scholarly journals Optimal Piperacillin-Tazobactam Dosing Strategies against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

2018 ◽  
Vol 63 (2) ◽  
pp. e01906-18 ◽  
Author(s):  
Henrietta Abodakpi ◽  
Kai-Tai Chang ◽  
Song Gao ◽  
Ana María Sánchez-Díaz ◽  
Rafael Cantón ◽  
...  
Keyword(s):  
Growth Suppression ◽  
Maximum Effect ◽  
Infection Model ◽  
Experimental Exposure ◽  
Content Type ◽  
Reference Isolate ◽  
Extended Spectrum ◽  
Optimal Dosing ◽  
Drug Concentrations ◽  
Dosing Strategies

ABSTRACT Piperacillin-tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae. However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin-tazobactam to efficacy, using a modified pharmacokinetic/pharmacodynamic index. Using a clinical Klebsiella pneumoniae isolate expressing CTX-M-15, piperacillin MIC values were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory maximum effect (Emax) model. A hollow-fiber infection model (HFIM) was used to evaluate the efficacy of escalating tazobactam dosing with a fixed piperacillin exposure. Simulated drug concentrations from the HFIM were incorporated in the Emax model to determine the percentage of free time above instantaneous MIC (%fT>MICi) associated with each experimental exposure. The target %fT>MICi associated with growth suppression was prospectively validated using an SHV-12-producing isolate of Escherichia coli and 2 other CTX-M-15-producing K. pneumoniae isolates. Based on our reference isolate, piperacillin-tazobactam exposures of %fT>MICi of ≥55.1% were associated with growth suppression. Despite underlying differences, these findings were consistent with prospective observations in 3 other clinical isolates. Our modeling approach can be applied relatively easily in the clinical setting, and it appeared to be robust in predicting the effectiveness of various piperacillin-tazobactam exposures. This modified pharmacokinetic/pharmacodynamic index could be used to characterize response to other β-lactam/β-lactamase inhibitor combinations.

scholarly journals In VivoEfficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae

2011 ◽  
Vol 55 (7) ◽  
pp. 3220-3225 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Jared L. Crandon ◽  
Guilherme H. Furtado ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Immune Status ◽  
Free Drug ◽  
Infection Model ◽  
The Novel ◽  
Immunocompetent Host ◽  
Content Type ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibitsin vitroactivity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producingEnterobacteriaceaewhen combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 againstEnterobacteriaceaein a murine thigh infection model.IMPORTANCETwelveEnterobacteriaceaeisolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log10CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistantEnterobacteriaceae.

scholarly journals Human Simulated Studies of Aztreonam and Aztreonam-Avibactam To Evaluate Activity against Challenging Gram-Negative Organisms, Including Metallo-β-Lactamase Producers

2013 ◽  
Vol 57 (7) ◽  
pp. 3299-3306 ◽  
Author(s):  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Free Drug ◽  
Bacterial Density ◽  
Infection Model ◽  
Bacterial Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Drug Concentrations ◽  
Gram Negative Organisms ◽  
The Stability ◽  
Immunocompetent Mice

ABSTRACTSecondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum β-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-β-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14Enterobacteriaceaeand 13Pseudomonas aeruginosaisolates, of which 25 produced metallo-β-lactamases. Additionally, sixP. aeruginosaisolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of theEnterobacteriaceaebacterial isolates (aztreonam MIC, ≤32 μg/ml;fT>MIC, ≥38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥128 μg/ml;fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14Enterobacteriaceaeisolates (aztreonam-avibactam MICs, ≤16 μg/ml;fT>MIC, ≥65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity againstP. aeruginosawas noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤16 μg/ml and variable efficacy noted when the MICs were ≥32 μg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.

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 Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Maria Goul Andersen ◽  
Anders Thorsted ◽  
Merete Storgaard ◽  
Anders N. Kristoffersson ◽  
Lena E. Friberg ◽  
...  
Keyword(s):  
Free Drug ◽  
Free Drug Concentration ◽  
Total Clearance ◽  
Prolonged Infusion ◽  
Target Attainment ◽  
Content Type ◽  
Optimal Dosing ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Antibiotic Dosing

ABSTRACTSufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC forPseudomonas aeruginosa(16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR(>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50%fTMIC) and 0.125 mg/liter (100%fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

scholarly journals In VivoPharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Streptococcus suis Serotype 2 at Varied Initial Inoculum Sizes

2015 ◽  
Vol 60 (2) ◽  
pp. 1114-1120 ◽  
Author(s):  
Chunna Guo ◽  
Xiaoping Liao ◽  
Mingru Wang ◽  
Feng Wang ◽  
Chaoqun Yan ◽  
...  
Keyword(s):  
Severe Disease ◽  
Streptococcus Suis ◽  
Dose Fractionation ◽  
Fourth Generation ◽  
Maximum Effect ◽  
Infection Model ◽  
Human Beings ◽  
Content Type

ABSTRACTStreptococcus suisserotype 2 is an emerging zoonotic pathogen and causes severe disease in both pigs and human beings. Cefquinome (CEQ), a fourth-generation cephalosporin, exhibits broad-spectrum activity against Gram-positive bacteria such asS. suis. This study evaluated thein vitroandin vivoantimicrobial activities of CEQ against four strains ofS. suisserotype 2 in a murine neutropenic thigh infection model. We investigated the effect of varied inoculum sizes (106to 108CFU/thigh) on the pharmacokinetic (PK)/pharmacodynamic (PD) indices and magnitudes of a particular PK/PD index or dose required for efficacy. Dose fractionation studies included total CEQ doses ranging from 0.625 to 640 mg/kg/24 h. Data were analyzed via a maximum effect (Emax) model using nonlinear regression. The PK/PD studies demonstrated that the percentage of time that serum drug levels were above the MIC of free drug (%ƒT>MIC) in a 24-h dosing interval was the primary index driving the efficacy of both inoculum sizes (R2= 91% andR2= 63%). CEQ doses of 2.5 and 40 mg/kg body weight produced prolonged postantibiotic effects (PAEs) of 2.45 to 8.55 h. Inoculum sizes had a significant influence on CEQ efficacy. Compared to the CEQ exposure and dosages in tests using standard inocula, a 4-fold dose (P= 0.006) and a 2-fold exposure time (P= 0.01) were required for a 1-log kill using large inocula of 108CFU/thigh.

scholarly journals Efficacy of Ceftaroline Fosamil in a Staphylococcal Murine Pneumonia Model

2012 ◽  
Vol 56 (12) ◽  
pp. 6160-6165 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Jared L. Crandon ◽  
Donald Biek ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Infection Model ◽  
Ceftaroline Fosamil ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Human Dose ◽  
Drug Concentrations ◽  
Exposure Profile ◽  
Dose Ranging ◽  
Relationship Of

ABSTRACTCeftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistantStaphylococcus aureus(MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil againstS. aureusin an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. SeventeenS. aureus(2 methicillin-susceptibleStaphylococcus aureus[MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. SerumfT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log10kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log10CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, thefT>MICs required for stasis and a 1-log10kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serumfT>MIC targets required in this lung infection model were similar to those observed with ceftaroline againstS. aureusin a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.

scholarly journals Identification of the In Vivo Pharmacokinetics and Pharmacodynamic Driver of Iclaprim

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Jee Hyun Park ◽  
William Craig ◽  
Karen Marchillo ◽  
David B. Huang ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Area Under The Curve ◽  
Infection Model ◽  
Content Type ◽  
Drug Concentrations ◽  
In Vivo Pharmacokinetics

ABSTRACT The neutropenic murine thigh infection model was used to define the pharmacokinetic/pharmacodynamic index linked to efficacy of iclaprim against Staphylococcus aureus ATCC 29213 and Staphylococcus pneumoniae ATCC 10813. The 24-h area under the curve (AUC)/MIC index was most closely linked to efficacy for S. aureus ( R 2 , 0.65), while both the 24-h AUC/MIC and the percentage of time that drug concentrations remain above the MIC (% T >MIC) were strongly associated with effect ( R 2 , 0.86 for both parameters) for S. pneumoniae .

scholarly journals Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3008-3012 ◽  
Author(s):  
Jing Wang ◽  
Qi Shan ◽  
Huanzhong Ding ◽  
Chaoping Liang ◽  
Zhenling Zeng
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Maximum Effect ◽  
Infection Model ◽  
Content Type ◽  
Chromatography Tandem Mass Spectrometry ◽  
Attractive Option ◽  
Liquid Chromatography Tandem Mass ◽  
Dosing Strategy

ABSTRACTCefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity againstStaphylococcus aureus. The objective of our study was to examine thein vivoactivity of cefquinome againstS. aureusstrains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).In vivopostantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected withS. aureusstrain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and producedin vivoPAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additionalS. aureusisolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %Tthat the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10CFU reduction from baseline, and a 1-log10CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused byS. aureus.

scholarly journals Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

2015 ◽  
Vol 59 (5) ◽  
pp. 2855-2866 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Roger J. M. Brüggemann ◽  
Jacques F. Meis ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Drug Exposure ◽  
Quantitative Relationship ◽  
Maximum Effect ◽  
Infection Model ◽  
Wild Type ◽  
Content Type ◽  
Type Isolate ◽  
Mouse Infection Model

ABSTRACTAzole resistance is an emerging problem inAspergillus fumigatuswhich translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. Thein vivoefficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg/kg of body weight/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg/kg/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinicalA. fumigatusisolates: a wild-type isolate (ISA MICEUCAST, 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in thecyp51Agene: G54W (ISA MICEUCAST, 0.5 mg/liter), M220I (ISA MICEUCAST, 4 mg/liter), and TR34/L98H (ISA MICEUCAST, 8 mg/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W mutant, and 256 mg/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR34/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC0–24/MICEUCASTratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC0–24/MIC) can be used to optimize the treatment of human infections byA. fumigatus, including strains with decreased susceptibility.

scholarly journals Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection

2015 ◽  
Vol 60 (1) ◽  
pp. 368-375 ◽  
Author(s):  
Johanna Berkhout ◽  
Maria J. Melchers ◽  
Anita C. van Mil ◽  
Seyedmojtaba Seyedmousavi ◽  
Claudia M. Lagarde ◽  
...  
Keyword(s):  
Lung Infection ◽  
Threshold Concentration ◽  
Lung Model ◽  
Dose Fractionation ◽  
Parameter Estimates ◽  
Content Type ◽  
Mean Values ◽  
Optimal Dosing ◽  
Drug Concentrations ◽  
Static Effect

ABSTRACTAvibactam is a new non-β-lactam β-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum β-lactamases (ESBLs) and carbapenemases such as KPCs, class C β-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistantPseudomonas aeruginosa, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first. Subsequently, the efficacy of adding avibactam every 2 h (q2h) or q8h to a fixed q2h dose of ceftazidime was determined in lung infection for two strains. Dosing avibactam q2h was significantly more efficacious, reducing the avibactam daily dose for static effect by factors of 2.7 and 10.1, whereas the mean percentage of the dosing interval that free drug concentrations remain above the threshold concentration of 1 mg/liter (%fT>CT1 mg/liter) yielding bacteriostasis was similar for both regimens, with mean values of 21.6 (q2h) and 18.5 (q8h). Dose fractionation studies of avibactam in both the thigh and lung models indicated that the effect of avibactam correlated well with %fT>CT1 mg/liter. This parameter of avibactam was further explored for fourP. aeruginosastrains in the lung model and six in the thigh model. Parameter estimates of %fT>CT1 mg/liter for avibactam ranged from 0 to 21.4% in the lung model and from 14.1 to 62.5% in the thigh model to achieve stasis. In conclusion, addition of avibactam enhanced the effect of ceftazidime, which was more pronounced at frequent dosing and well related with %fT>CT1 mg/liter. The thigh model appeared more stringent, with higher values, ranging up to 62.5%fT>CT1 mg/liter, required for a static effect.

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