scholarly journals 1241. In Vivo Efficacy of Meropenem Against Metallo-ß-Lactamase (MBL)-Harboring Pseudomonas aeruginosa and Correlation to In Vitro Susceptibility Upon Addition of EDTA

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S710-S710
Author(s):  
Abigail K Kois ◽  
Tomefa E Asempa ◽  
David P Nicolau
Keyword(s):  
Infection Model ◽  
Bacterial Killing ◽  
In Vitro Susceptibility ◽  
In Vivo Efficacy ◽  
Treatment Groups ◽  
Emax Model ◽  
Mueller Hinton ◽  
Pharmacodynamic Profile

Abstract Background Prior investigations evaluating the predictive value of zinc-depleted media for MBL-susceptibility testing have focused on Enterobacterales. Therein, bacterial killing observed with meropenem (MEM) in vivo was concordant with its pharmacodynamic profile using MIC values determined in zinc-depleted media compared with conventional cation-adjusted Mueller-Hinton broth (CAMHB). This study aims to evaluate the exposure-response relationship of MEM against VIM- and NDM-harboring P. aeruginosa (PSA) using the murine thigh infection model and zinc-depleted MICs. Methods MBL-harboring PSA isolates (VIM n=11; NDM n=10) were tested both in vivo (neutropenic murine thigh infection model) and in vitro (broth microdilution). The 24h murine thigh study was conducted with treatment groups receiving a humanized MEM 2g q8h (3h infusion) dose. Six different zinc-limited media were prepared by the addition of EDTA at concentrations ranging from 3 to 300 mg/L to CAMHB. MEM MICs were determined in triplicate in conventional CAMHB and zinc-limited media. Time > MIC values (generated in each zinc-depleted media) were then plotted against the change in 24h bacterial density count in an Emax model. Results Average 0 h bacterial densities were 5.21 ± 0.40 and 5.13 ± 0.81 log10 CFU/thigh for NDM and VIM isolates, respectively. MEM resulted in -0.09 CFU reduction to +3.69 CFU growth against NDM isolates. MEM resulted in -2.59 CFU reduction to +4.81 CFU growth against VIM isolates. All MEM MICs in conventional CAMHB were >64 µg/mL for NDM and ranged from 8 to >64 µg/mL for VIM isolates. Increasing EDTA concentrations resulted in several-fold MIC reductions and on average, a larger magnitude of reduction was observed among VIM- (6-fold) compared with NDM-harboring PSA (4-fold) in CAMHB-EDTA 300 mg/L relative to CAMHB. For both NDM- and VIM-harboring PSA, an Emax model with MICs generated in CAMHB+EDTA 30 mg/L (r2 = 0.88) provided the highest correlation with MEM in vivo activity compared with CAMHB (r2 = 0.55). Conclusion Results indicate that MIC values generated in conventional CAMHB do not appropriately characterize the in vivo efficacy of meropenem against MBL-harboring PSA, and addition of EDTA (30 mg/L) to CAMHB appears to be a viable option for in vitro testing of these organisms. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.)

scholarly journals 1533. Is Cation-Adjusted Mueller–Hinton Broth (CAMHB) Appropriate for Metallo-β-lactamase (MBL) Susceptibility Testing? Novel Insights in In Vitro–In Vivo Discordance Among MBL-Producing Enterobacteriaceae

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S558-S559
Author(s):  
Tomefa E Asempa ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
San Francisco ◽  
Susceptibility Testing ◽  
Case Reports ◽  
Bacterial Killing ◽  
In Vivo Efficacy ◽  
Phenotypic Profile ◽  
Pharmacodynamic Profile ◽  
High Level

Abstract Background MBLs, which require Zn for catalytic activity, are a major contributor to high-level β-lactam resistance when tested using conventional CAMHB. We have previously reported marked reductions in meropenem (MEM) MICs in Zn-depleted media (Chelex-CAMHB and EDTA-CAMHB; Zn [C] <0.002 mg/L) compared with conventional CAMHB (Zn [C] 0.959 mg/L) against a variety of MBL-producing isolates, whereas Zn-depletion had no impact on levofloxacin (LVX) MICs (ASM Microbe 2019, San Francisco. Abstract P508). To explore in vivo implications, we evaluated the efficacy of MEM human simulated regimen (HSR) against MBL-producing isolates in a murine pneumonia model. In addition, LVX HSR was examined for model validation. Methods Nine MBL-producing isolates (NDM, n = 5; VIM, n = 2; IMP, n = 2) were utilized. CAMHB, Chelex-CAMHB, and EDTA-CAMHB MEM MICs ranged from 16 to > 64, ≤0.0625 to 0.5, and ≤ 0.0625 to 0.5 mg/L, respectively. LVX MICs ranged from ≤ 0.0625 – > 64 mg/L. Neutropenic lung-infected ICR mice received a MEM HSR of 2g q8h [1.5 hours infusion], 2 lower MEM exposures or LVX 750 mg q24h HSR. Zn [C] were determined in the epithelial lining fluid (ELF) of infected mice. Results LVX displayed predictable in vivo efficacy consistent with its phenotypic profile irrespective of the media utilized for MIC testing (figure). Despite attaining zero %T> MIC using values generated in CAMHB, MEM HSR produced marked bacterial reductions against all MBL-producing isolates (figure). Reductions in MEM exposures produced bacterial killing concordant with its pharmacodynamic profile using Zn-depleted CAMHB MIC values. Zn [C] in infected murine ELF were undetectable, i.e., <0.002 mg/L. Conclusion Our results indicate that MEM in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in Zn-depleted media for MBL-producing Enterobacteriaceae. These observations are consistent with the case reports describing positive outcomes in MBL-infected patients following treatment with carbapenems (Infection 2018;46:1–13). Our translational data suggest that the use of conventional CAMHB for MBL susceptibility testing is inappropriate in distinguishing meaningful in vivo resistance given that Zn [C] are supraphysiologic in conventional CAMHB and negligible at infection sites. Disclosures All authors: No reported disclosures.

scholarly journals Correlation of In Vitro Activity, Serum Levels, and In Vivo Efficacy of Posaconazole against Rhizopus microsporus in a Murine Disseminated Infection

2009 ◽  
Vol 53 (12) ◽  
pp. 5022-5025 ◽  
Author(s):  
M. Mar Rodríguez ◽  
F. Javier Pastor ◽  
Enrique Calvo ◽  
Valentina Salas ◽  
Deanna A. Sutton ◽  
...  
Keyword(s):  
Serum Levels ◽  
Rhizopus Microsporus ◽  
In Vitro Susceptibility ◽  
In Vivo Efficacy ◽  
Susceptibility Data ◽  
Microdilution Method ◽  
Drug Concentrations ◽  
Broth Microdilution Method

ABSTRACT A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of Rhizopus microsporus. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated R. microsporus infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations.

scholarly journals 1366. In Vitro and In Vivo Activity of Cefiderocol against Stenotrophomonas maltophilia Clinical Isolates

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S418-S418 ◽  
Author(s):  
Akinobu Ito ◽  
Merime Ota ◽  
Rio Nakamura ◽  
Masakatsu Tsuji ◽  
Takafumi Sato ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Systemic Infection ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
Infection Model ◽  
In Vitro Activity ◽  
In Vivo Efficacy ◽  
Broth Microdilution Method

Abstract Background Cefiderocol (S-649266, CFDC) is a novel siderophore cephalosporin against Gram-negatives, including carbapenem (CR)-resistant strains. Its spectrum includes both the Enterobacteriaceae but also nonfermenters, including Stenotrophomonas maltophilia—an opportunistic pathogen with intrinsic resistance to carbapenem antibiotics. In this study, in vitro activity and in vivo efficacy of CFDC and comparators against S. maltophilia were determined. Methods MICs of CFDC and comparators (trimethoprim/sulfamethoxazole (TMP/SMX), minocycline (MINO), tigecycline (TGC), ciprofloxacin (CPFX), cefepime (CFPM), meropenem (MEPM), and colistin (CL)) were determined by broth microdilution method as recommended by CLSI. The MIC against CFDC was determined using iron-depleted cation-adjusted Mueller–Hinton broth. In vivo efficacy of CFDC, CFPM, ceftazidime–avibactam (CAZ/AVI), MEPM, and CL was evaluated using neutropenic murine systemic infection model caused by strain SR21970. The 50% effective doses (ED50s) were calculated by the logit method using the survival number at each dose 7 days after infection. Results MIC90 of CFDC and comparators against the 216 clinical isolates from global countries collected in SIDERO-CR 2014/2016 study are shown in the table. CFDC, TMP/SMX, MINO, and TGC showed good activity with MIC90 of 0.5, 0.25/4.75, 1, and 2 µg/mL, respectively. CFDC, MINO, and TGC inhibited growth of all tested strains at ≤1, ≤4, and ≤8 µg/mL although two strains showed resistance to TMP/SMX. MICs of CFPM, CAZ/AVI, MEPM, and CL were ≥32 µg/mL. The ED50 of CFDC against S. maltophilia SR21970 with MIC of 0.125 mg/mL was 1.17 mg/kg/dose. Conversely, MICs of CFPM, CAZ/AVI, MEPM/CS, and CL against SR21970 were 32 μg/mL or higher, and ED50s were &gt;100 mg/kg/dose, showing that CFDC had potent in vivo efficacy against S. maltophilia strain which was resistant to other antibiotics. Conclusion CFDC showed potent in vitro activity against S. maltophilia, including TMP/SMX-resistant isolates. CFDC also showed potent in vivo efficacy reflecting in vitro activity against S. maltophilia in murine systemic infection model. Disclosures A. Ito, Shionogi & Co., Ltd.: Employee, Salary. M. Ota, Shionogi & Co., Ltd.: Employee, Salary. R. Nakamura, Shionogi & Co., Ltd.: Employee, Salary. M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. T. Sato, Shionogi & Co., Ltd.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary.

scholarly journals 682. In Vivo Pharmacodynamics of VNRX-7145 in the Neutropenic Murine Thigh Infection Model When Administered in Combination with Humanized Exposures of Twice Daily Ceftibuten (CTB) Against Serine β-Lactamase-Producing Enterobacteriaceae (SBL-EB)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S311-S311 ◽  
Author(s):  
Lindsay M Avery ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Complicated Urinary Tract Infection ◽  
Dose Fractionation ◽  
Intrinsic Activity ◽  
Infection Model ◽  
Bacterial Burden ◽  
Dose Ratio ◽  
Time Curve ◽  
In Vitro Susceptibility

Abstract Background There is a pressing need for development of oral antibiotics with activity against SBL-EB, particularly carbapenemase-producers, for use in the community or as step-down therapy for complicated urinary tract infection. VNRX-7145 is a novel boronic acid-based SBL inhibitor with no intrinsic activity that was designed as an orally bioavailable prodrug. The active moiety (VNRX-5236) is known to restore in vitro susceptibility to (CTB), an oral cephalosporin, among CTB-resistant SBL-EB. Methods CTB-resistant SBL-EB (N = 21) with CTB MICs ≥32 µg/mL and CTB/VNRX-5236 MIC range 0.12–2 µg/mL (VNRX-5236 fixed at 4 µg/mL) were evaluated. Carbapenemases were produced by 9 strains (4 OXA, 5 KPC). Bacterial suspensions (~107 CFU/mL) were used to inoculate the thighs of neutropenic mice. A human-simulated regimen of ceftibuten (CTB HSR) equivalent to a 400 mg q12h dosage was developed in infected mice. In dose ranging studies, groups of 3 animals each received the CTB HSR as monotherapy or combined with escalating VNRX-5236 exposures (CTB:VNRX-5236 dose ratios ranging from 10:1 to 1:4). Efficacy was assessed as the change in log10 CFU/thigh at 24 hours from 0 hour burden. With previous in vivo dose fractionation studies indicating the free area under the VNRX-5236 concentration–time curve to MIC ratio (fAUC0-24/MIC) as the PK/PD driver of efficacy, the Hill equation was used to estimate the magnitude required to achieve a static endpoint. Results Compared with 0 hour controls (mean log10 CFU/thigh, 5.7 ± 0.3), the bacterial burden for all isolates increased in saline-dosed controls and CTB HSR groups by 3.1 ± 0.8 and 2.5 ± 0.8 log10 CFU/thigh, respectively. The addition of VNRX-5236 resulted in bacterial stasis in 20/21 strains; the mean reduction in bacterial burden with the 1:1 CTB:VNRX-5236 dose ratio was −0.2 ± 0.7 log10 CFU/thigh. A composite assessment of exposure-responses indicated a fAUC0-24/MIC of 9.0 (R2 = 0.70) was associated with stasis. Conclusion Against CTB-resistant SBL-EB, inclusive of OXA-48- and KPC-producing strains, VNRX-5236 potentiated the in vivo activity of the CTB human-simulated exposure. The identified fAUC0-24/MIC target associated with bacterial stasis should be considered when selecting VNRX-7145 doses for clinical studies. Disclosures All authors: No reported disclosures.

scholarly journals Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Su Mon Aye ◽  
Irene Galani ◽  
Heidi Yu ◽  
Jiping Wang ◽  
Ke Chen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Triple Therapy ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Killing ◽  
Standard Dosage ◽  
Time Kill

ABSTRACT Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae. Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.

scholarly journals Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria

2020 ◽  
Vol 76 (1) ◽  
pp. 179-183 ◽  
Author(s):  
Vincent H Tam ◽  
Henrietta Abodakpi ◽  
Weiqun Wang ◽  
Kimberly R Ledesma ◽  
Paul R Merlau ◽  
...  
Keyword(s):  
Standard Dose ◽  
Recursive Partitioning ◽  
Hollow Fibre ◽  
Infection Model ◽  
Emax Model ◽  
Inoculum Effect ◽  
The Impact ◽  
Lactamase Inhibitor

Abstract Objectives Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. Methods Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T&gt;MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. Results A concentration-dependent reduction in β-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T&gt;MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. Conclusions A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.

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