scholarly journals Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coli in Time-Kill Studies and in a Hollow-Fiber Infection Model

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Yiying Cai ◽  
Tze-Peng Lim ◽  
Jocelyn Qi-Min Teo ◽  
Suranthran Sasikala ◽  
Eric Chun Yong Chan ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Growth Rate ◽  
Bactericidal Activity ◽  
Hollow Fiber ◽  
Polymyxin B ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Time Kill

ABSTRACT Polymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli (CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow-fiber infection model (HFIM). TKS were conducted using 5 clinical CREC strains at 5 log10 CFU/ml against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. HFIMs simulating dosing regimens with polymyxin B (30,000U/kg/day) and tigecycline (100 mg every 12 h) alone and in combination were conducted against two CREC strains at 5 log10 CFU/ml over 120 h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate and stability of resistant phenotypes) of the resistant isolates was performed. All five CREC strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5 mg/liter to 2 mg/liter and from 0.25 mg/liter to 8 mg/liter, respectively. All antibiotics alone did not have bactericidal activity at 24 h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B plus tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8 h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with a reduced growth rate observed in one strain. Tigecycline alone resulted in a slow reduction in bacterial counts. Polymyxin B plus tigecycline resulted in rapid and sustained bactericidal killing up to 120 h. Polymyxin B plus tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.

scholarly journals Activity of Fosfomycin and Amikacin against Fosfomycin-Heteroresistant Escherichia coli Strains in a Hollow-Fiber Infection Model

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
I. Portillo-Calderón ◽  
M. Ortiz-Padilla ◽  
B. de Gregorio-Iaria ◽  
V. Merino-Bohorquez ◽  
J. Blázquez ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hollow Fiber ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
E Coli ◽  
Bacterial Cultures ◽  
Agar Dilution ◽  
Time Kill ◽  
Risk Of Treatment

ABSTRACT We evaluated human-like the efficacy of intravenous doses of fosfomycin of 8 g every 8 h (8 g/Q8h) and of amikacin (15 mg/kg/Q24h) in monotherapy and in combination against six fosfomycin-heteroresistant Escherichia coli isolates using a hollow-fiber infection model (HFIM). Six fosfomycin-heteroresistant E. coli isolates (four with strong mutator phenotype) and the control strain E. coli ATCC 25922 were used. Mutant frequencies for rifampin (100 mg/liter), fosfomycin (50 and 200 mg/liter), and amikacin (32 mg/liter) were determined. Fosfomycin and amikacin MICs were assessed by agar dilution (AD), gradient strip assay (GSA), and broth microdilution (BMD). Fosfomycin and amikacin synergies were studied by checkerboard and time-kill assays at different concentrations. The efficacies of fosfomycin (8 g/Q8h) and amikacin (15 mg/kg/Q24h) alone and in combination were assessed using an HFIM. Five isolates were determined to be resistant to fosfomycin by AD and BMD, but all were determined to be susceptible by GSA. All isolates were determined to be susceptible to amikacin. Antibiotic combinations were synergistic in two isolates, and no antagonism was detected. In time-kill assays, all isolates survived under fosfomycin at 64 mg/liter, although at 307 mg/liter only the normomutators and two hypermutators survived. Four isolates survived under 16 mg/liter amikacin, and none survived at 45 mg/liter. No growth was detected under combination conditions. In HFIM, fosfomycin and amikacin monotherapies failed to sterilize bacterial cultures; however, the combination of fosfomycin and amikacin yielded a rapid eradication. There may be a risk of treatment failure of fosfomycin-heteroresistant E. coli isolates using either amikacin or fosfomycin in monotherapy. These results support that the amikacin-fosfomycin combination can rapidly decrease bacterial burden and prevent the emergence of resistant subpopulations against fosfomycin-heteroresistant strains.

scholarly journals Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
John K. Diep ◽  
David M. Jacobs ◽  
Rajnikant Sharma ◽  
Jenna Covelli ◽  
Dana R. Bowers ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Population Analysis ◽  
Polymyxin B ◽  
Infection Model ◽  
Triple Combination Therapy ◽  
Content Type ◽  
Drug Regimens ◽  
Time Kill

ABSTRACT Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PBs) and polymyxin B-resistant (PBr) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [C ss] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PBs isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PBr isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PBr KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.

scholarly journals High-Dose Ampicillin-Sulbactam Combinations Combat Polymyxin-Resistant Acinetobacter baumannii in a Hollow-Fiber Infection Model

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Justin R. Lenhard ◽  
Nicholas M. Smith ◽  
Zackery P. Bulman ◽  
Xun Tao ◽  
Visanu Thamlikitkul ◽  
...  
Keyword(s):  
Body Weight ◽  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Polymyxin B ◽  
Infection Model ◽  
High Dose ◽  
Loading Dose ◽  
Content Type ◽  
Time Kill

ABSTRACT Acinetobacter baumannii is emerging with resistance to polymyxins. In 24-h time-kill experiments, high-dose ampicillin-sulbactam in combination with meropenem and polymyxin B achieved additivity or synergy against 108 CFU/ml of two clinical A. baumannii isolates resistant to all three drugs (maximum reductions, 1.6 and 3.1 logs). In a 14-day hollow-fiber infection model, high-dose ampicillin-sulbactam (8/4 g every 8 h, respectively) in combination with meropenem (2 g every 8 h) and polymyxin B (1.43 mg/kg of body weight every 12 h with loading dose) resulted in rapid (96 h) eradication of A. baumannii.

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 Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-Resistant Enterobacteriaceae

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
M. Thwaites ◽  
D. Hall ◽  
D. Shinabarger ◽  
A. W. Serio ◽  
K. M. Krause ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Minimum Bactericidal Concentration ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Next Generation ◽  
Content Type ◽  
Time Kill

ABSTRACT The next-generation aminoglycoside plazomicin, in development for infections due to multidrug-resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC50/90 of 0.5/4 μg/ml and sustained 3-log10 kill against MDR Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp.

scholarly journals Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam–β-Lactamase Inhibitor Combinations

2016 ◽  
Vol 60 (4) ◽  
pp. 1967-1973 ◽  
Author(s):  
Rachel L. Soon ◽  
Justin R. Lenhard ◽  
Zackery P. Bulman ◽  
Patricia N. Holden ◽  
Pamela Kelchlin ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Bactericidal Activity ◽  
Fold Increase ◽  
Multidrug Resistant ◽  
Content Type ◽  
Log Reduction ◽  
Wide Range ◽  
Tract Infections ◽  
Time Kill ◽  
The Hill

ABSTRACTDespite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains ofEscherichia colithat differed in the type of β-lactamase they expressed. The four investigational strains included 2805 (no β-lactamase), 2890 (AmpC β-lactamase), 2842 (CMY-10 β-lactamase), and 2807 (CTX-M-15 β-lactamase), with MICs to ceftolozane of 0.25, 4, 8, and >128 mg/liter with no tazobactam, and MICs of 0.25, 1, 4, and 8 mg/liter with 4 mg/liter tazobactam, respectively. All four strains were exposed to a 6 by 5 array of ceftolozane (0, 1, 4, 16, 64, and 256 mg/liter) and tazobactam (0, 1, 4, 16, and 64 mg/liter) over 48 h using starting inocula of 106and 108CFU/ml. While ceftolozane-tazobactam achieved bactericidal activity against all 4 strains, the concentrations of ceftolozane and tazobactam required for a ≥3-log reduction varied between the two starting inocula and the 4 strains. At both inocula, the Hill plots (R2> 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC50s) at tazobactam concentrations of ≤4 mg/liter than those at concentrations of ≥16 mg/liter (P< 0.01). Moreover, the EC50s at 108CFU/ml were 2.81 to 66.5 times greater than the EC50s at 106CFU/ml (median, 10.7-fold increase;P= 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of β-lactamase-producingE. colistrains.

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 In VitroandIn VivoActivities of OP0595, a New Diazabicyclooctane, against CTX-M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae

2016 ◽  
Vol 60 (5) ◽  
pp. 3001-3006 ◽  
Author(s):  
Akihiro Morinaka ◽  
Yuko Tsutsumi ◽  
Keiko Yamada ◽  
Yoshihiro Takayama ◽  
Shiro Sakakibara ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Content Type ◽  
Effective Combination ◽  
Time Kill ◽  
Lactamase Inhibitor

ABSTRACTGram-negative bacteria are evolving to produce β-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine β-lactamase inhibitor which acts also as an antibiotic and as a β-lactamase-independent β-lactam “enhancer” againstEnterobacteriaceae. Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, inin vitrotime-kill studies and anin vivoinfection model against five strains of CTX-M-15-positiveEscherichia coliand five strains of KPC-positiveKlebsiella pneumoniae. An OP0595 concentration of 4 μg/ml was found to be sufficient for an effective combination with all three β-lactam agents. In bothin vitrotime-kill studies and anin vivomodel of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all β-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a β-lactam agent is important to exert the antimicrobial functions of OP0595.

scholarly journals New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Zackery P. Bulman ◽  
Michael J. Satlin ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
Beom Soo Shin ◽  
...  
Keyword(s):  
Single Dose ◽  
Klebsiella Pneumoniae ◽  
Polymyxin B ◽  
Infection Model ◽  
Triple Combination ◽  
Content Type ◽  
High Single Dose ◽  
Dosing Strategies ◽  
Time Required ◽  
Time Kill

ABSTRACT Pharmacodynamics of a polymyxin B, meropenem, and rifampin triple combination were examined against Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) ST258. In time-kill experiments against three KPC-Kp isolates, triple combination generated 8.14, 8.19, and 8.29 log10 CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log10 CFU/ml at 78 h and the time required for regrowth was more than doubled versus the 2-drug combinations. Remarkably, combinations with a high single-dose polymyxin B burst plus rifampin preserved KPC-Kp polymyxin susceptibility (MIC240 h = 0.5 mg/liter) versus the same combination with traditionally dosed polymyxin B, where resistance was amplified (MIC240 h = 32 mg/liter).

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

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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