The paradoxical in vivo activity of β-lactams against metallo-β-lactamase-producing Enterobacterales is not restricted to carbapenems

2020 ◽  
Author(s):  
Kamilia Abdelraouf ◽  
Sergio Reyes ◽  
David P Nicolau
Keyword(s):  
Infection Model ◽  
Murine Models ◽  
Mueller Hinton ◽  
Fold Reduction ◽  
Testing Medium ◽  
Zinc Concentrations ◽  
Mueller Hinton Broth ◽  
Positive Controls

Abstract Background Using murine models of infection, we previously reported the potent in vivo activity of carbapenems against MBL-producing Enterobacterales despite the observed resistance in vitro. In the current study, we examined the in vivo activity of a cefepime human-simulated regimen against MBL-producing Enterobacterales in a murine thigh infection model. Methods A population of clinical isolates and isogenic engineered MBL-producing Enterobacterales transformants expressing MBLs but no detectable cefepime-hydrolysing serine β-lactamases were utilized. KPC-producing isolates were included as positive controls. Cefepime, piperacillin/tazobactam and meropenem MICs were determined using broth microdilution in conventional CAMHB and EDTA-supplemented (zinc-limited) broth. In vivo efficacy of a cefepime human-simulated regimen (2 g q8h as a 2 h infusion) was determined in the neutropenic murine thigh infection model against the test strains. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h controls. Results MBL-producing Enterobacterales strains were found to be cefepime, piperacillin/tazobactam and meropenem non-susceptible in conventional broth. Supplementation with EDTA at a concentration of 300 mg/L resulted in multi-fold reduction in the MICs and restoration of susceptibility. In accordance with the MICs generated in zinc-limited broth, administration of a cefepime human-simulated regimen was associated with substantial bacterial reductions among mice infected with MBL-producing Enterobacterales. Absence of MIC reduction in zinc-limited broth and lack of efficacy among mice infected with KPC-producing isolates were observed. Conclusions For MBL-producing Enterobacterales, susceptibility testing with Mueller–Hinton broth, a zinc-rich testing medium, is flawed since it does not recapitulate the host environment, in which zinc concentrations are low.

scholarly journals 1299. In Vitro-In Vivo Discordance with β-lactams against Metallo-β-lactamase-Producing Enterobacterales: Implications for Susceptibility Testing

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S664-S664
Author(s):  
Kamilia Abdelraouf ◽  
Sergio Reyes ◽  
David P Nicolau
Keyword(s):  
Susceptibility Testing ◽  
Infection Model ◽  
Research Support ◽  
In Vitro Susceptibility ◽  
Fold Reduction ◽  
Testing Medium ◽  
Zinc Concentrations ◽  
In Vitro Susceptibility Testing

Abstract Background Using murine models of thigh and lung infection, we previously reported the potent in vivo activity of carbapenem human-simulated regimens against metallo-β-lactamase-producing Enterobacterales despite the observed resistance in vitro (JAC 2020 Apr 1;75(4):997-1005, AAC 2014;58(3):1671-7). In the current study, we examined the in vivo activity of cefepime human-simulated regimen against metallo-β-lactamase-producing Enterobacterales in a murine thigh infection model. Methods A population of clinical (n=21) and isogenic engineered (n=5) metallo-β-lactamase-producing Enterobacterales isolates expressing VIM, IMP or NDM but not co-expressing ESBLs or serine carbapenemases were utilized. KPC-producing strains (n=3) were included as positive controls. MICs of cefepime, piperacillin-tazobactam and meropenem were determined using broth microdilution in conventional cation-adjusted Muller Hinton and EDTA-supplemented broth at EDTA concentration of 300 mg/L (zinc-limited). The in vivo efficacy of a cefepime human-simulated regimen (2 g q8h as 2 h infusion) was determined in the neutropenic murine thigh infection model against the test isolates. Efficacy was measured as the change in log10cfu/thigh at 24 h compared with 0 h controls. Results Metallo-β-lactamase-producing Enterobacterales were found to be cefepime, piperacillin-tazobactam and meropenem non-susceptible in conventional broth. Supplementation with EDTA resulted in multi-fold reduction in the MICs and restoration of susceptibility. In accordance with the MICs generated in the zinc-limited broth, the administration of cefepime human-simulated regimen was associated with substantial bacterial reductions among mice infected with the clinical as well as the isogenic engineered metallo-β-lactamase-producing isolates. As anticipated with serine-based resistance, absence of MIC reduction in zinc-limited broth and lack of in vivo activity against KPC-producers were observed. Conclusion For metallo-β-lactamase-producing Enterobacterales, in vitro susceptibility testing to β-lactams with conventional media such as cation-adjusted Muller Hinton broth, a zinc-rich testing medium, is flawed since it does not recapitulate the host environment in which zinc concentrations are low. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

scholarly journals In vitro Antimicrobial Potency of Lemon Fruit (Citrus limon) Extract on Salmonella typhi

2020 ◽  
Vol 11 (2) ◽  
pp. 69
Author(s):  
Farhan Haidar Fazlur Rahman ◽  
Lindawati Alimsardjono ◽  
Sunarni Zakaria
Keyword(s):  
Agar Plate ◽  
Antimicrobial Effect ◽  
Salmonella Typhi ◽  
Citrus Limon ◽  
Lemon Fruit ◽  
Mueller Hinton ◽  
Antibacterial Spectrum ◽  
Mueller Hinton Broth

Introduction: This study aimed to evaluate minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of lemon fruit (Citrus limon) extract in inhibiting Salmonella typhi growth in vitro.Methods: This research was categorized as a laboratory experimental study. Lemon fruit (Citrus limon) extract was prepared with concentration as follows: 100.000 ppm, 50.000 ppm, 25.000 ppm, 12.500 ppm, 6.250 ppm, 3.125 ppm, 1.562 ppm, 781 ppm, and 390 ppm. Dilution tests with Mueller-Hinton broth medium were performed to determine the MIC. After 24 hours of incubation, isolated Salmonella typhi inside the tube was inoculated back in MacConkey agar plate medium to determine the MBC. Replications were conducted 3 times according to Federer’s formula.Results: MIC of lemon fruit (Citrus limon) extract to Salmonella typhi was determined at 3.125 ppm. Meanwhile, MBC was determined at 6.250 ppm.Conclusion: This study showed the potential antimicrobial effect of lemon fruit (Citrus limon) extract against Salmonella typhi in-vitro. Further studies are still needed to determine its efficacy and safety in vivo and also its full antibacterial spectrum. 

Metallo-β-lactamase resistance in Enterobacteriaceae is an artefact of currently utilized antimicrobial susceptibility testing methods

2020 ◽  
Vol 75 (4) ◽  
pp. 997-1005 ◽  
Author(s):  
Tomefa E Asempa ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Susceptibility Testing ◽  
Bacterial Killing ◽  
Phenotypic Profile ◽  
Fold Reduction ◽  
Pharmacodynamic Profile ◽  
Zinc Depletion ◽  
Zinc Concentrations ◽  
The Impact

Abstract Background MBLs are a major contributor to β-lactam resistance when tested using CAMHB. Despite in vitro resistance, positive outcomes have been reported in MBL-infected patients following carbapenem treatment. The impact of physiological zinc concentrations on this in vitro–in vivo MBL discordance warrants investigation. Objectives To evaluate meropenem in vitro activity against MBL-producing Enterobacteriaceae in zinc-depleted broth (Chelex-CAMHB, EDTA-CAMHB) and assess meropenem efficacy in murine infection models. Methods Neutropenic mice received a meropenem human-simulated regimen of 2 g q8h or levofloxacin 750 mg q24h (for model validation). Zinc concentrations were determined in conventional CAMHB, zinc-depleted CAMHB and epithelial lining fluid (ELF) of lung-infected mice. Results All MBL-producing isolates (NDM, n = 25; VIM, n = 3; IMP, n = 2) examined were meropenem resistant in CAMHB and susceptible in zinc-depleted CAMHB (5- to 11-fold reduction), with zinc depletion having no impact on levofloxacin MICs. Zinc concentrations (mean ± SD) in CAMHB were 0.959 ± 0.038 mg/L and in both zinc-depleted CAMHB and ELF were <0.002 mg/L. In vivo, levofloxacin displayed predictable efficacy consistent with its phenotypic profile, while meropenem produced >1 log unit bacterial killing despite in vitro resistance in conventional CAMHB. Conclusions Results indicate that meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in zinc-depleted media for MBL-producing Enterobacteriaceae. These translational data suggest that the use of conventional CAMHB for MBL susceptibility testing is inappropriate in distinguishing meaningful in vivo resistance given that zinc concentrations are supraphysiological in conventional CAMHB and negligible at infection sites.

scholarly journals Variability in Zinc Concentration among Mueller-Hinton Broth Brands: Impact on Antimicrobial Susceptibility Testing of Metallo-β-Lactamase-Producing Enterobacteriaceae

2020 ◽  
Vol 58 (12) ◽  
Author(s):  
Anastasia Bilinskaya ◽  
Douglas J. Buckheit ◽  
Michael Gnoinski ◽  
Tomefa E. Asempa ◽  
David P. Nicolau
Keyword(s):  
Antimicrobial Susceptibility ◽  
Inductively Coupled Plasma ◽  
Zinc Concentration ◽  
Becton Dickinson ◽  
Inductively Coupled ◽  
Mueller Hinton ◽  
Zinc Concentrations ◽  
The Impact ◽  
Mueller Hinton Broth

ABSTRACT Zinc concentrations in cation-adjusted Mueller-Hinton broth (caMHB) from different manufacturers have been found to differ. Here, we evaluated the impact of utilizing different brands and lots of commercially available caMHB on the classification of the antimicrobial susceptibility of metallo-β-lactamase (MBL)-harboring Enterobacteriaceae. We also evaluated the addition of EDTA to caMHB as a means of achieving zinc-limited media. Fifteen clinical Enterobacteriaceae isolates (harboring NDM [n = 7], VIM [n = 3], IMP [n = 2], or KPC [n = 3]) and nine different commercial lots from three caMHB manufacturers (Becton, Dickinson; Oxoid; and Sigma-Aldrich) were utilized. Zinc-limited media were prepared by the addition of EDTA at concentrations ranging from 3 to 300 μg/ml. Meropenem MICs were determined in triplicate for each lot of conventional caMHB and zinc-limited media by broth microdilution. The zinc concentration in each lot of conventional caMHB was determined by inductively coupled plasma mass spectrometry. Up to 8-fold differences in meropenem MICs were observed between the commercial lots, resulting in different classifications of susceptibility among MBL-harboring isolates. Mean zinc concentrations were highest among conventional Becton, Dickinson caMHB lots relative to those for Oxoid and Sigma-Aldrich broth. Among MBL-harboring isolates, the impact of EDTA on MICs was dependent on the lot, correlating with initial zinc availability (i.e., less MIC reduction with higher initial zinc concentrations), while MICs for KPC-harboring isolates were unchanged. In summary, zinc variability was observed among commercial lots of caMHB, resulting in different classifications of susceptibility among MBL-harboring Enterobacteriaceae. The addition of EDTA at concentrations of ≥30 μg/ml was sufficient to provide a zinc-limited medium, resulting in MICs that reflect in vivo meropenem activity.

scholarly journals Effect of Simulated Gastrointestinal Conditions on Biofilm Formation bySalmonella1,4,[5],12:i:-

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
R. Seixas ◽  
M. Gabriel ◽  
J. Machado ◽  
L. Tavares ◽  
F. Bernardo ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Biofilm Formation ◽  
Contributing Factors ◽  
Biofilm Growth ◽  
Biofilm Production ◽  
Gastrointestinal Conditions ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

SalmonellaTyphimurium 1,4,[5],12:i:- is a major serovar responsible for human salmonellosis whose biofilm-forming ability, influenced by environmental conditions like those found in the gastrointestinal tract, is one of the main contributing factors to its ability to persist in the host and thus one of the main causes of chronic relapsing infections. Most studies to evaluate biofilm formation are performed in microtiter assays using standard media. However, no reports are available on the ability of this serovar to produce biofilm underin vitrosimulated gastrointestinal conditions which better correlate with the environment found in the gastrointestinal tract. To address this, a modified biofilm assay simulating intestinal fluid was conceived to assess the biofilm formation of 133SalmonellaTyphimurium 1,4,[5],12:i:- isolates with and without agitation and at three different time points (24 h, 48 h, and 72 h). The results were then compared to the existing microtiter method using conventional biofilm growth medium (Mueller Hinton Broth). Statistical analysis revealed significant differences in the results obtained between the three protocols used. The simulated human intestinal environment impaired biofilm production demonstrating that conditions like pH, agitation or the presence of enzymes can influence biofilm production. Therefore, results fromin vitrosimulation ofin vivoconditions may contribute to unravelling factors relating to biofilm formation and persistence in the context of the human host.

scholarly journals Determination of Tedizolid in Bacterial Growth Medium Mueller-Hinton Broth by High-Performance Liquid Chromatography and Its Application to an In Vitro Study in the Hollow-Fiber Infection Model

Separations ◽  
2021 ◽  
Vol 8 (9) ◽  
pp. 141
Author(s):  
Khalid Iqbal ◽  
Aliki Milioudi ◽  
Elena Haro Martínez ◽  
Sebastian Georg Wicha
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Growth Medium ◽  
Bacterial Growth ◽  
High Performance ◽  
Infection Model ◽  
Growth Media ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

Pharmacokinetic/pharmacodynamic (PKPD) studies of anti-infectives are frequently performed in in vitro infection models where accurate quantification of antibiotic concentrations in bacterial growth media is crucial to establish PK/PD relationships. Here, a sensitive and rapid high-performance liquid chromatography (HPLC) method was developed to quantify tedizolid (TDZ) in the bacterial growth medium Mueller-Hinton broth (MHB). Matrix components were separated by direct protein precipitation with methanol (1:1). The chromatographic separation was carried out in a Dionex Ultimate 3000 HPLC system using an Accucore® C-18 RPMS HPLC column (2.6 µm, 100 × 2.1 mm) using isocratic elution with 25% acetonitrile and 75% of 0.1% formic acid. The lower limit of quantification was 0.03 mg/L when measured at 300 nm. Following relevant European Medicine Agency guidelines, the method was successfully validated for linearity, selectivity, recovery, inter- and intra-day precision, and accuracy and stability. When applied to in vitro PKPD studies, the method successfully quantified a range of TDZ concentration (Cmin, 0.09-Cmax, 0.65 mg/L) in MHB. The analyzed concentrations were in line with the planned PK profiles. The application of the developed method to quantify TDZ in MHB in in vitro PKPD studies is warranted.

scholarly journals 607. Scope and Predictive Genetic/Phenotypic Signatures of “Bicarbonate [NaHCO3]-Responsivity” and β-Lactam Sensitization among Methicillin-Resistant Staphylococcus aureus (MRSA)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S284-S284
Author(s):  
Selvi Ceren. Ersoy ◽  
Brianne Zapata-Davila ◽  
Mariam Otmishi ◽  
Vanessa Milan ◽  
Liang Li ◽  
...  
Keyword(s):  
Methicillin Resistant Staphylococcus Aureus ◽  
Clonal Complex ◽  
Broth Microdilution ◽  
Standard Medium ◽  
Mueller Hinton ◽  
Solid Foundation ◽  
Mrsa Strains ◽  
Mueller Hinton Broth

Abstract Background Selected MRSA strains become susceptible to β-lactams (e.g., oxacillin [OX]; cefazolin [CFZ]) in vitro when tested in a standard medium (cation-adjusted Mueller–Hinton Broth; CA-MHB) supplemented with NaHCO3 (“NaHCO3-responsivity”). In vivo activity of β-lactams was demonstrated for MRSA strains with this phenotype in a rabbit endocarditis model (Ersoy et al Antimicrob Agents Chemother 2019). The current study was designed to: (i) determine the prevalence of the NaHCO3-responsive phenotype in a large collection of clinical MRSA isolates; and (ii) identify genetic and phenotypic predictors of this phenotype. Methods. 58 recent MRSA bloodstream isolates representing contemporary clonal complex (CC) genotypes were screened for the NaHCO3-responsive phenotype by broth microdilution MICs in CA-MHB, with or without NaHCO3 supplementation (25–44 mM). Methods 58 recent MRSA bloodstream isolates representing contemporary clonal complex (CC) genotypes were screened for the NaHCO3-responsive phenotype by broth microdilution MICs in CA-MHB, with or without NaHCO3 supplementation (25–44 mM). Results 43/58 (74.1%) and 21/58 (36.2%) were rendered susceptible to CFZ and OX, respectively, in the presence of NaHCO3; 20 of the 21 OX-susceptible strains were also susceptible to CFZ in the presence of NaHCO3. High baseline β-lactam MICs (i.e., MICs in CA-MHB alone ≥64 µg/mL) was not predictive of NaHCO3 responsivity. The CC8 genotype was correlated with NaHCO3 responsivity for OX, but not CFZ (P < 0.05). Conclusion The NaHCO3-responsive phenotype is relatively common for both OX and especially CFZ among clinical MRSA isolates. Identification of specific genetic factors linked to this phenotype remains ongoing. Confirmation in relevant animal models that this phenotype is predictive of β-lactam efficacy in vivo could provide a solid foundation for a paradigm shift in antimicrobial susceptibility testing of MRSA. Disclosures All authors: No reported disclosures.

scholarly journals Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Iron Overload ◽  
Plasma Concentrations ◽  
Infection Model ◽  
Iron Dextran ◽  
Iron Availability ◽  
Murine Models ◽  
Plasma Pharmacokinetics ◽  
And Control

ABSTRACT Siderophore-antibiotic conjugates have increased in vitro activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. In vivo models of infection with iron overload and deficiency are needed to perform this assessment. The standard neutropenic murine thigh infection model was supplemented with iron-altering treatments: iron dextran at 100 mg/kg of body weight daily for 14 days to load iron or deferoxamine at 100 mg/kg daily plus a low-iron diet for up to 30 days to deplete iron. Human-simulated regimens of cefiderocol and meropenem were administered in both models to assess any impact of iron alteration on plasma pharmacokinetics. Median iron in overloaded mice was significantly higher than that of controls in plasma (1,657 versus 336 μg/dl; P < 0.001), liver (2,133 versus 11 μg/g; P < 0.001), and spleen (473 versus 144 μg/g; P < 0.001). At 30 days, depleted mice had significantly lower iron than controls in liver (2.4 versus 6.5 μg/g; P < 0.001) and spleen (72 versus 133 μg/g; P = 0.029) but not plasma (351 versus 324 μg/dl; P = 0.95). Cefiderocol and meropenem plasma concentrations were similar in iron overloaded and control mice but varied in iron-depleted mice. The iron-overloaded murine thigh infection model was established, and human-simulated regimens of cefiderocol and meropenem were validated therein. While deferoxamine successfully reduced liver and splenic iron, this depleting treatment altered the pharmacokinetics of both antimicrobials.

scholarly journals In VivoPharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Rio Nakamura ◽  
Tsukasa Ito-Horiyama ◽  
Miki Takemura ◽  
Shinsuke Toba ◽  
Shuhei Matsumoto ◽  
...  
Keyword(s):  
Lung Infection ◽  
Infection Model ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Mueller Hinton ◽  
Infection Models ◽  
Resistant Strains ◽  
The Mean ◽  
Mueller Hinton Broth

ABSTRACTThe pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with thein vivoefficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused byPseudomonas aeruginosashowed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT>MIC) rather than the free peak level divided by the MIC (fCmax/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT>MICdetermined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected thein vivoefficacy of cefiderocol than the %fT>MICdetermined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MICof cefiderocol required for a 1-log10reduction against 10 strains ofEnterobacteriaceaeand 3 strains ofPseudomonas aeruginosain the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MICforEnterobacteriaceae,P. aeruginosa,Acinetobacter baumannii, andStenotrophomonas maltophiliain the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that thein vivoefficacy correlated with thein vitroMIC under iron-deficient conditions.

scholarly journals Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

2015 ◽  
Vol 59 (12) ◽  
pp. 7743-7752 ◽  
Author(s):  
Aryun Kim ◽  
Amy Kutschke ◽  
David E. Ehmann ◽  
Sara A. Patey ◽  
Jared L. Crandon ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Body Weight ◽  
Iron Uptake ◽  
Threshold Concentration ◽  
Content Type ◽  
Adaptive Resistance ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

ABSTRACTThe objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 inPseudomonas aeruginosaby using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of thein vivomodel, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake:piuA,piuC,pirR,fecI, andpvdS. Against fourP. aeruginosaisolates, SMC-3176 displayed predictable efficacy corresponding to thefT>MIC using the MIC in CDMHB (R2= 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate forP. aeruginosaisolate JJ 4-36, as thein vivoresponses were inconsistent withfT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against whichin vivofailures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy inP. aeruginosadue to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantialin vivotesting is warranted for compounds using the siderophore approach to thoroughly screen for thisin vitro-in vivodisconnect inP. aeruginosa.

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