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

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.

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

10.21203/rs.2.21032/v2 ◽

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.

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

10.21203/rs.2.21032/v3 ◽

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

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

BMC Pharmacology and Toxicology ◽

10.1186/s40360-020-0396-5 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

L Zhao ◽

X Li ◽

X He ◽

L Jian

Keyword(s):

Pseudomonas Aeruginosa ◽

Renal Function ◽

Critically Ill ◽

Hollow Fiber ◽

Critically Ill Patients ◽

Infection Model ◽

Abnormal Renal Function

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00065-10 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2646-2654 ◽

Cited By ~ 46

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01682-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 9

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.

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Meropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01679-19 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

Rajbharan Yadav ◽

Phillip J. Bergen ◽

Kate E. Rogers ◽

Carl M. J. Kirkpatrick ◽

Steven C. Wallis ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Hollow Fiber ◽

Critically Ill Patients ◽

Infection Model ◽

Augmented Renal Clearance ◽

Bacterial Killing ◽

Content Type ◽

Carbapenem Resistant ◽

Combination Regimens ◽

Rapid Regrowth

ABSTRACT Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM). Pharmacokinetic profiles representing substantial ARC (creatinine clearance of 250 ml/min) were generated in the HFIM for meropenem (1 g or 2 g administered every 8 h as 30-min infusion and 3 g/day or 6 g/day as continuous infusion [CI]) and tobramycin (7 mg/kg of body weight every 24 h as 30-min infusion) regimens. The time courses of total and less-susceptible bacterial populations and MICs were determined for the monotherapies and all four combination regimens. Mechanism-based mathematical modeling (MBM) was performed. In the HFIM, maximum bacterial killing with any meropenem monotherapy was ∼3 log10 CFU/ml at 7 h, followed by rapid regrowth with increases in resistant populations by 24 h (meropenem MIC of up to 128 mg/liter). Tobramycin monotherapy produced extensive initial killing (∼7 log10 at 4 h) with rapid regrowth by 24 h, including substantial increases in resistant populations (tobramycin MIC of 32 mg/liter). Combination regimens containing meropenem administered intermittently or as a 3-g/day CI suppressed regrowth for ∼1 to 3 days, with rapid regrowth of resistant bacteria. Only a 6-g/day CI of meropenem combined with tobramycin suppressed regrowth and resistance over 7 days. MBM described bacterial killing and regrowth for all regimens well. The mode of meropenem administration was critical for the combination to be maximally effective against carbapenem-resistant P. aeruginosa.

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Evaluation of Several Dosing Regimens of Cefepime, with Various Simulations of Renal Function, against Clinical Isolates ofPseudomonas aeruginosa in a Pharmacodynamic Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.1.129 ◽

1999 ◽

Vol 43 (1) ◽

pp. 129-133 ◽

Cited By ~ 7

Author(s):

Diane M. Cappelletty

Keyword(s):

Renal Function ◽

Combination Therapy ◽

Creatinine Clearance ◽

Single Agent ◽

Clinical Isolates ◽

Infection Model ◽

Dosing Interval ◽

Killing Activity ◽

Central Chamber ◽

Drug Concentrations

ABSTRACT The objectives of this study were as follows: (i) to examine the killing activity of 2-g doses of cefepime against two clinical isolates (mucoid and nonmucoid) of Pseudomonas aeruginosa in a pharmacodynamic in vitro infection model, (ii) to compare the percentage of time above the MIC (T > MIC) for each of the regimens against P. aeruginosa, and (iii) to evaluate the area under the bactericidal curve for each regimen. Cefepime was administered at intervals of 8, 12, and 24 h with and without tobramycin, and two different levels of renal function were simulated: normal (creatinine clearance [CLCR] = 90 ml/min) and decreased (CRCL = 60 ml/min). Also, the killing activity of cefepime with and without tobramycin was compared to the killing activity of ceftazidime (2 g every 8 h) with and without tobramycin. The T > MIC was 100% in the central chamber except for the regimen in which cefepime was administered every 12 h and the CLCR was 90 ml/min, which provided concentrations above the MIC for 92% of the dosing interval against the C31 (mucoid; MIC of cefepime, 4 μg/ml) isolate and for 75% of the interval against the C34 (nonmucoid; MIC of cefepime, 8 μg/ml) isolate. All cefepime and ceftazidime monotherapy simulations resulted in 99.9% killing of the nonmucoid isolate within 4 to 8 h and within 4 to 6 h, respectively. Against the mucoid isolate, 99.9% killing was achieved only with combination therapy. The results of this study indicate that cefepime dosed at 2 g every 12 h under conditions of normal renal function and every 24 h with decreased creatinine clearance (60 ml/min) is effective both as monotherapy and in combination therapy against a nonmucoid strain of P. aeruginosa. With cefepime MICs of 4 and 8 μg/ml, the single-agent regimens provided T > MIC values in the central chamber for 92 and ≥75% of the dosing interval against the mucoid and nonmucoid isolates, respectively. Cefepime dosed at 2 g every 12 h, with a creatinine clearance of 90 ml/min, and every 24 h, with a creatinine clearance of 60 ml/min, resulted in killing activity equivalent to that of ceftazidime dosed at 2 g every 8 h. None of the monotherapies provided adequate killing of the mucoid strain of P. aeruginosa despite drug concentrations being above the MIC for ≥92% of all dosing intervals. Finally, combination therapy with tobramycin and either cefepime or ceftazidime enhanced the killing of both the mucoid and nonmucoidP. aeruginosa isolates.

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Evaluation of Ceftolozane-Tazobactam in Combination with Meropenem against Pseudomonas aeruginosa Sequence Type 175 in a Hollow-Fiber Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00026-18 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 8

Author(s):

M. Montero ◽

Brian D. VanScoy ◽

Carla López-Causapé ◽

Haley Conde ◽

Jonathan Adams ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Hollow Fiber ◽

Sequence Type ◽

University Hospital ◽

Infection Model ◽

Content Type ◽

Clinical Exposure ◽

Density Reduction ◽

Drug Concentrations ◽

Serial Samples

ABSTRACT The aim of this study was to investigate the efficacy of ceftolozane-tazobactam in combination with meropenem against an extensively drug-resistant (XDR) Pseudomonas aeruginosa high-risk clone, sequence type 175, isolated in a Spanish university hospital. A 14-day hollow-fiber infection model was used to simulate clinical exposure of the two drug regimens alone and in combination, and serial samples were collected to determine drug concentrations and CFU counts. The untreated control failed, as did each study regimen when administered alone. However, when ceftolozane-tazobactam was administered in combination with meropenem, there was a >4-log 10 CFU/ml bacterial density reduction and suppression of resistance for the duration of the study. These data suggest that ceftolozane-tazobactam plus meropenem may be a useful combination for treating XDR P. aeruginosa .

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

10.1101/2021.12.23.474080 ◽

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.

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Low Plasma Cefepime Levels in Critically Ill Septic Patients: Pharmacokinetic Modeling Indicates Improved Troughs with Revised Dosing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.10.2559 ◽

1999 ◽

Vol 43 (10) ◽

pp. 2559-2561 ◽

Cited By ~ 79

Author(s):

J. Lipman ◽

S. C. Wallis ◽

C. Rickard

Keyword(s):

Pseudomonas Aeruginosa ◽

Renal Function ◽

Critically Ill ◽

Normal Renal Function ◽

Plasma Drug ◽

Drug Concentrations ◽

Dosing Intervals ◽

Trough Levels ◽

Trough Plasma ◽

Plasma Drug Concentrations

ABSTRACT The pharmacokinetics of a 2-g bolus of cefepime were measured in critically ill patients with normal renal function. Variable and low trough plasma drug concentrations were found, and 8 of 10 patients had levels below the MIC at which 50% of the isolates are inhibited forPseudomonas aeruginosa. Computer simulations predicted that continuous infusion and shorter dosing intervals would increase trough levels.

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