scholarly journals Evaluation of Meropenem Regimens Suppressing Emergence of Resistance in Acinetobacter baumannii with Human Simulated Exposure in anIn VitroIntravenous-Infusion Hollow-Fiber Infection Model

2014 ◽  
Vol 58 (11) ◽  
pp. 6773-6781 ◽  
Author(s):  
Xin Li ◽  
Lin Wang ◽  
Xian-Jia Zhang ◽  
Yang Yang ◽  
Wei-Tao Gong ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Dosage Interval ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Dosage Regimens ◽  
Drug Concentrations ◽  
Emergence Of Resistance

ABSTRACTThe emergence of resistance to carbapenems inPseudomonas aeruginosacan be suppressed by optimizing the administration of meropenem. However, whether the same is true forAcinetobacter baumanniiis not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance inA. baumanniiwith human simulated exposure in anin vitrointravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistantA. baumannii(CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio ofT>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Ourin vitrodata support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.

scholarly journals Combating Carbapenem-ResistantAcinetobacter baumanniiby an Optimized Imipenem-plus-Tobramycin Dosage Regimen: Prospective Validation via Hollow-Fiber Infection and Mathematical Modeling

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Tae Hwan Kim ◽  
Beom Soo Shin ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Dosage Regimen ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACTWe aimed to prospectively validate an optimized combination dosage regimen against a clinical carbapenem-resistantAcinetobacter baumannii(CRAB) isolate (imipenem MIC, 32 mg/liter; tobramycin MIC, 2 mg/liter). Imipenem at constant concentrations (7.6, 13.4, and 23.3 mg/liter, reflecting a range of clearances) was simulated in a 7-day hollow-fiber infection model (inoculum, ∼107.2CFU/ml) with and without tobramycin (7 mg/kg q24h, 0.5-h infusions). While monotherapies achieved no killing or failed by 24 h, this rationally optimized combination achieved >5 log10bacterial killing and suppressed resistance.

scholarly journals Optimization and Evaluation of Piperacillin-Tobramycin Combination Dosage Regimens againstPseudomonas aeruginosafor Patients with Altered Pharmacokinetics via the Hollow-Fiber Infection Model and Mechanism-Based Modeling

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Phillip J. Bergen ◽  
Jürgen B. Bulitta ◽  
Carl M. J. Kirkpatrick ◽  
...  
Keyword(s):  
Critically Ill ◽  
Hollow Fiber ◽  
Critically Ill Patient ◽  
Infection Model ◽  
Case Scenario ◽  
Bacterial Killing ◽  
Worst Case ◽  
Content Type ◽  
Dosage Regimens ◽  
Time Kill

ABSTRACTAugmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated againstPseudomonas aeruginosaby use of the hollow-fiber infection model (HFIM). Using aP. aeruginosaisolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (105.8and 107.6CFU/ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log10versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log10initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log10at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log10killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.

scholarly journals Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

2016 ◽  
Vol 60 (7) ◽  
pp. 3921-3933 ◽  
Author(s):  
Soon-Ee Cheah ◽  
Jian Li ◽  
Brian T. Tsuji ◽  
Alan Forrest ◽  
Jürgen B. Bulitta ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Public Health Problem ◽  
Polymyxin B ◽  
Major Public Health Problem ◽  
Bacterial Killing ◽  
Bacterial Populations ◽  
Content Type ◽  
Dosage Regimens ◽  
Drug Concentrations ◽  
The Impact

ABSTRACTInfections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinicalA. baumanniistrains in a dynamic one-compartmentin vitromodel. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log10killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log10CFU/ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.

scholarly journals Effect of Linezolid plus Bedaquiline againstMycobacterium tuberculosisin Log Phase, Acid Phase, and Nonreplicating-Persister Phase in anIn VitroAssay

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Carolina de Miranda Silva ◽  
Amirhossein Hajihosseini ◽  
Jenny Myrick ◽  
Jocelyn Nole ◽  
Arnold Louie ◽  
...  
Keyword(s):  
Treatment Success ◽  
Infection Model ◽  
Phase Growth ◽  
Bacterial Killing ◽  
Content Type ◽  
Metabolic States ◽  
Resistant Strains ◽  
Emergence Of Resistance

ABSTRACTTuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening the therapy duration forMycobacterium tuberculosisis a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using anin vitrostrategy to ultimately be tested in anin vitrohollow fiber infection model (HFIM) and in animal models. We studied the effect of the combination of linezolid (LZD) and bedaquiline (BDQ) onM. tuberculosisstrain H37Rv in log- and acid-phase growth andM. tuberculosisstrain 18b in log- and nonreplicating-persister-phase growth in a plate system containing a 9-by-8 matrix of concentrations of both drugs alone and in combinations. A characterization of the interaction as antagonistic, additive, or synergistic was performed using the Greco universal response surface approach (URSA) model. Our results indicate that the interaction between LZD and BDQ is additive for bacterial killing in both strains for both of the metabolic states tested. This prescreen strategy was suitable to identify LZD and BDQ as a promising combination to be further tested in the HFIM. The presence of nonoverlapping mechanisms of drug action suggests each drug in the combination will likely be effective in suppressing the emergence of resistance byM. tuberculosisto the companion drug, which holds promise in improving treatment outcomes for tuberculosis.

scholarly journals Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Aaron J. Heffernan ◽  
Fekade B. Sime ◽  
Derek S. Sarovich ◽  
Michael Neely ◽  
Yarmarly Guerra-Valero ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
Infection Model ◽  
High Dose ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Initial Inoculum

ABSTRACT Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two P. aeruginosa isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼108 CFU/ml was used to test different amikacin dosing regimens. Three regimens (15, 25, and 50 mg/kg) were tested to simulate a blood exposure, while a 30 mg/kg regimen simulated the epithelial lining fluid (ELF) for potential respiratory tract infection. Data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole-genome sequencing was used to identify mutations associated with resistance emergence. While bacterial density was reduced by >6 logs within the first 12 h in simulated blood exposures following this initial bacterial kill, there was amplification of a resistant subpopulation with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (<5 log) bacterial killing in the simulated ELF exposure for either isolate tested. Simulation studies suggested that a dose of 30 and 50 mg/kg may provide maximal bacterial killing for bloodstream and VAP infections, respectively. Our results suggest that amikacin efficacy may be improved with the use of high-dose therapy to rapidly eliminate susceptible bacteria. Subsequent doses may have reduced efficacy given the rapid amplification of less-susceptible bacterial subpopulations with amikacin monotherapy.

scholarly journals Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber In Vitro Infection Model

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Brian D. VanScoy ◽  
Nicole E. Scangarella-Oman ◽  
Steven Fikes ◽  
Sharon Min ◽  
Jianzhong Huang ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Hollow Fiber ◽  
Therapy Resistance ◽  
Model System ◽  
Bacterial Density ◽  
Infection Model ◽  
Drug Resistant ◽  
Content Type ◽  
Drug Concentrations

ABSTRACT Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 106 CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 108 CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections.

scholarly journals Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Debora Rubio-Aparicio ◽  
Thomas G. Nolan ◽  
Jonathan Parkinson ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Hollow Fiber ◽  
Phase 1 ◽  
Phase 3 ◽  
Fiber Model ◽  
Content Type ◽  
Development Of Resistance ◽  
Carbapenem Resistant ◽  
Dosage Regimens

ABSTRACT The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

scholarly journals Activity of Meropenem-Vaborbactam againstPseudomonas aeruginosaandAcinetobacter baumanniiin a Neutropenic Mouse Thigh Infection Model

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Clinical Isolates ◽  
Infection Model ◽  
Model Data ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTWe have evaluated the activity of meropenem-vaborbactam against clinical isolates ofPseudomonas aeruginosaandAcinetobacter baumanniiin a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused byP. aeruginosaandA. baumannii.

scholarly journals A FASII Inhibitor Prevents Staphylococcal Evasion of Daptomycin by Inhibiting Phospholipid Decoy Production

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Carmen J. E. Pee ◽  
Vera Pader ◽  
Elizabeth V. K. Ledger ◽  
Andrew M. Edwards
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Therapeutic Interventions ◽  
Bacterial Killing ◽  
Content Type ◽  
Serious Infections ◽  
Fatty Acid Biosynthetic Pathway ◽  
Emergence Of Resistance ◽  
Host Tissues

ABSTRACT Daptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus. We have shown recently that S. aureus can evade daptomycin by releasing phospholipid decoys that sequester and inactivate the antibiotic, leading to treatment failure. Since phospholipid release occurs via an active process, we hypothesized that it could be inhibited, thereby increasing daptomycin efficacy. To identify opportunities for therapeutic interventions that block phospholipid release, we first determined how the host environment influences the release of phospholipids and the inactivation of daptomycin by S. aureus. The addition of certain host-associated fatty acids to the growth medium enhanced phospholipid release. However, in serum, the sequestration of fatty acids by albumin restricted their availability to S. aureus sufficiently to prevent their use in the generation of released phospholipids. This finding implies that in host tissues S. aureus may be completely dependent upon endogenous phospholipid biosynthesis to generate lipids for release, providing a target for therapeutic intervention. To test this, we exposed S. aureus to AFN-1252, an inhibitor of the staphylococcal FASII fatty acid biosynthetic pathway, together with daptomycin. AFN-1252 efficiently blocked daptomycin-induced phospholipid decoy production, even in the case of isolates resistant to AFN-1252, which prevented the inactivation of daptomycin and resulted in sustained bacterial killing. In turn, daptomycin prevented the fatty acid-dependent emergence of AFN-1252-resistant isolates in vitro. In summary, AFN-1252 significantly enhances daptomycin activity against S. aureus in vitro by blocking the production of phospholipid decoys, while daptomycin blocks the emergence of resistance to AFN-1252.

scholarly journals In VivoEfficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae

2011 ◽  
Vol 55 (7) ◽  
pp. 3220-3225 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Jared L. Crandon ◽  
Guilherme H. Furtado ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Immune Status ◽  
Free Drug ◽  
Infection Model ◽  
The Novel ◽  
Immunocompetent Host ◽  
Content Type ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibitsin vitroactivity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producingEnterobacteriaceaewhen combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 againstEnterobacteriaceaein a murine thigh infection model.IMPORTANCETwelveEnterobacteriaceaeisolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log10CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistantEnterobacteriaceae.

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