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 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 The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of Mycobacterium tuberculosis as Determined in a Hollow-Fiber Infection Model

mBio ◽  
2010 ◽  
Vol 1 (3) ◽  
Author(s):  
G. L. Drusano ◽  
Nicole Sgambati ◽  
Adam Eichas ◽  
David L. Brown ◽  
Robert Kulawy ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Bacterial Cell ◽  
Infection Model ◽  
Bacterial Burden ◽  
Log Reduction ◽  
Significant Difference ◽  
Cell Kill ◽  
The Impact

ABSTRACTMoxifloxacin is under development for expanded use againstMycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P= 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P= 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill.IMPORTANCEM. tuberculosisinfects one-third of the world’s population. Multiresistant organisms have become more frequent, threatening our ability to provide adequate chemotherapy. Moxifloxacin has been seen as an important new agent with the potential to supplant isoniazid or add to the rifampin/isoniazid combination.M. tuberculosisalso exists in different physiological states, including the NRP phenotype. We examined the moxifloxacin/rifampin combination in a newin vitrosystem to allow judgment of how moxifloxacin would interact with rifampin and allow its performance in clinical trials to be placed into perspective. Importantly, the combination suppressed resistance emergence, but at the price of slightly slowing bacterial cell kill. This new combination is a welcome addition to the physician’s armamentarium.

scholarly journals Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

2020 ◽  
Author(s):  
Lei Zhao ◽  
Xiaobing Li ◽  
Xiaojing He ◽  
Lingyan Jian
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Renal Function ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Normal Renal Function ◽  
Randomized Clinical Trials ◽  
Infection Model ◽  
Drug Concentrations ◽  
Combination Regimens ◽  
Abnormal Renal Function

Abstract Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as both monotherapy and combination therapy, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16–20 mL/min) renal function. Common clinical administration regimens to provide reference values were also evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853). This simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. The total and resistant populations were quantified. Drug concentrations were determined by High-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8h, whilst combination regimens resulted in 2- to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6h, and was seen at 0h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0h, there was a certain downward trend after 8h, while resistant population in the normal renal function group increased after 16h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.

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 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 Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model

2013 ◽  
Vol 58 (3) ◽  
pp. 1365-1371 ◽  
Author(s):  
Seth T. Housman ◽  
Jared L. Crandon ◽  
Wright W. Nichols ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Confidence Limit ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Drug Concentrations ◽  
Lung Infections ◽  
Host Infection ◽  
The Impact

ABSTRACTThis study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28Pseudomonas aeruginosaisolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. ThefT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28P. aeruginosastrains used, the ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of ceftazidime were 8 to >128 μg/ml. The change in log10CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10CFU againstP. aeruginosawith ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit forfT>MIC [ELFfT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 μg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 μg/ml (ELFfT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 μg/ml (ELFfT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 μg/ml (ELFfT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 μg/ml, where the ELFfT>MIC was 0%. ELFfT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective againstP. aeruginosa, with MICs of up to 32 μg/ml with an ELFfT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused byP. aeruginosa.

scholarly journals Experimental Validation of a Mathematical Framework to Simulate Antibiotics with Distinct Half-Lives Concurrently in an In Vitro Model

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1256
Author(s):  
Brianna M. Eales ◽  
Cole S. Hudson ◽  
Iordanis Kesisoglou ◽  
Weiqun Wang ◽  
Michael Nikolaou ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Compartment Model ◽  
Multidrug Resistant ◽  
Design Stage ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Mathematical Framework ◽  
Multidrug Resistant Bacteria ◽  
Drug Concentrations

Antimicrobial resistance has been steadily increasing in prevalence, and combination therapy is commonly used to treat infections due to multidrug resistant bacteria. Under certain circumstances, combination therapy of three or more drugs may be necessary, which makes it necessary to simulate the pharmacokinetic profiles of more than two drugs concurrently in vitro. Recently, a general theoretical framework was developed to simulate three drugs with distinctly different half-lives. The objective of the study was to experimentally validate the theoretical model. Clinically relevant exposures of meropenem, ceftazidime, and ceftriaxone were simulated concurrently in a hollow-fiber infection model, with the corresponding half-lives of 1, 2.5, and 8 h, respectively. Serial samples were obtained over 24 h and drug concentrations were assayed using validated LC-MS/MS methods. A one-compartment model with zero-order input was used to characterize the observed concentration-time profiles. The experimentally observed half-lives corresponding to exponential decline of all three drugs were in good agreement with the respective values anticipated at the experiment design stage. These results were reproducible when the experiment was repeated on a different day. The validated benchtop setup can be used as a more flexible preclinical tool to explore the effectiveness of various drug combinations against multidrug resistant bacteria.

scholarly journals Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

2020 ◽  
Author(s):  
Lei Zhao ◽  
Xiaobing Li ◽  
Xiaojing He ◽  
Lingyan Jian
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Renal Function ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Normal Renal Function ◽  
Randomized Clinical Trials ◽  
Infection Model ◽  
Drug Concentrations ◽  
Combination Regimens ◽  
Abnormal Renal Function

Abstract Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as monotherapy and in combination, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16–20 mL/min) renal function. Common clinical administration regimens to provide reference values were also evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853). This simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. The total and resistant populations were quantified. Drug concentrations were determined by High-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8h, whilst combination regimens resulted in 2- to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6h, and was seen at 0h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0h, there was a certain downward trend after 8h, while resistant population in the normal renal function group increased after 16h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.

scholarly journals Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

2020 ◽  
Author(s):  
Lei Zhao ◽  
Xiaobing Li ◽  
Xiaojing He ◽  
Lingyan Jian
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Renal Function ◽  
Combination Therapy ◽  
Hollow Fiber ◽  
Normal Renal Function ◽  
Randomized Clinical Trials ◽  
Infection Model ◽  
Drug Concentrations ◽  
Combination Regimens ◽  
Abnormal Renal Function

Abstract Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as both monotherapy and combination therapy, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16–20 mL/min) renal function. Common clinical administration regimens to provide reference values were also evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853). This simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. The total and resistant populations were quantified. Drug concentrations were determined by High-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8h, whilst combination regimens resulted in 2- to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6h, and was seen at 0h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0h, there was a certain downward trend after 8h, while resistant population in the normal renal function group increased after 16h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.

scholarly journals Impact of Bolus Dosing versus Continuous Infusion of Piperacillin and Tazobactam on the Development of Antimicrobial Resistance in Pseudomonas aeruginosa

2013 ◽  
Vol 57 (12) ◽  
pp. 5811-5819 ◽  
Author(s):  
T. W. Felton ◽  
J. Goodwin ◽  
L. O'Connor ◽  
A. Sharp ◽  
L. Gregson ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Nosocomial Pneumonia ◽  
Bacterial Resistance ◽  
Bacterial Density ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Drug Concentrations ◽  
The Impact

ABSTRACTManagement of nosocomial pneumonia is frequently complicated by bacterial resistance. Extended infusions of beta-lactams are increasingly being used to improve clinical outcomes. However, the impact of this strategy on the emergence of antimicrobial resistance is not known. A hollow-fiber infection model withPseudomonas aeruginosa(PAO1) was used. Pharmacokinetic (PK) profiles of piperacillin-tazobactam similar to those in humans were simulated over 5 days. Three dosages of piperacillin-tazobactam were administered over 0.5 h or 4 h, with redosing every 8 h. Two initial bacterial densities were investigated (∼104CFU/ml and ∼107CFU/ml). The time courses of the total bacterial population and the resistant subpopulation were determined. All data were described using a mathematical model, which was then used to define the relationship between drug concentrations, bacterial killing, and emergence of piperacillin resistance. There was logarithmic growth in controls in the initial 24 h, reaching a plateau of ∼9 log10CFU/ml. Bacterial killing following administration of piperacillin via bolus dosing and that after extended infusions were similar. For the lower initial bacterial density, trough total plasma piperacillin concentration/MIC ratios of 3.4 and 10.4 for bolus and extended-infusion regimens, respectively, were able to suppress the emergence of piperacillin resistance. For the higher initial bacterial density, all regimens were associated with progressive growth of a resistant subpopulation. A stratified approach, according to bacterial density, is required to treat patients with nosocomial pneumonia. Antimicrobial monotherapy may be sufficient for some patients. However, for patients with a high bacterial burden, alternative therapeutic strategies are required to maximize bacterial killing and prevent antimicrobial resistance.

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