In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

ABSTRACT The pharmacokinetic (PK)/pharmacodynamic (PD) parameters and the antibacterial activity of S-013420, a novel bicyclolide, against Haemophilus influenzae and Streptococcus pneumoniae, including macrolide-resistant isolates, were investigated using an in vitro PD model. Various time-concentration curves were artificially constructed by modifying the PK data obtained in phase I studies. The activity against H. influenzae was evaluated using two parameters, that is, the area above the killing curve (AAC) and the viable cell reduction at 24 h. The relationships between the antibacterial activity of S-013420 and the three PK/PD parameters were investigated by fitting the data to the sigmoid maximum effective concentration model. The square of the correlation coefficient (R 2) values for AAC versus the area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC, the peak concentration (C max)/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeded the MIC under steady-state PK conditions (%T MIC) were 0.92, 0.87, and 0.49, respectively. The R 2 values for viable cell reduction at 24 h versus AUC0-24/MIC, C max/MIC, and %T MIC were 0.93, 0.61, and 0.56, respectively. These results demonstrated that AUC0-24/MIC is the most significant parameter for evaluation of the antibacterial activity of S-013420. The values of AUC0-24/MIC required for maximum and static efficacy were 10.8 and 9.63, respectively, for H. influenzae and 16.3 to 22.3 and 4.66 to 9.01, respectively, for S. pneumoniae. This analysis is considered useful for determining the AUC value at the infection site, which would be required for efficacy in clinical use.

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Pharmacodynamic Assessment Based on Mutant Prevention Concentrations of Fluoroquinolones To Prevent the Emergence of Resistant Mutants of Streptococcus pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01372-06 ◽

2007 ◽

Vol 51 (11) ◽

pp. 3810-3815 ◽

Cited By ~ 23

Author(s):

Tomoyuki Homma ◽

Toshihiko Hori ◽

Giichi Sugimori ◽

Yoshinori Yamano

Keyword(s):

Streptococcus Pneumoniae ◽

Population Analysis ◽

Pharmacodynamic Model ◽

Time Curve ◽

Concentration Time ◽

Mutant Prevention Concentration ◽

Resistant Mutants ◽

The Relationship ◽

Concentration Curves

ABSTRACT The objective of this study was to investigate the relationship between pharmacokinetic and pharmacodynamic parameters, on the basis of the mutant prevention concentration (MPC) concept, and the emergence of resistant mutants of Streptococcus pneumoniae to fluoroquinolone antibacterials. Some clinical isolates with various MIC and MPC values of moxifloxacin and levofloxacin were exposed under conditions simulating the time-concentration curves observed when moxifloxacin (400 or 80 mg, once a day) or levofloxacin (200 mg, twice a day) was orally administered by using an in vitro pharmacodynamic model. The decrease in susceptibility was evaluated by altering the population analysis profiles after moxifloxacin or levofloxacin treatment for 72 h. When the area under the concentration-time curve from 0 to 24 h (AUC0-24)/MPC and peak concentration (C max)/MPC were above 13.41 and 1.20, respectively, complete eradication occurred and no decrease in susceptibility was observed. On the other hand, when AUC0-24/MPC and C max/MPC were below 0.84 and 0.08, respectively, the susceptibility decreased. However, the time inside the mutant selective window and the time above the MPC did not show any correlation with the decrease in susceptibility. These results suggest that AUC0-24/MPC and C max/MPC are important parameters for predicting the emergence of resistant mutants and that higher values indicate greater effectiveness.

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Evaluation of T-3811ME (BMS-284756), a New Des-F(6)-Quinolone, for Treatment of Meningitis Caused by Penicillin-Resistant Streptococcus pneumoniae in Rabbits

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.6.1760-1765.2002 ◽

2002 ◽

Vol 46 (6) ◽

pp. 1760-1765 ◽

Cited By ~ 2

Author(s):

Masahiro Takahata ◽

Hiroshi Yamada ◽

Teiichi Morita ◽

Shinichi Furubou ◽

Shinzaburo Minami ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Viable Cell ◽

Treated Group ◽

Dependent Manner ◽

Free Base ◽

Time Curve ◽

Gram Positive Bacteria ◽

Cell Counts ◽

Concentration Time ◽

Dose Dependent

ABSTRACT T-3811ME (BMS-284756) is a new des-F(6)-quinolone with high levels of activity against gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae (PRSP) strains. T-3811, the free base of T-3811ME, exhibited potent activity against 28 clinical strains of PRSP isolated clinically (MIC at which 90% of the isolates tested are inhibited, 0.0625 μg/ml). After the intravenous dosing of T-3811ME (20 mg/kg of body weight as T-3811) in rabbits with meningitis caused by PRSP, the area under the concentration-time curve (AUC) of T-3811 in cerebrospinal fluid (CSF) was 5.79 μg · h/ml and was 4.5-fold higher than that of T-3811in the CSF of rabbits without meningitis. In addition, the AUC/MIC for T-3811ME (20 mg/kg as T-3811) in CSF was 185, which was 4.3-fold higher than that for ceftriaxone (administered intravenously at 100 mg/kg). After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner. In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (P < 0.01). By histopathological evaluation, 6 h after the administration of T-3811ME (20 mg/kg as T-3811), the thickening of the cerebral meninx and the infiltration of neutrophils into the cerebral meninx were less severe in the treated group than in the nontreated group. T-3811ME (BMS-284756) may be expected to be evaluated for the management of meningitis caused by highly penicillin-resistant pneumococci.

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Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02265-19 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 2

Author(s):

Brian D. VanScoy ◽

Elizabeth A. Lakota ◽

Haley Conde ◽

Jennifer McCauley ◽

Lawrence Friedrich ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Antimicrobial Agents ◽

Nonlinear Least Squares ◽

Infection Model ◽

Least Squares Regression ◽

Total Drug ◽

Time Curve ◽

Content Type ◽

Concentration Time

ABSTRACT Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

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Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.8.2606-2614.2003 ◽

2003 ◽

Vol 47 (8) ◽

pp. 2606-2614 ◽

Cited By ~ 41

Author(s):

George P. Allen ◽

Glenn W. Kaatz ◽

Michael J. Rybak

Keyword(s):

Streptococcus Pneumoniae ◽

Pharmacodynamic Model ◽

The Other ◽

Time Curve ◽

Development Of Resistance ◽

Concentration Time ◽

Mutant Prevention Concentration ◽

Resistant Mutants ◽

Selection Of

ABSTRACT The differential effects of moxifloxacin and levofloxacin on the development of resistance in four Streptococcus pneumoniae isolates were examined by using an in vitro pharmacodynamic model. Therapeutic regimens (moxifloxacin: peak, 4.5 μg/ml; half-life [t 1/2], 12 h; and levofloxacin: peak, 6 μg/ml; t 1/2, 6 h) were tested against two fluoroquinolone-susceptible isolates (strains 79 and ATCC 49619) and KD2138 and KD2139 (parC and gyrA mutants, respectively, of ATCC 49619). Mutant prevention concentration (MPC)-targeted regimens with modified pharmacokinetics of each drug were simulated to match the area under the concentration-time curve (AUC) above the MPC for the two fluoroquinolones. Moxifloxacin MICs and MPCs (MIC/MPC) for isolates 79, ATCC 49619, KD2138, and KD2139, respectively, were 0.125 and 0.5, 0.125 and 0.5, 0.25 and 8, and 0.25 and 4 μg/ml. Levofloxacin MICs and MPCs for the same isolates were 1 and 4, 0.5 and 2, 1 and 64, and 0.5 and 32 μg/ml, respectively. Therapeutic levofloxacin concentrations led to isolation of mutants of ATCC 49619 (S79Y in ParC), KD2138 (S81Y in GyrA), and KD2139 (S79Y in ParC). Therapeutic moxifloxacin concentrations against the gyrA mutant KD2139 resulted in outgrowth of a mutant with a ParC substitution (S79Y) but caused no emergence of mutants of the other three isolates. MPC-targeted moxifloxacin (lower-than-normal peak = 0.75 to 1.5 μg/ml, administered at levofloxacin's t 1/2) caused growth of a GyrA variant (S81Y) of KD2138 and a ParC variant (S79Y) of KD2139, while no mutants of ATCC 49619 were recovered. MPC-targeted levofloxacin (higher-than-normal peak = 14.5 to 29.5 μg/ml, administered at moxifloxacin's t 1/2) against KD2138 and KD2139 did not prevent the development of the mutations observed in therapeutic regimens, but resistance in the fluoroquinolone-susceptible ATCC 49619 was no longer noted. Normalization of the respective AUC/MPC ratios of moxifloxacin and levofloxacin did not eliminate differences in resistance selectivity of the two agents in all cases. We conclude that the reduced recovery of resistant mutants of S. pneumoniae following moxifloxacin exposure compared to levofloxacin may be due to intrinsic differences between the drugs. Increasing the concentration and exposure (t 1/2) to exceed the MPC may prevent mutations from occurring in fluoroquinolone-susceptible strains. However, this strategy did not prevent the selection of secondary mutants in strains with preexisting mutations. Further study of the MPC concept to evaluate these relationships is warranted.

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Fluoroquinolone Resistance in Streptococcus pneumoniae: Area Under the Concentration-Time Curve/MIC Ratio and Resistance Development with Gatifloxacin, Gemifloxacin, Levofloxacin, and Moxifloxacin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00646-06 ◽

2007 ◽

Vol 51 (4) ◽

pp. 1315-1320 ◽

Cited By ~ 21

Author(s):

Kerry L. LaPlante ◽

Michael J. Rybak ◽

Brian Tsuji ◽

Thomas P. Lodise ◽

Glenn W. Kaatz

Keyword(s):

Streptococcus Pneumoniae ◽

Sequence Analysis ◽

Fluoroquinolone Resistance ◽

Second Step ◽

Wild Type ◽

Time Curve ◽

Resistance Development ◽

Concentration Time ◽

Structural Differences

ABSTRACT The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (108.5 to 109 log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/MICs of 51 and ≤60, 34 and 37, ≤82 and ≤86, and ≤24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. pneumoniae, whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P < 0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P < 0.002) than those of gatifloxacin. The order of resistance development determined from fAUC/MIC breakpoints was levofloxacin > gatifloxacin > moxifloxacin = gemifloxacin, which may be related to structural differences within the class.

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Increasing Chloramphenicol Resistance in Streptococcus pneumoniae Isolates from Papua New Guinean Children with Acute Bacterial Meningitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00526-11 ◽

2011 ◽

Vol 55 (9) ◽

pp. 4454-4456 ◽

Cited By ~ 7

Author(s):

Laurens Manning ◽

Moses Laman ◽

Andrew R. Greenhill ◽

Audrey Michael ◽

Peter Siba ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Bacterial Meningitis ◽

Haemophilus Influenzae ◽

Acute Bacterial Meningitis ◽

Time Curve ◽

Chloramphenicol Resistance ◽

Content Type ◽

Concentration Time ◽

Data Support ◽

Papua New Guinean

ABSTRACTIn Papua New Guinean (PNG) children with acute bacterial meningitis (ABM), allHaemophilus influenzaeisolates were resistant to chloramphenicol. AlthoughStreptococcus pneumoniaeisolates had a median chloramphenicol MIC of 3 μg/ml, it was ≥4 μg/ml in 42.8%, and the likelihood of an area under the 24-hour concentration-time curve/MIC ratio of >100 h at a MIC of ≥4 μg/ml was approximately 50%. All isolates were ceftriaxone sensitive. These data support ceftriaxone rather than conventional chloramphenicol for all PNG children with suspected ABM.

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Kill Rate and Evaluation of Ex Vivo PK/PD Integration of Cefquinome Against Actinobacillus pleuropneumoniae

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.751957 ◽

2021 ◽

Vol 8 ◽

Author(s):

Longfei Zhang ◽

Hongbing Xie ◽

Hongjuan Wang ◽

Huanzhong Ding ◽

Gaiping Zhang ◽

...

Keyword(s):

Antibacterial Activity ◽

Maximum Concentration ◽

Ex Vivo ◽

Area Under The Curve ◽

Actinobacillus Pleuropneumoniae ◽

Time Curve ◽

Concentration Time ◽

Dosage Regimens ◽

Kill Rate

We wished to study the detailed and precise antibacterial activity of cefquinome against Actinobacillus pleuropneumoniae (APP) in vitro and ex vivo. We analyzed the relationships between kill rate and cefquinome concentration in broth and between pharmacokinetic/pharmacodynamic (PK/PD) parameters and antibacterial effect in serum and tissue cage fluid (TCF) of piglets. Cefquinome exhibited time-dependent antibacterial activity against APP according to the kill rate. The maximum kill rate was 0.48 log10 CFU/mL/h at the 0-9-h period in broth. In the ex vivo PK/PD study, the maximum concentration (Cmax), time to reach the maximum concentration (Tmax), terminal half-life (T1/2β), and area under the concentration time curve (AUCinfinity) were 5.65 μg/ml, 0.58 h, 2.24 h, and 18.48 μg·h/ml in serum and 1.13 μg/ml, 2.60 h, 12.22 h, and 20.83 μg·h/ml in TCF, respectively. The values of area under the curve during 24 h/minimum inhibitory concentration (AUC24h/MIC) for bacteriostatic, bactericidal, and bacterial eradication effects were 18.94, 246.8, and 1013.23 h in serum and 4.20, 65.81, and 391.35 h in TCF, respectively. Our findings will provide a valuable basis for optimization of dosage regimens when applying cefquinome to treat APP infection.

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Activities of Garenoxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.3.765-773.2004 ◽

2004 ◽

Vol 48 (3) ◽

pp. 765-773 ◽

Cited By ~ 11

Author(s):

E. Azoulay-Dupuis ◽

J. P. Bédos ◽

J. Mohler ◽

G. Peytavin ◽

R. Isturiz ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Wild Type Strain ◽

Survival Rates ◽

Pharmacokinetic Parameters ◽

Gram Negative Bacteria ◽

Single Mutation ◽

Wild Type ◽

Time Curve ◽

Concentration Time

ABSTRACT Garenoxacin is a novel des-F(6) quinolone with enhanced in vitro activities against both gram-positive and gram-negative bacteria. We compared the activity of garenoxacin with that of trovafloxacin (TVA) against Streptococcus pneumoniae, together with their efficacies and their capacities to select for resistant mutants, in a mouse model of acute pneumonia. In vitro, garenoxacin was more potent than TVA against wild-type S. pneumoniae and against a mutant with a single mutation (parC), a mutant with double mutations (gyrA and parC), and a mutant with triple mutations (gyrA, parC, and parE). Swiss mice were infected with 105 CFU of virulent, encapsulated S. pneumoniae strain P-4241 or its derived isogenic parC, gyrA, gyrA parC, and efflux mutants and 107 CFU of poorly virulent clinical strains carrying a parE mutation or gyrA, parC, and parE mutations. The drugs were administered six times, every 12 h, beginning at either 3 or 18 h postinfection. The pulmonary pharmacokinetic parameters in mice infected with strain P-4241 and treated with garenoxacin or TVA (25 mg/kg of body weight) were as follows: maximum concentration of drug in serum (C max; 17.3 and 21.2 μg/ml, respectively), C max/MIC ratio (288 and 170, respectively), area under the concentration-time curve (AUC; 48.5 and 250 μg · h/ml, respectively), and AUC/MIC ratio (808 and 2,000, respectively). Garenoxacin at 25 and 50 mg/kg was highly effective (survival rates, 85 to 100%) against the wild-type strain and mutants harboring a single mutation. TVA was as effective as garenoxacin against these strains. TVA at 200 mg/kg and garenoxacin at 50 mg/kg were ineffective against the mutant with the parC and gyrA double mutations and the mutant with the gyrA, parC, and parE triple mutations. The efficacy of garenoxacin was reduced only when strains bore several mutations for quinolone resistance.

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Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.1.188-194.2005 ◽

2005 ◽

Vol 49 (1) ◽

pp. 188-194 ◽

Cited By ~ 15

Author(s):

Pamela R. Tessier ◽

Holly M. Mattoes ◽

Prachi K. Dandekar ◽

Charles H. Nightingale ◽

David P. Nicolau

Keyword(s):

Streptococcus Pneumoniae ◽

Infection Model ◽

Pharmacokinetic Studies ◽

Time Curve ◽

Phenotypic Resistance ◽

Concentration Time ◽

Pharmacodynamic Profile

ABSTRACT The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were ≤0.5 μg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 105 to 106 CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.

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Evidence for Establishing the Clinical Breakpoint of Cefquinome against Haemophilus Parasuis in China

Pathogens ◽

10.3390/pathogens10020105 ◽

2021 ◽

Vol 10 (2) ◽

pp. 105

Author(s):

Kun Mi ◽

Da Sun ◽

Mei Li ◽

Haihong Hao ◽

Kaixiang Zhou ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Antibacterial Activity ◽

Inhibitory Concentration ◽

High Morbidity ◽

Haemophilus Parasuis ◽

Wild Type ◽

Time Curve ◽

Resistance Change ◽

Concentration Time ◽

Clinical Experiments

Haemophilus parasuis can cause high morbidity and mortality in swine. Cefquinome possesses excellent antibacterial activity against pathogens causing diseases of the respiratory tract. This study aimed to establish the clinical breakpoint (CBP) of cefquinome against H. parasuis and to monitor the resistance change. Referring to the minimum inhibitory concentration (MIC) distribution of cefquinome against 131 H. parasuis isolates, the MIC50 and MIC90 were determined to be 0.125 and 1 μg/mL, respectively. And the epidemiological cutoff (ECOFF) value was 1 μg/mL. HPS42 was selected as a representative strain for the pharmacodynamic (PD) experiment, pharmacokinetic (PK) experiment and clinical experiments. The PK/PD index values, area under concentration-time curve (AUC)/MIC, of the bacteriostatic, bactericidal, and bacterial elimination effects were 23, 41, and 51 h, respectively. The PK/PD cutoff was calculated as 0.125 μg/mL by Monte Carlo simulation (MCS), and the clinical cutoff was 0.25−4 μg/mL by WindoW. Combing these three values, the CBP of cefquinome against H. parasuis was found to be 1 μg/mL. In conclusion, this was the first study to integrate various cutoffs to establish the CBP in the laboratory. It is helpful to distinguish wild type H. parasuis and reduce the probability of treatment failure.

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