scholarly journals Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Arnold Louie ◽  
Michael Maynard ◽  
Brandon Duncanson ◽  
Jocelyn Nole ◽  
Michael Vicchiarelli ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
The United States ◽  
Infection Model ◽  
Combination Regimen ◽  
Bacterial Cells ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type

ABSTRACT Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log 10 (CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with Enterobacteriaceae ( in vitro systems) and P. aeruginosa (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

scholarly journals The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber Infection Model

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
G. L. Drusano ◽  
M. N. Neely ◽  
W. M. Yamada ◽  
Brandon Duncanson ◽  
David Brown ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Bacterial Infections ◽  
Clinical Problem ◽  
The United States ◽  
Resistance Mechanisms ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type

ABSTRACT Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log10 CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden Pseudomonas aeruginosa infections and requires further study.

scholarly journals New Dosing Strategies for an Old Antibiotic: Pharmacodynamics of Front-Loaded Regimens of Colistin at Simulated Pharmacokinetics in Patients with Kidney or Liver Disease

2013 ◽  
Vol 58 (3) ◽  
pp. 1381-1388 ◽  
Author(s):  
Gauri G. Rao ◽  
Neang S. Ly ◽  
Curtis E. Haas ◽  
Samira Garonzik ◽  
Alan Forrest ◽  
...  
Keyword(s):  
Renal Failure ◽  
Viable Count ◽  
Infection Model ◽  
Combination Regimen ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Dosing Regimens ◽  
The Impact

ABSTRACTIncreasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized anin vitropharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (108CFU/ml) ofPseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2of 14.8 h) disease. Front-loaded regimens (n= 5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n= 14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum ofP. aeruginosa. The current study, which utilizes anin vitropharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.

scholarly journals Evaluation of Once-Daily Vancomycin against Methicillin-Resistant Staphylococcus aureus in a Hollow-Fiber Infection Model

2011 ◽  
Vol 56 (2) ◽  
pp. 682-686 ◽  
Author(s):  
Anthony M. Nicasio ◽  
Jürgen B. Bulitta ◽  
Thomas P. Lodise ◽  
Rebecca E. D'Hondt ◽  
Robert Kulawy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hollow Fiber ◽  
Daily Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTFor methicillin-resistantStaphylococcus aureus(MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in anin vitrohollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼106CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.

scholarly journals Evaluating mono and combination therapy of meropenem and amikacin against Pseudomonas aeruginosa bacteremia in the Hollow-Fiber Infection Model

2021 ◽  
Author(s):  
Minyon L Avent ◽  
Kate L. McCarthy ◽  
Fekade Sime ◽  
saiyuri naicker ◽  
Aaron James Heffernan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Day Treatment ◽  
Infection Model ◽  
Combination Regimen ◽  
Bacterial Killing ◽  
Initial Inoculum ◽  
Potential Synergy

Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied extent of bacterial killing and resistance emergence of meropenem and amikacin as monotherapy and as a combination therapy against susceptible and resistant P. aeruginosa isolates from bacteremic patients using the dynamic in vitro hollow-fiber infection model. Three P. aeruginosa isolates (meropenem MICs 0.125, 0.25 & 64 mg/L) were used simulating bacteremia with an initial inoculum ~ 1×105 CFU/mL and the expected pharmacokinetics of meropenem and amikacin in critically ill patients. For isolates susceptible to amikacin and meropenem (isolates 1 and 2), the rate of bacterial killing was increased with the combination regimen when compared with monotherapy of either antibiotic. Both the combination and meropenem monotherapy were able to sustain bacterial killing throughout the seven-day treatment course, whereas regrowth of bacteria occurred with amikacin monotherapy after 12 hours. For the meropenem-resistant P. aeruginosa isolate (isolate 3), only the combination regimen demonstrated bacterial killing. Given that tailored antibiotic regimens can maximize potential synergy against some isolates, future studies should explore the benefit of combination therapy against resistant P. aeruginosa.

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 Exploring the Pharmacokinetic/Pharmacodynamic Relationship of Relebactam (MK-7655) in Combination with Imipenem in a Hollow-Fiber Infection Model

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Jin Wu ◽  
Fred Racine ◽  
Michael K. Wismer ◽  
Katherine Young ◽  
Donna M. Carr ◽  
...  
Keyword(s):  
Hollow Fiber ◽  
Bacterial Infections ◽  
New Drugs ◽  
Dose Fractionation ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Relationship Of

ABSTRACT Resistance to antibiotics among bacterial pathogens is rapidly spreading, and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (REL; MK-7655) in a hollow-fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow-fiber infection model to confirm the efficacy of human exposures associated with the phase 2 doses (imipenem at 500 mg plus REL at 125 or 250 mg administered intravenously every 6 h as a 30-min infusion) against imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae . Dose fractionation experiments confirmed that the pharmacokinetic parameter that best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex, as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the MIC of imipenem as dynamic: it changes with time, and this change is directly related to REL levels. For the strains tested, the percentage of the dosing interval time that the concentration remains above the dynamic MIC for imipenem was maintained at the carbapenem target of 30 to 40%, required for maximum efficacy, for imipenem at 500 mg plus REL at 250 mg.

scholarly journals The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both Pseudomonas aeruginosa Kill Rate and Resistance Suppression

2010 ◽  
Vol 54 (6) ◽  
pp. 2646-2654 ◽  
Author(s):  
Arnold Louie ◽  
Caroline Grasso ◽  
Nadzeya Bahniuk ◽  
Brian Van Scoy ◽  
David L. Brown ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Infection Model ◽  
Combination Regimen ◽  
Time Data ◽  
Kaplan Meier ◽  
Drug Concentrations ◽  
Cell Kill ◽  
The Impact

ABSTRACT New approaches are needed for the treatment of Pseudomonas aeruginosa infections. All available single agents are suboptimal, especially for resistance suppression. Classical β-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the P. aeruginosa PAO1 wild type and its isogenic MexAB pump-overexpressed mutant. The drugs were studied using an in vitro hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2- to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.

scholarly journals Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Jürgen B. Bulitta ◽  
Veronika Wirth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

scholarly journals Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Melanie Roch ◽  
Maria Celeste Varela ◽  
Agustina Taglialegna ◽  
Warren E. Rose ◽  
Adriana E. Rosato
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Galleria Mellonella ◽  
Therapeutic Option ◽  
The United States ◽  
Infection Model ◽  
Content Type ◽  
Complicated Skin ◽  
Hospital Acquired

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90. We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.

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