scholarly journals Optimization of a Meropenem-Tobramycin Combination Dosage Regimen against Hypermutable and NonhypermutablePseudomonas aeruginosavia Mechanism-Based Modeling and the Hollow-Fiber Infection Model

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Tae Hwan Kim ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Hollow Fiber ◽  
Time Profile ◽  
Total Daily Dose ◽  
Infection Model ◽  
Bacterial Killing ◽  
Complete Replacement ◽  
Content Type ◽  
Dose Time ◽  
Concentration Time

ABSTRACTHypermutablePseudomonas aeruginosastrains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutSstrain (MICmeropenemof 1.0 mg/liter and MICtobramycinof 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼108.4CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutSstrain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10bacterial killing followed by regrowth to >6 log10CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutableP. aeruginosastrain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

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 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 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 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 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.

scholarly journals Preferential Emergence of Reduced Vancomycin Susceptibility in Health Care-Associated Methicillin-Resistant Staphylococcus aureus Isolates during Continuous-Infusion Vancomycin Therapy in anIn VitroDynamic Model

2011 ◽  
Vol 55 (7) ◽  
pp. 3627-3630 ◽  
Author(s):  
Sheryl Zelenitsky ◽  
Noha Alkurdi ◽  
Zhanni Weber ◽  
Robert Ariano ◽  
George Zhanel
Keyword(s):  
Health Care ◽  
Staphylococcus Aureus ◽  
Continuous Infusion ◽  
Total Serum ◽  
Vancomycin Therapy ◽  
Time Curve ◽  
Bacterial Killing ◽  
Methicillin Resistant ◽  
Content Type ◽  
Concentration Time

ABSTRACTBacterial killing and the development of reduced vancomycin susceptibility during continuous-infusion vancomycin (CIV) therapy were dependent on the area under the concentration-time curve over 24 h divided by the MIC (ƒAUC24/MIC), with values of ≥240 (equivalent total serum AUC24/MICs of ≥480) being bactericidal and suppressing emerging resistance in methicillin-resistantStaphylococcus aureus(MRSA). Also, vancomycin therapy was less likely to be bactericidal and 4.4 times more likely to lead to reduced vancomycin susceptibility in health care-associated MRSA than in community-associated MRSA.

scholarly journals Evaluation of Meropenem Regimens Suppressing Emergence of Resistance in Acinetobacter baumannii with Human Simulated Exposure in anIn VitroIntravenous-Infusion Hollow-Fiber Infection Model

2014 ◽  
Vol 58 (11) ◽  
pp. 6773-6781 ◽  
Author(s):  
Xin Li ◽  
Lin Wang ◽  
Xian-Jia Zhang ◽  
Yang Yang ◽  
Wei-Tao Gong ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Dosage Interval ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Dosage Regimens ◽  
Drug Concentrations ◽  
Emergence Of Resistance

ABSTRACTThe emergence of resistance to carbapenems inPseudomonas aeruginosacan be suppressed by optimizing the administration of meropenem. However, whether the same is true forAcinetobacter baumanniiis not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance inA. baumanniiwith human simulated exposure in anin vitrointravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistantA. baumannii(CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio ofT>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Ourin vitrodata support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.

scholarly journals ComparativeIn VitroandIn VivoEfficacies of Human Simulated Doses of Ceftazidime and Ceftazidime-Avibactam against Pseudomonas aeruginosa

2012 ◽  
Vol 56 (12) ◽  
pp. 6137-6146 ◽  
Author(s):  
Jared L. Crandon ◽  
Virna J. Schuck ◽  
Mary Anne Banevicius ◽  
Marie-Eve Beaudoin ◽  
Wright W. Nichols ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
Time Profile ◽  
Fiber System ◽  
Content Type ◽  
Concentration Time ◽  
Infection Models ◽  
Immunocompetent Mice

ABSTRACTThe combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, includingPseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinicalP. aeruginosaisolates with ceftazidime MICs of 8 to 128 mg/liter and ceftazidime-avibactam MICs of 4 to 32 mg/liter were utilized in neutropenic mouse studies; 15 of the isolates were also evaluated in immunocompetent mice. Six isolates were studied in both the hollow-fiber system and the neutropenic mouse. In both systems, the free drug concentration-time profile seen in humans given 2 g of ceftazidime every 8 h (2-h infusion), with or without avibactam at 500 mg every 8 h (2-h infusion), was evaluated.In vivoactivity was pharmacodynamically predictable based on the MIC. Ceftazidime decreased bacterial densities by ≥0.5 log unit for 10/27 isolates, while ceftazidime-avibactam did so for 22/27 isolates. In immunocompetent animals, enhancements in activity were seen for both drugs, with ceftazidime achieving reductions of ≥0.3 log unit for 10/15 isolates, whereas ceftazidime-avibactam did so against all 15 isolates.In vitro, ceftazidime resulted in regrowth by 24 h against all isolates, while ceftazidime-avibactam achieved stasis or better against 4/7 isolates. Mutants with elevated ceftazidime-avibactam MICs appeared after 24 h from 3/7 isolates studiedin vitro; however, no resistant mutants were detectedin vivo. Against this highly ceftazidime-nonsusceptible population ofP. aeruginosa, treatment with human simulated doses of ceftazidime-avibactam resulted in pharmacodynamically predictable activity, particularlyin vivo, against isolates with MICs of ≤16 mg/liter, and this represents a potential new option to combat these difficult-to-treat pathogens.

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 Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Fekade Bruck Sime ◽  
Adam Johnson ◽  
Sarah Whalley ◽  
Anahi Santoyo-Castelazo ◽  
A. Bruce Montgomery ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Hollow Fiber ◽  
Severe Pneumonia ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Infection Model ◽  
Bacterial Killing ◽  
Bacterial Populations ◽  
Content Type

ABSTRACT There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae. In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

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