Resistance Emergence Mechanism and Mechanism of Resistance Suppression by Tobramycin for Cefepime for Pseudomonas aeruginosa

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC meropenem 0.25 mg/ liter) was studied in the hollow-fiber infection model (inoculum ϳ10 7.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ϳ10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (Յϳ2.5 log 10 ). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5-and 1-g regimens with normal renal function (fT Ͼ5ϫMIC ϭ 56 and 69%, fC min /MIC Ͻ 2); the emergence of less-susceptible populations (Ն32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT Ͼ5ϫMIC Ն 82%, fC min /MIC Ն 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

Section: Effect Of Meropenem Clearance On Antibacterial Effectsmentioning

confidence: 68%

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model

Bergen

Bulitta

Kirkpatrick

et al. 2017

“…HFIM. The HFIM was used to simulate the time course of unbound plasma concentrations observed in patients receiving polymyxin B regimens by using an approach that was previously described (19,20). Cellulosic hollow-fiber cartridges (C3008; Fiber Cell Systems, Fredrick, MD) were utilized in all experiments, and samples were serially collected for 336 h. Total population counts were quantified by depositing appropriately diluted bacterial samples on Mueller-Hinton agar (MHA) plates.…”

Section: Methodsmentioning

confidence: 99%

Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Tsuji

Landersdorfer

Lenhard

et al. 2016

f Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of Acinetobacter baumannii in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (t 1/2 ‫؍‬ 8 h): nonloading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both A. baumannii isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of ؊1.25, ؊1.43, ؊2.84, ؊2.84, and ؊3.40 log 10 CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an fAUC 0 -24 (area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density A. baumannii infections.T he polymyxin antibiotics have emerged as a last line of defense for the treatment of Gram-negative strains resistant to all other currently available antibiotics (1-3). Polymyxin B and colistin are often the only available agents with activity against these Gram-negative superbugs (4, 5). Even more worrisome is the first report of plasmid-mediated polymyxin resistance in Escherichia coli, which could be transferred to other Gram-negative strains (6). Furthermore, current dosage regimens for both polymyxin B and colistin result in polymyxin plasma concentrations that are suboptimal in a significant proportion of patients (7-10). In vitro and animal studies clearly demonstrate that antibiotic resistance is amplified during exposure to suboptimal polymyxin concentrations, especially against polymyxin-heteroresistant strains that are frequently isolated in Acinetobacter baumannii (11)(12)(13)(14).Administering nontraditional, high-intensity polymyxin regimens may be a strategy to maximize bacterial killing while minimizing resistance and potential toxicity. We have previously determined that front-loading colistin resulted in greater bacteri...

“…Control study arms included studies using Mueller-Hinton broth or Mueller-Hinton broth supplemented with 8 or 10% sodium chloride. Onemilliliter specimens were collected for CFU determination at 0, 1,2,3,4,6,8,12, and 24 h. Samples were centrifuged, washed, and resuspended with sterile normal saline solution twice to prevent drug carryover and then cultured onto Trypticase soy agar enriched with 5% sheep blood. Plated samples were incubated at 35°C for 24 h. One-milliliter specimens for drug assay were collected at 1, 3, 5, 7, and 24 h and then immediately frozen at Ϫ80°C until assayed for drug concentration.…”

Section: Methodsmentioning

confidence: 99%

“…Two pharmacokinetics-pharmacodynamics (PK-PD) in vitro infection models, a one-compartment model and a hollow-fiber model, each previously described (11,12), were used in these studies. All studies were conducted in duplicate.…”

Section: Methodsmentioning

confidence: 99%

“…To explore the relationship between bacterial replication rate and duration of antimicrobial therapy, we utilized temperature-controlled in vitro infection models in which human antimicrobial agent concentration-time profiles can be accurately simulated and the impact of drug exposure on bacterial density can be readily measured (11,12). More specifically, the overarching objectives of these studies were to demonstrate that the bacterial replication rate was coupled to the rate and extent of antimicrobial bactericidal effects and, subsequently, that therapy duration could be modulated by altering the bacterial replication rate.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Bacterial Replication Rate Modulation in Combination with Antimicrobial Therapy: Turning the Microbe against Itself

Ambrose

VanScoy

Conde

et al. 2017

Self Cite

A major clinical challenge for treating infectious diseases is the duration of antimicrobial therapy required to eradicate the pathogen. We hypothesized that modulation of the bacterial replication rate in the context of an antimicrobial exposure is coupled with the rate and extent of bactericidal effects. Herein we describe results from in vitro infection model (one compartment, 24-h model; hollow fiber, 10-day model) studies designed to probe the relationship between the bacterial replication rate and the rate and extent of bactericidal effects in the context of an effective antibiotic exposure. The bacterial replication rate was modulated by adjusting the sodium chloride concentration (0 to 8%) in the growth media (Mueller-Hinton II broth). The study drug selected was levofloxacin, and the challenge isolate was Staphylococcus aureus ATCC 29213 (levofloxacin MIC, 0.125 mg/liter). Within each in vitro infection model, human levofloxacin concentration-time profiles (half-life, 7 h) were simulated and the challenge isolate was subjected to an effective exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio], 65; administered as a single dose or daily for 10 days). Over the course of each study, samples were taken from each model for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the 24-h one-compartment in vitro infection model studies, as the bacterial replication rate increased, so too did the rate (slope, 0 to 4 h) and extent (24-h CFU count per milliliter) of bacterial killing. In the 10-day hollow-fiber infection model studies, the times until a reduction of bacterial density to 1 ϫ 10 2 CFU/ml occurred were 10 days in the media in which the challenge isolate grew slowly and approximately 2 days in the media in which the challenge isolate grew rapidly. Together, these data provide a proof of concept for new adjunctive therapeutic options with respect to the use of antimicrobial agents alone that reduce treatment durations. Such adjunctive therapies hold promise for marked reductions in the tonnage of antimicrobial agents administered to patient populations and selection pressure toward antimicrobial resistance.