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Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation

Open AccessPublished:July 11, 2016DOI:https://doi.org/10.1016/j.ijid.2016.06.017

      Highlights

      • MICs90 of fosfomycin for MDR PA and non MDR PA were high in this study.
      • Approximately 40% of the non-MDR PA was carbapenem-resistant strains.
      • The combination of fosfomycin and carbapenems decreased the MICs of both drugs.
      • Prolonged infusion of fosfomycin combination provided the best PK/PD targets.

      Abstract

      Objective

      The purpose of the study was to determine the optimal dosing regimen of intravenous fosfomycin for the treatment of Pseudomonas aeruginosa (PA) based on PK/PD targets.

      Method

      A total of 120 PA isolates were recovered from various clinical specimens at university hospital in Thailand. Minimum Inhibitory Concentrations (MICs) of all the isolates were determined by the E-test method. PK parameters were obtained from a published study. Monte Carlo simulation was performed to calculate the percentage of target attainment (PTA) and cumulative fraction of response (CFR).

      Results

      MIC90 of fosfomycin alone, fosfomycin in combination with carbapenem, carbapenems alone and carbapenems in combination with fosfomycin were >1,024, 1,024, >32 and 32 μg/ml, for multidrug resistant (MDR)-PA and 512, 128, 8 and 3 μg/ml respectively, for non-MDR PA. Approximately 40% of the non-MDR PA were carbapenem-resistant strains. For non-MDR PA with CRPA, fosfomycin 16 g continuous infusion in combination with carbapenems provided %PTA of approximately 80 and %CFR of > 88. While, %PTA and %CFR > 90 were achieved with fosfomycin 24 g/day prolonged infusion in combination with carbapenem.

      Conclusions

      Prolonged infusion of fosfomycin 16 - 24 g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA.

      Keywords

      1. Introduction

      Pseudomonas aeruginosa (PA) is a highly prevalent pathogen of nosocomial infections worldwide.
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      Pharmacokinetic/pharmacodynamic (PK/PD) studies, especially in Monte Carlo simulations, have played roles for selecting appropriate antibiotic doses with the goal of increasing treatment efficacy and reducing the risk of selecting multidrug-resistant pathogens.
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      However, previous Monte Carlo simulation studies of PK/PD dosages did not include fosfomycin.
      The purpose of this current study was to find the optimal dosage regimen of fosfomycin when used in combination with carbapenem for the treatment of non-MDR-PA and MDR-PA based on PK/PD targets in critically ill patients.

      2. Materials and methods

      2.1 Microbiology

      P. aeruginosa isolates recovered from various clinical specimens (sputum, urine, skin and soft tissue, blood, pleural fluid) at the Faculty of Medicine at Siriraj Hospital in Bangkok, Thailand, were collected between June and September 2011. A total of 120 non-MDR and MDR isolates were obtained. Minimum inhibitory concentrations (MICs) of carbapenems (imipenem, meropenem and doripenem) and fosfomycin by E test were determined for all isolates. Isolate preparation was performed according to the Clinical and Laboratory Standards Institute (CLSI 2011) protocol.
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      Performance Standards for Antimicrobial Susceptibility Testing: Twenty-first Informational Supplement. CLSI document M100-S21.
      The MDR phenotype was identified for isolates expressing resistance to at least three different antibiotic groups: beta-lactams (penicillin, cephalosporin or carbapenems (except monobactam e.g. aztreonam), aminoglycosides and fluoroquinolones.
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      Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology.
      Synergy studies were conducted using an E test of fosfomycin in combination with carbapenems. E test strips of each drug used in the combination were applied in cross direction to each other and the MIC values of each drug were measured after combination.
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      • Bosso J.A.
      Evaluation of antibiotic synergy against Acinetobacter baumannii: a comparison with Etest, time-kill, and checkerboard methods.

      2.2 Pharmacodynamic Model

      Pharmacodynamic exposure was measured by percentage of time above the MIC (%T > MIC) of each drug.
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      Fosfomycin enhances the active transport of tobramycin in Pseudomonas aeruginosa.
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      Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint.
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      Pharmacokinetics/pharmacodynamics of antibacterials in the intensive care unit: setting appropriate dosage regimens.
      Simulations were conducted for IV infusions of the various agents and regimens: fosfomycin 1- 8 g given every 6 - 12 hours, infused over 30 minutes - 24 hours, meropenem 0.5 – 2.0 g given every 6 - 8 hours, infused over 30 minutes - 3 hours, imipenem 0.5 - 1.0 g given every 6 - 8 hours, infused over 30 minutes - 3 hours, and doripenem 0.5-2.0 given every 8 hours, infused over 30 minutes - 4 hours. PK/PD targets were defined as 70% T>MIC for fosfomycin. This breakpoint (70% T>MIC) applies when effective dosage regimens for all cell wall-active antimicrobials require serum drug concentrations exceeding the MIC of the pathogens
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      Fosfomycin enhances the active transport of tobramycin in Pseudomonas aeruginosa.
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      • Andes D.
      • et al.
      Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint.
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      The pharmacodynamics of beta-lactams.
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      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
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      • Rodríguez-Gascón A.
      • Isla A.
      Applications of the pharmacokinetic/pharmacodynamics (PK/PD) analysis of antimicrobial agents.
      • Scaglione F.
      • Paraboni L.
      Pharmacokinetics/pharmacodynamics of antibacterials in the intensive care unit: setting appropriate dosage regimens.
      and 40% T>MIC for the carbapenems. The value 40% T>MIC is required for near-maximal bactericidal effect of the dosing interval for Pseudomonas aeruginosa.
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      The pharmacodynamics of beta-lactams.
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      Applications of the pharmacokinetic/pharmacodynamics (PK/PD) analysis of antimicrobial agents.
      • Scaglione F.
      • Paraboni L.
      Pharmacokinetics/pharmacodynamics of antibacterials in the intensive care unit: setting appropriate dosage regimens.

      2.3 Pharmacokinetic Model

      Pharmacokinetic data were obtained from previously published studies of critically ill patients.
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      • et al.
      Extracellular concentrations of fosfomycin in lung tissue of septic patients.
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      Lin. Population pharmacokinetics of doripenem based on data from phase 1 studies with healthy volunteers and phase 2 and 3 studies with critically ill patients.
      A set of parameters was randomly generated according to each mean and standard deviation of the parameters. Steady-state concentration versus time was simulated using a one-compartment model for fosfomycin
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      • et al.
      Extracellular concentrations of fosfomycin in lung tissue of septic patients.
      and a two-compartment model for carbapenems to calculate %T>MIC.
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      • et al.
      Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial.
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      • Nicolau D.P.
      Optimization of meropenem dosage in the critically ill population based on renal function.
      • Nandy P.
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      • Lin R.
      Lin. Population pharmacokinetics of doripenem based on data from phase 1 studies with healthy volunteers and phase 2 and 3 studies with critically ill patients.

      2.4 Monte Carlo Simulation

      Pharmacodynamic/pharmacokinetic analysis was conducted via a 10,000-subject Monte Carlo simulation (Crystal Ball 2010 v.2.2; Decisioneering Inc., Denver, CO) for IV dosage regimens of fosfomycin and carbapenems to calculate %T> MIC based on the linear pharmacokinetic behavior of each agent. Log-normal distributions were evaluated for between-patient variability. The probability of target attainment (PTA) was calculated as the percentage of all 10,000 estimates that had a probability of attaining 40% T>MIC for carbarpenems and 70% T>MIC for fosfomycin, either used alone or in combination. The cumulative fraction of response (CFR) was calculated as the proportion of %PTA of each MIC according to the MIC distribution. The PTA and CFR ≥ 90% was considered optimal against a bacterial population, whereas a CFR between 80% and 90% was associated with moderate probabilities of success.
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      • Preston S.L.
      • Hardalo C.
      • Hare R.
      • Banfield C.
      • Andes D.
      • et al.
      Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint.
      • Bradley J.S.
      • Dudley M.N.
      • Drusano G.L.
      Predicting efficacy of antiinfectives with pharmacodynamics and Monte Carlo simulation.

      3. Results

      MDR-PA had MIC90 >1,024 μg/ml for fosfomycin monotherapy, 1,024 μg/ml for fosfomycin combined with carbapenems, >32 μg/ml for carbapenems monotherapy, and 32 μg/ml for carbapenems combined with fosfomycin (Table 1). While, MIC90 for non-MDR PA were 512 μg/ml for fosfomycin monotherapy, 128 μg/ml for fosfomycin combined with carbapenems, >32 μg/ml, 8 μg/ml and 4 μg/ml for imipenem, meropenem, and doripenem monotherapy, respectively. For carbapenem combination, MIC90 were 12 μg/ml for imipenem combined with fosfomycin, 3 μg/ml for meropenem combined with fosfomycin and 2 μg/ml for doripenem combined with fosfomycin, respectively. The doripenem combination with fosfomycin had a MICs lower than the other carbapenems (Figure 1). Approximately 40% of non-MDR-PA was carbapenem-resistant PA (CRPA).
      Table 1MICs of non-MDR PA and MDR PA isolates against tested agents, mono drugs and combination drugs.
      Antimicrobial agentAntimicrobial mono and combination drugsNon-MDRMDR#
      MIC range (μg/ml)MIC90 (μg/ml)MIC90 Of CRPA* (μg/ml)MIC range (μg/ml)MIC90 (μg/ml)
      Imipenemmonodrug0.75 - >32>32>321.0->32>32
      IPM + FOF0.047 - > 3212120.38-3232
      Meropenemmonodrug0.016 - >328>321.0->32>32
      MEM + FOF0.006 - 32360.38-3232
      Doripenemmonodrug0.023 - >32460.5->32>32
      DOM + FOF0.006 - >48220.38-3232
      Fosfomycinmonodrug1.5 - >1024512>10248.0 - >1024>1024
      FOF + IPM1.0 - 10241281928.0 - 10241024
      FOF + MEM0.75 - 10241281928.0 - 10241024
      FOF + DOM0.064 -10241281288.0 - 10241024
      MDR= multidrug resistance, MICs=minimum inhibitory concentrations (μg/ml), PA=P.aeroginosa, CRPA= carbapenem-resistant P.aeroginosa, FOF = fosfomycin, DOM=doripenem, IPM=imipenem, MEM=meropenem., *= 40% of CRPA in non-MDR isolates, The susceptibility breakpoint MIC for carbapenems is less than 2 ug/ml. # The MDR isolates was defined as resistance at least three different antibiotic groups: beta-lactams (penicillin, cephalosporin or carbapenems (except monobactam e.g. aztreonam), aminoglycosides and fluoroquinolones.
      Figure thumbnail gr1
      Figure 1Minimum inhibitory concentrations (MICs) distribution of drugs in combination for carbapenem-resistant P.aeroginosa (CRPA), FOF = fosfomycin, DOM=doripenem, IPM=imipenem, MEM=meropenem, doripenem combination with fosfomycin had MICs lower than the other carbapenems. MIC90 of fosfomycin in CRPA was 128 μg/ml and MIC50 was 48 μg/ml.
      A combination of fosfomycin and carbapenems decreases the MIC of CRPA. Doripenem alone has an MIC90 of 6 mg/ml, and fosfomycin alone has an MIC90 of 1024 μg/ml, whereas the combination of fosfomycin with doripenem decreases the MIC90 of doripenem to 2 μg/ml and fosfomycin to 128 μg/ml.(Table 1).

      3.1 %PTA of fosfomycin monotherapy

      Analyses of various fosfomycin regimens to test %PTA against MICs of PA for the fosfomycin monotherapy are shown in Figure 2. All fosfomycin dosage regimens achieved more than 90% PTA at MIC < 3 μg/ml. Prolonged and continuous infusions have been shown to improve PK/PD exposure compared to dosage regimens using traditional 30-minute infusions. At the susceptibility breakpoint (MIC < 32 μg/ml) from the European Committee on Antimicrobial Susceptibility Testing (EUCAST), fosfomycin 4 g every 8 hr or more dose achieved above 90% PTA. For MIC 64 μg/ml, fosfomycin 4 g every 4 hr or more dose or prolonged infusion achieved above 90% PTA. No fosfomycin monotherapy regimens were able to achieve PK/PD targets for MIC90 512 and >1024 μg/ml for non-MDR-PA and MDR-PA, respectively.
      Figure thumbnail gr2
      Figure 2The probability of target attainment (%PTA) of fosfomycin monotherapy achieve more than 70% time above MIC.

      3.2 %PTA of fosfomycin combination with carbapenem

      The %PTA in each combination of fosfomycin and carbapenem which achieved more than 70% T>MIC90 and 40% T>MIC90, respectively, for non-MDR PA, are summarized in table 2. For MDR-PA, all fosfomycin combinations, with carbapenems, could not achieve the PK/PD targets. For non-MDR PA, fosfomycin 16 g continuous infusion combined with meropenem 1- 2 g, 3-hour infusion every 8 hours and doripenem 1 g, 4-hour infusion every 8 hours achieved approximately 80% for MIC90 128 μg/ml of fosfomycin, 3 μg/ml for meropenem and 2 μg/ml doripenem (table 2). The highest dose of fosfomycin, 8 g every 8 hours infusion over 6 hours in combination with high-dose meropenem or doripenem prolonged infusion can achieve better than 95% PTA. Imipenem combined with fosfomycin achieved the PK/PD target at MIC90 of non-MDR PA of less than 70%.
      Table 2The maximum of %PTA for fosfomycin (FOF) achive more than 70% time above MIC90 and carbapenem (doripenem (DOM), imipenem (IPM), meropenem (MEM)) 40% time above MIC90 of non MDR-PA
      fosfomycin combined with carbapenems had MIC90 12μg/ml for imipenem combined with fosfomycin, 3μg/ml for meropenem combined with fosfomycin and 2μg/ml for doripenem combined with fosfomycin and 128μg/ml for fosfomycin combined with carbapenems # The PTA ≥ 90% was considered optimal against a bacterial population, whereas a PTA between 80% and 90% was associated with moderate probabilities of success.
      when combinations.
      %PTA of combinationsIPM

      1 g q 8 h
      IPM

      1 g in 3 h q 8 h
      DOM

      1 g q 8 h
      DOM

      1 g in 4 h q 8 h
      MEM

      1 g q 8 h
      MEM

      1 g in 3 h q 8 h
      MEM

      2 g q 8 h
      MEM

      2 g in 3 h q 8 h
      FOF 4 g q 12 h00000000
      FOF 8 g q 12 h00000000
      FOF 4 g q 8 h12233333
      FOF 4 g q 6 h1123232424242424
      FOF 8 g q 8 h3030494949495050
      FOF 16 g

      continuous infusion
      3233778080808080
      FOF 8 g in 6 h

      q 8 h
      3435939595969696
      * fosfomycin combined with carbapenems had MIC90 12 μg/ml for imipenem combined with fosfomycin, 3 μg/ml for meropenem combined with fosfomycin and 2 μg/ml for doripenem combined with fosfomycin and 128 μg/ml for fosfomycin combined with carbapenems# The PTA ≥ 90% was considered optimal against a bacterial population, whereas a PTA between 80% and 90% was associated with moderate probabilities of success.
      Considering the CRPA subgroup, fosfomycin 16 g continuous infusion combined with doripenem 1 g, 4-hour infusion every 8 hours achieved approximately 80% of PTA for MIC90
      (128 μg/ml of fosfomycin, 2 μg/ml of doripenem) and combined with meropenem 2 g, 3-hour infusion every 8 hours, or Imipenem higher dose prolonged infusion, achieved the PK/PD target at MIC90 of CRPA less than 50% PTA. The highest dose of fosfomycin, 8 g every 8 hours infusion over 6 hours in combination with doripenem prolonged infusion, can achieve better than 95% PTA. High-dose meropenem prolonged infusion in combination with the highest dose of fosfomycin, 8 g every 8 hours infusion over 6 hours, achieved better than 65% PTA at MIC90 of CRPA (192 μg/ml of fosfomycin, 6 μg/ml of meropenem). For PTA of more than 90% of meropenem in combination with fosfomycin, the dosage should be fosfomycin, 8 g every 8 hours infusion over 6 hours in combination with meropenem 2 g every 8 hr prolonged infusion at MIC90 less than 128 μg/ml of fosfomycin and less than 6 μg/ml for meropenem. All Imipenem regimen combinations with the highest dose of fosfomycin, 8 g every 8 hours infusion over 6 hours achieved less than 50% PTA at MIC90 of CRPA combination.

      3.3 %CFR of fosfomycin combination with carbapenem

      For non-MDR PA, fosfomycin 16 g continuous infusion combined with prolonged infusion of meropenem (1-2 g infusion over 3 hours every 8 hours) and doripenem (1 g infusion over 4 hours every 8 hours) achieved CFR of more than 88% (Table 3). The CFR was more than 90% with fosfomycin 8 g prolonged infusion (at least 6 hours) every 8 hours combined with high-dose prolonged infusion of meropenem or doripenem. However, PK/PD targets of %CFR for MDR-PA strains were not achieved for any fosfomycin-carbapenem combinations.
      Table 3%CFR of fosfomycin(FOF) - carbapenems combination regimens ((doripenem (DOM), imipenem (IPM), meropenem (MEM)) of non-MDR PA.
      %CFR of combinationsIPM 1 g q 8 hIPM 1 g in 3 h q 8 hDOM 1 g q 8 hDOM 1 g in 4 h q 8 hMEM 1 g q 8 hMEM 1 g in 3 h q 8 hMEM 2 g q 8 hMEM 2 g in 3 h q 8 h
      FOF 4 g q 12 h1922222321212121
      FOF 8 g q 12 h1113121312121212
      FOF 4 g q 8 h4953515151525252
      FOF 4 g q 6 h6574697275757576
      FOF 8 g q 8 h7072768082828383
      FOF 16 g continuous infusion7172838888888888
      FOF 8 g in 6 h q 8 h7576879389929393
      #The CFR ≥ 90% was considered optimal against a bacterial population, whereas a CFR between 80% and 90% was associated with moderate probabilities of success.
      For the CRPA subgroup, fosfomycin 16 g continuous infusion combined with doripenem 1 g, 4-hour infusion every 8 hours or meropenem 2 g, 3-hour infusion every 8 hours achieved approximately 80% CFR. The highest dose of fosfomycin, 8 g every 8 hours infusion over 6 hours in combination with doripenem high dose prolonged infusion can achieve approximately 90%CFR and with high-dose meropenem (2 g, 3-hour infusion every 8 hours prolonged infusion) achieve above 85%CFR. The combination of fosfomycin with imipenem achieved less than 50% CFR.

      4. Discussion

      P. aeruginosa infections are likely to affect critically ill patients who require intensive care and treatment with antimicrobial agents. ICUs have a high prevalence of P. aeruginosa and the placement of several invasive devices introduces multiple opportunities for failure of infection control, resulting in ICUs being under considerable pressure to select broad-spectrum antibiotics.
      • Giesecke M.T.
      • Schwabe P.
      • Wichlas F.
      • Trampuz A.
      • Kleber C.
      Impact of high prevalence of pseudomonas and polymicrobial gram-negative infections in major sub-/total traumatic amputations on empiric antimicrobial therapy: a retrospective study.
      • Álvarez-Lerma F.
      • Grau S.
      Management of Antimicrobial Use in the Intensive Care Unit.
      • Aloush V.
      • Navon-Venezia S.
      • Seigman-Igra Y.
      • Cabili S.
      • Carmeli Y.
      Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact.
      The PK of antimicrobial agents in critically ill patients varies especially in volume of distribution (Vd) and clearance (CL), which may affect the drug concentration at the target sites.
      • Scaglione F.
      • Paraboni L.
      Pharmacokinetics/pharmacodynamics of antibacterials in the Intensive Care Unit: setting appropriate dosing regimens.
      Thus, our study chose published phamacokinetic studies of critically ill patients. Knowing the PK/PD properties of the drugs used for the management of critically ill patients is essential for selecting the appropriate dosage regimens, which will finally optimize patient outcomes.
      • Chant C.
      • Leung A.
      • Friedrich J.O.
      Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis.
      Fosfomycin inhibits uridine diphosphate-N-acetylglucosamine enolpyruvyl transferase, which is a key enzyme in early bacterial cell-wall synthesis steps.
      • Popovic M.
      • Steinort D.
      • Pillai S.
      • Joukhadar C.
      Fosfomycin: an old, new friend?.
      The MICs of fosfomycin for P. aeruginosa in our study were within the range of 1.5 - >1024 μg/ml which were higher than the range indicated in other studies (1-512 μg/ml).
      • Walsh C.C.
      • McIntosh M.P.
      • Peleg A.Y.
      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
      In our study, the MIC90 for non-MDR PA (512 μg/ml) and MDR-PA (>1024 μg/ml) were higher than those in other studies (128 and 512 μg/ml for non-MDR PA and MDR-PA, respectively).
      • Falagas M.E.
      • Kastoris A.C.
      • Karageorgopoulos D.E.
      • Rafailidis P.I.
      Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies.
      • Michalopoulos A.S.
      • Livaditis I.G.
      • Gougoutas V.
      The revival of fosfomycin.
      • Walsh C.C.
      • McIntosh M.P.
      • Peleg A.Y.
      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
      • Popovic M.
      • Steinort D.
      • Pillai S.
      • Joukhadar C.
      Fosfomycin: an old, new friend?.
      However, a study in a teaching hospital in Thailand showed similar results to our study. That study reported MICs in the range 2->1024 μg/ml and MIC90 of > 1024 μg/ml.
      • Hortiwakul T.
      • Chayakul P.
      • Ingviya N.
      • Chayakul V.
      In Vitro Activity of Colistin, Fosfomycin, and Piperacillin/tazobactam Against Acinetobacter baumannii and Pseudomonas aeruginosa in Songklanagarind Hospital, Thailand.
      Therefore, we make the point that the teaching hospital showing a higher MIC than a general hospital, as indicated in that previous study, might be due to the high antimicrobial consumption rate in the teaching hospital.
      • Roberts R.R.
      • Hota B.
      • Ahmad I.
      • Scott 2nd, R.D.
      • Foster S.D.
      • et al.
      Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship.
      Our study had 40% of CRPA indicating a high prevalence of carbapenem-non susceptible P. aeruginosa in this teaching hospital. Therefore, monotherapy of fosfomycin in our study could not achieve the target indicated above. However, the combination of fosfomycin and carbapenem in our study showed decreased MICs of PA for both drugs. In the CRPA subgroup in our study, the combination of fosfomycin and doripenem decreased the MIC of the doripenem to 2 mg/ml, and the fosfomycin in combination with meropenem decreased the MIC of meropenem by more than a third (table 1). This was similar to an in vitro combination study which found that fosfomycin combined with carbapems decreased the MIC of both drugs together in combination.
      • Samonis G.
      • Maraki S.
      • Karageorgopoulos D.E.
      • Vouloumanou E.K.
      • Falagas M.E.
      Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates.
      PD studies of fosfomycin show a time-dependent killing effect on Staphylococcus aureus and P. aeroginosa. In contrast, its effectiveness in killing Escherichia coli or Proteus mirabilis is concentration- dependent activity.
      • Michalopoulos A.S.
      • Livaditis I.G.
      • Gougoutas V.
      The revival of fosfomycin.
      • MacLeod D.L.
      • Velayudhan J.
      • Kenney T.F.
      • Therrien J.H.
      • Sutherland J.L.
      • Barker L.M.
      • et al.
      Fosfomycin enhances the active transport of tobramycin in Pseudomonas aeruginosa.
      • Walsh C.C.
      • McIntosh M.P.
      • Peleg A.Y.
      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
      Thus, the most predictive PK/PD parameter of fosfomycin for P. aeruginosa eradication is the time that the drug is present in the blood at or above the minimum inhibitory concentration (T>MIC).
      • MacLeod D.L.
      • Velayudhan J.
      • Kenney T.F.
      • Therrien J.H.
      • Sutherland J.L.
      • Barker L.M.
      • et al.
      Fosfomycin enhances the active transport of tobramycin in Pseudomonas aeruginosa.
      • Turnidge J.D.
      The pharmacodynamics of beta-lactams.
      • Walsh C.C.
      • McIntosh M.P.
      • Peleg A.Y.
      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
      The PK/PD targets in this study were chosen for their propensity to achieve the greatest %PTA and %CFR of 70% T>MIC for fosfomycin. However, these targets were determined based on limited information. Basically, effective dosage regimens for all time-dependent antimicrobials require serum drug concentrations exceeding the MIC of the causative pathogen for at least 40 to 70% of the dosing interval in the immunocompetent host,
      • Craig W.A.
      Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins.
      • Drusano G.L.
      Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’.
      • Yuan Z.
      • Ledesma K.R.
      • Singh R.
      • Hou J.
      • Prince R.A.
      • Tam V.H.
      Quantitative assessment of combination antimicrobial therapy against multidrug-resistant bacteria in a murine pneumonia model.
      although %T>MIC of 70 - 100% is required in difficult-to-treat infections and/or in cases with neutropenia.
      • Scaglione F.
      • Paraboni L.
      Pharmacokinetics/pharmacodynamics of antibacterials in the Intensive Care Unit: setting appropriate dosing regimens.
      • Craig W.A.
      Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins.
      • Drusano G.L.
      Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’.
      These compounds which have the ability to inhibit bacterial cell wall synthesis may be shared with fosfomycin. As well, fosfomycin has a PAE of approximately 0.3-5.5 hours for P. aeruginosa.
      • Walsh C.C.
      • McIntosh M.P.
      • Peleg A.Y.
      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
      Thus, 70% - 100% of the time above MIC could be appropriate for fosfomycin in the treatment of P. aeruginosa in critically ill patients. In addition, there is clear evidence suggesting that carbapenems require a PK/PD target of 40% T>MIC for the treatment of gram-negative infection in critically ill patients.
      • Turnidge J.D.
      The pharmacodynamics of beta-lactams.
      • Walsh C.C.
      • McIntosh M.P.
      • Peleg A.Y.
      • Kirkpatrick C.M.
      • Bergen P.J.
      In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa.
      • Asín-Prieto E.
      • Rodríguez-Gascón A.
      • Isla A.
      Applications of the pharmacokinetic/pharmacodynamics (PK/PD) analysis of antimicrobial agents.
      For the combination model in our study, we calculated two achievable treatment targets for each patient. First, the 70 - 100% T>MIC of fosfomycin, and second, the PK/PD target of 40% T>MIC for carbapenems. This approach taken in our study has been described in published PK/PD combination model studies.
      • Yuan Z.
      • Ledesma K.R.
      • Singh R.
      • Hou J.
      • Prince R.A.
      • Tam V.H.
      Quantitative assessment of combination antimicrobial therapy against multidrug-resistant bacteria in a murine pneumonia model.
      In our Monte Carlo simulation, we tested both the maximum recommended dose of fosfomycin monotherapy, which is 16 g/day, and also the highest dose of 24 g/day with prolonged or continuous infusion. These simulations were carried out on both non-MDR PA and MDR PA samples. We found that for monotherapy of fosfomycin, neither dosages achieved 80-90% of CFR or PTA in either non-MDR PA or MDR PA. Likewise, other PK studies of fosfomycin in critically ill patients have shown that IV 8 g every 8 hours, with a mean of Cmax 307 ± 101 μg/ml,
      • Pfausler B.
      • Spiss H.
      • Dittrich P.
      • Zeitlinger M.
      • Schmutzhard E.
      • Joukhadar C.
      Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis.
      could not achieve the PK/PD target at MIC90 (> 1024 μg/ml) when applied to all PA groups in our study. The reason is a higher MIC90 of all PA in our study as we discussed above.
      However, our study of the combination of fosfomycin with carbapenems in non-MDR PA found that 8 g of fosfomycin given every 8 hours for prolonged infusion over 6 hours in combination with carbapenems showed %PTA or %CFR more than 90%. Fortunately, in CRPA,
      the combination of high dose prolonged infusion fosfomycin and doripenem showed greater than 95% PTA at MIC90 and approximately 90% CFR. Meropenem in combination with fosfomycin in the CRPA group had 85% CFR but 65% PTA at MIC90. However, 90% PTA of high dose prolonged infusion fosfomycin and meropenem can achieve at MIC90 less than 128 μg/ml of fosfomycin and less than 6 μg/ml for meropenem. Fosfomycin in combination with imipenem achieved %PTA and %CFR less than 50% at very high MIC90 of imipenem for PA in our study. Thus, empirical therapy for treating PA with area high MIC (less than 128 μg/ml) can use high dose prolonged infusion of fosfomycin and doripenem and a more specific therapy of high dose prolonged infusion of either fosfomycin in combination with doripenem or fosfomycin in combination with meropenem. Our results are similar to those of other PK studies, which calculated that the steady state average concentration (Cssave) of fosfomycin 8 g IV every 8 hours (24 g/day) was 184 μg/ml in the abscess fluid.
      • Sauermann R.
      • Karch R.
      • Langenberger H.
      • Kettenbach J.
      • Mayer-Helm B.
      • Petsch M.
      • et al.
      Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles.
      This level was more than the MIC90 (128 μg/ml) in non-MDR PA and CRPA of fosfomycin combined with carbapenems in our study.
      Although 24 g/day of fosfomycin in combination might be promising, this high dose may cause adverse side effects. The reported adverse effects from IV fosfomycin in a clinical trial
      • Florent A.
      • Chichmanian R.M.
      • Cua E.
      • Pulcini C.
      Adverse events associated with intravenous fosfomycin.
      were hypokalemia (26%), followed by pain at the injection site (4%) and heart failure or hypertension (3%). However, some small clinical studies of high dose fosfomycin (24 g) did not show those side effects.
      • Pontikis K.
      • Karaiskos I.
      • Bastani S.
      • Dimopoulos G.
      • Kalogirou M.
      • Katsiari M.
      • et al.
      Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria.
      Alternatively, continuous fosfomycin 16 g infusion combination with doripenem 1 g with 4- hour infusion every 8 hours had 80%PTA at MIC90 (128 μg/ml) of non-MDR PA or CRPA and CFR was more than 88% at MIC90 and 80% at MIC90 respectively. Thus, this regimen might be an option for combination therapy when empirically or specifically treating PA with high MIC (less than 128 μg/ml). However, the loading dose of fosfomycin needed in a continuous infusion regimen will apply. Clinical data suggests that prolonged infusions of beta-lactams are effective for gram-negative infections treatment. Meta-analysis studies have found that prolonged infusions of piperacillin-tazobactam in critically ill patients were associated with a mortality benefit compared with intermittent infusions.
      • Roberts J.A.
      • Kirkpatrick C.M.
      • Lipman J.
      Monte Carlo simulations: maximizing antibiotic pharmacokinetic data to optimize clinical practice for critically ill patients.
      • Lodise Jr., T.P.
      • Lomaestro B.
      • Rodvold K.A.
      • Danziger L.H.
      • Drusano G.L.
      Pharmacodynamic profiling of piperacillin in the presence of tazobactam in patients through the use of population pharmacokinetic models and Monte Carlo simulation.
      • Lodise Jr., T.P.
      • Lomaestro B.
      • Drusano G.L.
      Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy.
      • Yang H.
      • Zhang C.
      • Zhou Q.
      • Wang Y.
      • Chen L.
      Clinical outcomes with alternative dosing strategies for piperacillin/tazobactam: a systematic review and meta-analysis.
      Our Monte Carlo simulation for monotherapy of fosfomycin might be effective regimen guides (figure 1) when we only know the MIC of fosfomycin before combinations. A PTA of more than 80 - 90% at MIC less than 32 μg/ml (EUCAST ‘s susceptibility breakpoint of fosfomycin for P.aeruginosa

      European Committee on Antimicrobial Susceptibility Testing (EUCAST). http://www.eucast.org/clinical_breakpoints/.[accessed 19 Feb 2016].

      ) was achieved by fosfomycin monotherapy of 4 g IV every 8 hours, 8 g IV every 12 hours or higher dose. This is similar to the result from a PK study which showed fosfomycin 8 g IV every 12 hours could achieve a MIC less than 32 μg/ml.
      • Joukhadar C.
      • Klein N.
      • Dittrich P.
      • Zeitlinger M.
      • Geppert A.
      • Skhirtladze K.
      • et al.
      Target site penetration of fosfomycin in critically ill patients.
      Limitations of this study are as follows. First, we did not simulate the drug level in renally-impaired patients. These patients usually have a high level of drug concentration in the blood which would lower the dosage requirements.
      • Roberts J.A.
      • Kirkpatrick C.M.
      • Lipman J.
      Monte Carlo simulations: maximizing antibiotic pharmacokinetic data to optimize clinical practice for critically ill patients.
      • Crandon J.L.
      • Ariano R.E.
      • Zelenitsky S.A.
      • Nicasio A.M.
      • Kuti J.L.
      • Nicolau D.P.
      Optimization of meropenem dosage in the critically ill population based on renal function.
      Second, the isolates of the P. aeruginosa were from MIC distributions at the University Hospital, Bangkok, which might be different from those taken from other hospitals or in other countries. These are factors which may well affect the antimicrobial combination of the dose based on the CFR results.
      • Asín-Prieto E.
      • Rodríguez-Gascón A.
      • Isla A.
      Applications of the pharmacokinetic/pharmacodynamics (PK/PD) analysis of antimicrobial agents.
      Third, the one compartment model used to simulate the fosfomycin level in our study is different from the two compartment model in a recently published article.
      • Parker S.L.
      • Frantzeskaki F.
      • Wallis S.C.
      • Diakaki C.
      • Giamarellou H.
      • Koulenti D.
      • et al.
      Population Pharmacokinetics of Fosfomycin in Critically Ill Patients.
      Nonetheless, for the purpose of calculating T>MIC, there should not be a great difference between these two models. Fourth, our simulation was based on plasma phamacokinetics and not on tissue pharmacokinetics. However, fosfomycin has good penetration to tissue, almost entirely unbound to proteins. Several investigations in vivo have confirmed the achievement of a complete concentration equilibrium between plasma and in-tissue fluid shortly after administration. Similarly, PK studies on many tissue levels (skin, urine, lung) showed little difference in plasma.
      • Matzi V.
      • Lindenmann J.
      • Porubsky C.
      • Kugler S.A.
      • Maier A.
      • Dittrich P.
      • et al.
      Extracellular concentrations of fosfomycin in lung tissue of septic patients.
      • Sauermann R.
      • Karch R.
      • Langenberger H.
      • Kettenbach J.
      • Mayer-Helm B.
      • Petsch M.
      • et al.
      Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles.
      • Roussos N.
      • Karageorgopoulos D.E.
      • Samonis G.
      • Falagas M.E.
      Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections.
      Therefore, our results might be applicable to those sites of infection. Fifth, fosfomycin PK/PD targets were determined based on limited information but we chose by considering the most important information about compounds which have the ability to inhibit bacterial cell wall synthesis.
      • Scaglione F.
      • Paraboni L.
      Pharmacokinetics/pharmacodynamics of antibacterials in the Intensive Care Unit: setting appropriate dosing regimens.
      • Craig W.A.
      Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins.
      • Paul M.
      • Carmeli Y.
      • Durante-Mangoni E.
      • Mouton J.W.
      • Tacconelli E.
      • Theuretzbacher U.
      • et al.
      Combination therapy for carbapenem-resistant Gram-negative bacteria.
      Finally, during the period of our study we could not find a previous population PK study of fosfomycin, thus, we chose a PK study of fosfomycin in critically ill patients.

      5. Conclusion

      The PTA and CFR ≥80- 90% were considered optimal against a bacterial population. Any monotherapy or combination of fosfomycin regimen achieved this target for both of our MDR groups. fosfomycin in combination with imipenem did not achieve this target in any of our PA groups. However, The combination of fosfomycin with doripenem achieved the target especially in CRPA. Fosfomycin in combination with meropem achieved the target, shown only by the CFR result. Therefore, it is suggested that 8 g IV every 8 hours with prolonged infusion of more than 6 hours combination with doripenem 1 g infused 4 hours every 8 hours can be used for non-MDR PA with CRPA with empirical therapy. Optionally, a regimen of continuous fosfomycin 16 g infusion in combination with doripenem could be used. For specific treatment, high dose prolonged infusion of fosfomycin in combination with high dose prolong infusion of meropenem or doripenem (MIC90 of combination less than 128 μg/ml for fosfomycin and less than 6 μg/ml for meropenem and less than 2 μg/ml for doripenem) may be necessary.

      Acknowledgements

      Many thanks to Mr. Roy Morien of the Naresuan University Language Centre for his editing assistance and advice on English expression in this document.
      Conflict of Interest: None
      Funding: None

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