scholarly journals LasR-regulated proteases in acute vs. chronic lung infection: a double-edged sword

2021 ◽  
Vol 8 (7) ◽  
pp. 161-163
Author(s):  
Lisa C. Hennemann ◽  
Dao Nguyen
Keyword(s):  
Virulence Factors ◽  
Airway Epithelium ◽  
Lung Infection ◽  
Airway Epithelial Cells ◽  
Host Immunity ◽  
Protease Production ◽  
Infection Model ◽  
Markers Of Inflammation

Pseudomonas aeruginosa is a gram-negative opportunistic pathogen capable of causing both acute and chronic infections, particularly in individuals with compromised host defenses. The quorum sensing transcriptional activator LasR is widely recognized for its role in regulating the expression of acute virulence factors, notably several secreted proteases which cause direct host damage and subvert host immunity in acute infections. Paradoxically, lung infections caused by LasR-deficient variants, which are found in at least a third of cystic fibrosis (CF) patients with chronic P. aeruginosa infections, are associated with accelerated lung disease and increased markers of inflammation compared to infections caused by strains with a functional LasR system. While the loss of LasR function often (although not always) results in impaired production of LasR-controlled acute virulence factors, the implication of this pathoadaptation on host-pathogen interactions and chronic disease pathology is less well recognized. We recently observed that loss of LasR function in lasR variants, which results in impaired secreted protease production, led to increased expression of the membrane-bound surface adhesion molecule mICAM-1 in the airway epithelium, and increased neutrophilic inflammation. Specifically, human airway epithelial cells stimulated with lasR variants had higher mICAM-1 expression and greater neutrophil binding in vitro compared to stimulation with wild-type P. aeruginosa. In a subacute non-lethal P. aeruginosa lung infection model, lasR variant infection also induced higher mICAM-1 expression in the murine airway epithelium and was associated with increased neutrophilic pulmonary inflammation in vivo. Here, we discuss how (loss of) LasR function and LasR-regulated proteases affect host immunity, inflammation and tissue pathology in acute vs. chronic P. aeruginosa lung infection.

scholarly journals In Vitro and Murine Efficacy and Toxicity Studies of Nebulized SCC1, a Methylated Caffeine-Silver(I) Complex, for Treatment of Pulmonary Infections

2009 ◽  
Vol 53 (8) ◽  
pp. 3285-3293 ◽  
Author(s):  
Carolyn L. Cannon ◽  
Lisa A. Hogue ◽  
Ravy K. Vajravelu ◽  
George H. Capps ◽  
Aida Ibricevic ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Airway Epithelial Cells ◽  
Clinical Strain ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Airway Epithelial ◽  
Tract Infections

ABSTRACT The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.

scholarly journals 1066. In Vitro and in Vivo Antimicrobial Activity of Cefiderocol and Comparators against Achromobacter spp

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S625-S626
Author(s):  
Ryuichiro Nakai ◽  
Ayaka makino ◽  
Hitomi Hama ◽  
Toriko Yoshitomi ◽  
Rio Nakamura ◽  
...  
Keyword(s):  
Rat Model ◽  
Murine Model ◽  
Lung Infection ◽  
Vitro Activity ◽  
Infection Model ◽  
In Vitro Activity ◽  
Independent Contractor ◽  
In Vivo Efficacy

Abstract Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated. Methods A total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined. Results CFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs > 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused > 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT >MIC: < 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P< 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were >16, >64, >32, and >8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by >1 log10 CFU/lung compared with baseline controls (P< 0.05). MEM showed no significant activity. In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%). Conclusion CFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections. Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

scholarly journals 1058. In Vitro and In Vivo Antibacterial Activity of Cefiderocol against Burkholderia spp

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S621-S621
Author(s):  
Merime Oota ◽  
Hitomi Hama ◽  
Toriko Yoshitomi ◽  
Rio Nakamura ◽  
Miki Takemura ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Lung Infection ◽  
Bacterial Suspension ◽  
Infection Model ◽  
Rat Lung ◽  
Independent Contractor ◽  
Broth Microdilution Method ◽  
Tract Infections

Abstract Background Burkholderia spp. is an opportunistic pathogen associated with respiratory infections. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active in vitro against carbapenem-resistant Gram-negative bacteria including Burkholderia spp. This study examined in vitro and in vivo activity of CFDC against Burkholderia spp. Methods MICs of CFDC and 13 marketed antibacterial drugs against 462 clinical isolates of Burkholderia spp. collected in 2014 - 2019 in 13 countries were determined by broth microdilution method according to CLSI guidelines. Only for CFDC, iron-depleted CAMHB was used. In a rat lung infection model, B. cepacia ATCC 25416 (CFDC MIC: ≤ 0.031 μg/mL, MEM MIC: 4 μg/mL) was used. Male CD (SD, immunocompetent, n=4-5) rats were infected by intrabronchial inoculation of the bacterial suspension including 1% nutrient agar. The humanized PK in plasma by administration of CFDC 2 g every 8 h (3-h infusion) and MEM 1 g every 8 h (0.5-h infusion) were recreated via the continuous intravenous infusion for 4 days, and the viable cfu in lungs were counted. Results Against 462 strains, including 185 MEM non-susceptible isolates, CFDC showed MIC50/MIC90 of ≤ 0.031/1 µg/mL, which was the lowest among the tested antibiotics. Among 185 MEM non-susceptible isolates, 94% of the isolates exhibited ≤ 4 µg/mL of CFDC MIC. In a rat lung infection model, CFDC and MEM showed bactericidal activity with 2.8 and 2.4 log10 CFU/lung decrease compared with non-treated control, respectively. By recreating the humanized PK exposure in this model, 100% and ca.35% of fT >MIC of CFDC and MEM in plasma has been achieved, respectively. The bactericidal activities of both compounds vs B. cepacia ATCC 25416 would be reasonable because the fT >MIC achieved in this model exceeds the target fT >MIC (75% for CFDC and 26% for MEM against Acinetobacter baumannii, respectively) required to cause 1 log10 reduction in murine thigh infection models1,2). 1) M. Sabet. 2019. AAC 2) R. Nakamura. 2019. AAC In vitro activity of CFDC and comparator agents against Burkholderia spp. Conclusion CFDC has potential for treating respiratory tract infections caused by Burkholderia spp. In critically ill patients, the recommended dosing regimen achieves 100% of fT >MIC of ≤ 4 ug/mL3).3) N. Kawaguchi. 2021. AAC Disclosures Merime Oota, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

scholarly journals Blockade of Airway Inflammation by Kaempferol via Disturbing Tyk-STAT Signaling in Airway Epithelial Cells and in Asthmatic Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Ju-Hyun Gong ◽  
Daekeun Shin ◽  
Seon-Young Han ◽  
Sin-Hye Park ◽  
Min-Kyung Kang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Airway Inflammation ◽  
Airway Epithelium ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Bronchial Inflammation ◽  
Stat Signaling ◽  
Socs3 Expression

Asthma is characterized by bronchial inflammation causing increased airway hyperresponsiveness and eosinophilia. The interaction between airway epithelium and inflammatory mediators plays a key role in the asthmatic pathogenesis. Thein vitrostudy elucidated inhibitory effects of kaempferol, a flavonoid found in apples and many berries, on inflammation in human airway epithelial BEAS-2B cells. Nontoxic kaempferol at ≤20 μM suppressed the LPS-induced IL-8 production through the TLR4 activation, inhibiting eotaxin-1 induction. Thein vivostudy explored the demoting effects of kaempferol on asthmatic inflammation in BALB/c mice sensitized with ovalbumin (OVA). Mouse macrophage inflammatory protein-2 production and CXCR2 expression were upregulated in OVA-challenged mice, which was attenuated by oral administration of ≥10 mg/kg kaempferol. Kaempferol allayed the airway tissue levels of eotaxin-1 and eotaxin receptor CCR3 enhanced by OVA challenge. This study further explored the blockade of Tyk-STAT signaling by kaempferol in both LPS-stimulated BEAS-2B cells and OVA-challenged mice. LPS activated Tyk2 responsible for eotaxin-1 induction, while kaempferol dose-dependently inhibited LPS- or IL-8-inflamed Tyk2 activation. Similar inhibition of Tyk2 activation by kaempferol was observed in OVA-induced mice. Additionally, LPS stimulated the activation of STAT1/3 signaling concomitant with downregulated expression of Tyk-inhibiting SOCS3. In contrast, kaempferol encumbered STAT1/3 signaling with restoration of SOCS3 expression. Consistently, oral administration of kaempferol blocked STAT3 transactivation elevated by OVA challenge. These results demonstrate that kaempferol alleviated airway inflammation through modulating Tyk2-STAT1/3 signaling responsive to IL-8 in endotoxin-exposed airway epithelium and in asthmatic mice. Therefore, kaempferol may be a therapeutic agent targeting asthmatic diseases.

scholarly journals Synergistic Activity of Berberine with Azithromycin against Pseudomonas Aeruginosa Isolated from Patients with Cystic Fibrosis of Lung In Vitro and In Vivo

2017 ◽  
Vol 42 (4) ◽  
pp. 1657-1669 ◽  
Author(s):  
YongTao Li ◽  
JianRong Huang ◽  
LanJuan Li ◽  
LinSheng Liu
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Infection ◽  
Extracellular Dna ◽  
Pcr Analysis ◽  
Infection Model ◽  
Synergistic Activity ◽  
Time Kill

Background/Aims: Pseudomonas aeruginosa (PA) is one of the major opportunistic pathogens which can cause chronic lung infection of cystic fibrosis (CF). The formation of PA biofilm promotes CF development and restricts the antimicrobial efficacies of current antibiotics. Methods: The antimicrobial effects of azithromycin (AZM) and berberine (BER) alone and in combination were evaluated using microdilution method, checkerboard assay, time-kill test, qRT-PCR analysis and absorption method. The treatments of AZM and/or BER were further evaluated in an animal lung infection model via observing survival rate, bacterial burden and histopathology of lung, the levels of pro-/anti-inflammatory cytokines. Results: AZM-BER were demonstrated to be synergistic against ten clinical PA isolates as well as the standard reference PA ATCC27853, in which PA03 was the most susceptible isolate to AZM-BER with FICI of 0.13 and chosen for subsequent experiments. The synergism of AZM-BER was further confirmed against PA03 in time-kill test and scanning electron microscope (SEM) at their concentrations showing synergism. In PA03, we found that AZM-BER could significantly attenuate productions of a series of virulence factors including alginate, LasA protease, LasB protease, pyoverdin, pyocyanin, chitinase as well as extracellular DNA, and remarkably inhibit the levels of quorum sensing (QS) molecules and the expressions of lasI, lasR, rhlI, rhlR at 1/2×MIC, 1×MIC and 2×MIC. In the infection model, the mice survival were increased markedly, the inflammations of infected lungs were improved greatly along with reduced IL-6, IL-8 and ascended IL-10 at 0.8 mg/kg of AZM combined with 3.2 mg/kg of BER. Conclusion: BER might be a promising synergist to enhance the antimicrobial activity of AZM in vitro and in vivo.

scholarly journals In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Klebsiella pneumoniae Strains

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
S. M. Stainton ◽  
M. L. Monogue ◽  
D. P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Infection Model ◽  
Clinical Implications ◽  
Content Type ◽  
Murine Lung ◽  
Resistance Profile ◽  
Phenotypic Profile

ABSTRACT Recent findings have identified Klebsiella pneumoniae strains that are pan-β-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro. We assessed the efficacy of a humanized exposure of piperacillin-tazobactam (TZP) against 12 TZP-R/PBL-S K. pneumoniae isolates in an immunocompromised murine lung infection model. Discordance between the in vitro resistance profile and the in vivo efficacy of human-simulated TZP exposures against this phenotypic profile was observed. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

scholarly journals In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
M. L. Monogue ◽  
L. M. Abbo ◽  
R. Rosa ◽  
J. F. Camargo ◽  
O. Martinez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
New Delhi ◽  
Beta Lactamase ◽  
Bacterial Reduction ◽  
Content Type

ABSTRACT The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

scholarly journals Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Catharine C. Bulik ◽  
Ólanrewaju O. Okusanya ◽  
Elizabeth A. Lakota ◽  
Alan Forrest ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Lung Infection ◽  
Free Drug ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Drug Plasma ◽  
Infection Models

ABSTRACT Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae. Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log10 CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (C max) to the MIC (C max/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r 2 = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log10 CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively.

scholarly journals In Vivo Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine-β-lactamase-Producing Enterobacterales and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection Model

2021 ◽  
Author(s):  
Maxwell J. LASKO ◽  
Kamilia ABDELRAOUF ◽  
David P. NICOLAU
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Systemic Exposure ◽  
Lung Infection ◽  
Infection Model ◽  
High Dose ◽  
Bacterial Burden ◽  
Variable Activity ◽  
Potential Activity

Abstract (248/250) Introduction: WCK 4282 (cefepime 2g/tazobactam 2g) maximizes systemic exposure of tazobactam and restores cefepime activity against various extended-spectrum β-lactamase (ESBL)- and cephalosporinase-producing strains in vitro. We describe clinical WCK 4282 exposure efficacy against various serine β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa in a murine pneumonia model. Clinical cefepime-resistant isolates (17 Enterobacterales and 2 P. aeruginosa) were utilized. Isolates expressed ESBLs, cephalosporinases, and/or serine carbapenemases (KPC, OXA-48-like). WCK 4282 MICs were 4-32 μg/mL. For in vivo experiments, lungs of neutropenic mice were inoculated using standard inoculum (107 log10 CFU/mL). Serine-carbapenemase-producing isolates were also assessed using a low inoculum (1:5 dilution). Treatment mice received HSR of cefepime, meropenem (control for serine carbapenemase expression with low inoculum experiments), or WCK 4282 human-simulated regimens. Efficacy was assessed as change in log10 CFU/lung at 24h compared with 0h controls. Results: At standard inoculum, mean 0h bacterial burden was 6.65±0.23 log10 CFU/lung and increased at 24h by 2.48 ± 0.60 log10 CFU/lung among untreated controls. Lower inoculums initial bacterial burdens ranged from 5.81±0.12-6.39±0.13 log10 CFU/lung. At standard and/or low inoculums, cefepime and meropenem provided minimal activity. WCK 4282 produced >1-log10 reduction against 9/9 ESBL/cephalosporinase-producing strains. WCK 4282 provided variable activity among mice infected with standard or lower inoculums of OXA-48-like-producers. WCK 4282 exposures provided 0.53±1.07 log10 CFU/lung growth against KPC-producers at standard versus bacteriostasis (-0.15±0.54 change in log10 CFU/lung) at low inoculum. Conclusion: WCK 4282 produced potent in vivo activity against ESBL- and cephalosporinase-producing Enterobacterales and P. aeruginosa, and potential activity against OXA-48-like-producing Enterobacterales in a neutropenic pneumonia model.

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