) Pamela Moise, PharmD, Merck (Employee) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee) Katherine Young, MS, Merck (Employee)

In vitro activity of aztreonam/avibactam against a global collection of Klebsiella pneumoniae collected from defined culture sources in 2016 and 2017

ObjectivesThis study reports on the activity of aztreonam/avibactam (ATM-AVI) against a collection of Klebsiella pneumoniae collected in 2016 and 2017. MethodsNon-duplicate K. pneumoniae isolates were collected from four regions (Africa/Middle East, n = 785; Asia-Pacific, n = 1433; Europe, n = 4236; Latin America, n = 1499) and five culture sources (blood, n = 902; intra-abdominal, n = 992; urinary tract, n = 2148; skin and skin structure, n = 1409; lower respiratory tract, n = 2502). MICs were determined at a central laboratory using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology. Susceptibility was determined using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. ResultsFor all culture sources, against all K. pneumoniae, the highest rates of susceptibility were seen for amikacin (>84%), ceftazidime/avibactam (>94%), colistin (>92%) and meropenem (>83%), and >99.9% of isolates were inhibited at an ATM-AVI MIC of ≤4 mg/L. Among meropenem-resistant (MEM-R, n = 583) and meropenem-resistant metallo-β-lactamase-negative (MEM-R-MBLN; n = 469) isolates, susceptibility was highest to ceftazidime/avibactam (79.9% and 99.4%, respectively) and colistin (67.2% and 62.7%, respectively). All MEM-R-MBLN isolates from blood, intra-abdominal, urinary tract and skin and skin structure sources, and all but one isolate from respiratory sources, were inhibited at an ATM-AVI MIC of ≤2 mg/L. Against the meropenem-resistant metallo-β-lactamase positive (MEM-R-MBLP; n = 114) isolates, susceptibility to colistin was between 75.0% (urinary tract isolates) and 93.3% (lower respiratory tract isolates). All MEM-R-MBLP isolates were inhibited at an ATM-AVI MIC of ≤0.5 mg/L. ConclusionsATM-AVI is active against K. pneumoniae isolates from a range of culture sources across Africa/Middle East, Asia-Pacific, Europe and Latin America. ATM-AVI also has activity against MEM-R-MBLN and MEM-R-MBLP isolates.

Activity of imipenem/relebactam against MDR Pseudomonas aeruginosa in Europe: SMART 2015-17.

Relebactam is a diazabicyclooctane non-β-lactam inhibitor of Ambler class A and C β-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosa submitted to the SMART global surveillance programme in 2015-17 by 67 clinical laboratories in 22 European countries. MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam. Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50-77 percentage points higher than the rate of susceptibility to imipenem or any other β-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype. Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients.

Activities of carbapenem and comparator agents against contemporary US Pseudomonas aeruginosa isolates from the CAPITAL surveillance program

Antimicrobial susceptibilities of contemporary Pseudomonas aeruginosa clinical isolates were determined from the CAPITAL 2010 surveillance program. Isolates were collected from 100 sites throughout the USA and Puerto Rico, and included isolates representing a range of patient demographics and infection types. A total of 2722 isolates were tested for susceptibility to a broad spectrum of agents, with susceptibilities ranging from 98.8% for colistin to 74% for levofloxacin. Doripenem was the most active carbapenem agent, with 88.6% of isolates susceptible, in comparison with 78.1% and 84.6% for imipenem and meropenem, respectively. Lower respiratory tract isolates and isolates from the intensive care unit setting were the least susceptible overall. Resistance rates were typically highest in lower respiratory tract isolates, with the exception of urinary tract isolates, which displayed the highest resistance for levofloxacin. Overall, multidrug-resistant isolates comprised 14.8% of the total sample population.

Multidrug resistance among Acinetobacter spp. in the USA and activity profile of key agents: results from CAPITAL Surveillance 2010

Multidrug resistance among Acinetobacter spp. leaves few effective antibiotic options for treatment. To monitor antibiotic resistance in Acinetobacter spp., the US CAPITAL 2010 Surveillance data were evaluated by patient demographics, specimen source, and hospital ward. Isolates (N=514) were collected from 65 sites across the USA and Puerto Rico. Isolates were centrally tested for susceptibility to carbapenems and key antimicrobials by broth microdilution. Colistin was the most effective agent tested, with 95% susceptibility. The overall susceptibility of Acinetobacter spp. was low (39% for piperacillin/tazobactam, 41% for levofloxacin, 45% for ceftazidime, 47–51% for the carbapenems, and 58% for tobramycin). Multidrug resistance (MDR), defined as resistance to ≥3 antimicrobial agent groups, was detected in 54% of the isolates. MDR isolates were most common among elderly patients (65%), lower respiratory tract isolates (62%), and inpatient/intensive care unit isolates (54–58%). These data update trends in the distribution and prevalence of the MDR phenotype in Acinetobacter spp.

Molecular basis of increased serum resistance among pulmonary isolates of non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi), a common commensal of the human pharynx, is also an opportunistic pathogen if it becomes established in the lower respiratory tract (LRT). In comparison to colonizing isolates from the upper airway, LRT isolates, especially those associated with exacerbations of chronic obstructive pulmonary disease, have increased resistance to the complement- and antibody-dependent, bactericidal effect of serum. To define the molecular basis of this resistance, mutants constructed in a serum resistant strain using the mariner transposon were screened for loss of survival in normal human serum. The loci required for serum resistance contribute to the structure of the exposed surface of the bacterial outer membrane. These included loci involved in biosynthesis of the oligosaccharide component of lipooligosaccharide (LOS), and vacJ, which functions with an ABC transporter encoded by yrb genes in retrograde trafficking of phospholipids from the outer to inner leaflet of the cell envelope. Mutations in vacJ and yrb genes reduced the stability of the outer membrane and were associated with increased cell surface hyrophobicity and phospholipid content. Loss of serum resistance in vacJ and yrb mutants correlated with increased binding of natural immunoglobulin M in serum as well as anti-oligosaccharide mAbs. Expression of vacJ and the yrb genes was positively correlated with serum resistance among clinical isolates. Our findings suggest that NTHi adapts to inflammation encountered during infection of the LRT by modulation of its outer leaflet through increased expression of vacJ and yrb genes to minimize recognition by bactericidal anti-oligosaccharide antibodies.

Hemophilus influenzae biotypes and chronic bronchitis.

Hemophilus influenzae can be differentiated into 6 biotypes on the basis of 3 biochemical reactions. This study was undertaken to determine the biotypes of respiratory isolates from an adult population with chronic bronchitis and to compare the biotypes of upper and lower respiratory tract isolates of individual patients. For rapid biotyping of serologically nontypable H. influenzae, we used 2 commercially prepared kits (Minitek and IDS RapID Systems). Twenty-three of 29 isolates (79%) had biochemical characteristics of biotype II with the Minitek system. Eighteen of the same 29 isolates were retested with the IDS RapID System and reacted as biotype II organisms. Seven of 9 and 4 of 4 paired transtracheal/oropharyngeal samples had identical biotypes when tested with the Minitek and IDS RapID System, respectively. These findings suggest that H. influenzae organisms are exchanged between the oropharynx and tracheobronchial tree of elderly male patients with chronic bronchitis.