scholarly journals Predicting the Effects of Carbapenem/Carbapenemase Inhibitor Combinations against KPC-Producing Klebsiella pneumoniae in Time-Kill Experiments: Alternative versus Traditional Approaches to MIC Determination

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1520
Author(s):  
Alla V. Filimonova ◽  
Maria V. Golikova ◽  
Elena N. Strukova ◽  
Yury A. Portnoy ◽  
Anastasiya A. Kuznetsova ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Klebsiella Pneumoniae ◽  
Concentration Ratio ◽  
Traditional Approach ◽  
Inhibitor Concentration ◽  
Antibacterial Effects ◽  
Time Curve ◽  
Concentration Time ◽  
Traditional Approaches ◽  
Time Kill

Traditionally, the antibacterial activity of β-lactam antibiotics in the presence of β-lactamase inhibitors is determined at the fixed inhibitor concentration. This traditional approach does not consider the ratio of antibiotic-to-inhibitor concentrations achieved in humans. To explore whether an alternative pharmacokinetically based approach to estimate MICs in combinations is predictive of antimicrobial efficacy, the effects of imipenem and doripenem alone and in combination with relebactam were studied in time-kill experiments against carbapenemase-producing Klebsiella pneumoniae. The carbapenem-to-relebactam concentration ratios in time-kill assays were equal to the therapeutic 24-h area under the concentration-time curve (AUC) ratios of the drugs (1.5/1). The simulated levels of carbapenem and relebactam were equal to their concentrations achieved in humans. When effects of combined regimens were plotted against respective C/MICs, a sigmoid relationship was obtained only with MICs determined by pharmacokinetically based method. The effectiveness of both carbapenems in the presence of relebactam was comparable by the results of time-kill experiments. These findings suggest that (1) antibiotic/inhibitor MICs determined at a pharmacokinetically based concentration ratio allow an adequate assessment of carbapenem susceptibility in carbapenemase-producing K. pneumoniae strains and can be used to predict antibacterial effects; (2) in time-kill experiments, the effects of imipenem and doripenem in the presence of relebactam are comparable.

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

Pathogens ◽  
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.

scholarly journals Synergistic activity of fosfomycin–meropenem and fosfomycin–colistin against carbapenem resistant Klebsiella pneumoniae: an in vitro evidence

2020 ◽  
pp. FSO461 ◽  
Author(s):  
Yamuna Devi Bakthavatchalam ◽  
Abirami Shankar ◽  
Dhiviya Prabaa Muthuirulandi Sethuvel ◽  
Kalaiarasi Asokan ◽  
Kalaiarasi Kanthan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Klebsiella Pneumoniae ◽  
Blood Cultures ◽  
Synergistic Activity ◽  
Carbapenem Resistant ◽  
Resistant Genes ◽  
Time Kill ◽  
Synergistic Antibacterial Activity

Aim: To evaluate the antibacterial activity of fosfomycin–meropenem and fosfomycin–colistin combinations against carbapenem-resistant Klebsiella pneumoniae (CR-Kp). Methods: A total of 50 CR-Kp isolates recovered from blood cultures were included in this study. All the CR-Kp isolates were screened for the presence of carbapenem resistant genes blaIMP. blaVIM. blaNDM. blaOXA-48 like, blaKPC. blaGES.#x00A0;and blaSPM. Combination testing of fosfomycin–meropenem and fosfomycin–colistin were performed using time-kill assay. Results: Fosfomycin–meropenem combination showed synergy in 20% of the tested CR-Kp isolates. While, fosfomycin–colistin exhibited synergy against 16% of the isolates. A total of 68% (n = 34) of CR-Kp isolates were characterised as OXA-48-like producers and 22% (n = 11) as NDM producers. Synergistic activity of these combinations was observed against OXA-48, NDM and NDM + OXA-48 co-producers. Conclusion: Considerable synergistic antibacterial activity of fosfomycin–meropenem and fosfomycin–colistin was not observed against CR-Kp isolates. Therefore, these combinations may not be promising for infections associated with CR-Kp.

scholarly journals Synergistic antibacterial effects of colistin in combination with aminoglycoside, carbapenems, cephalosporins, fluoroquinolones, tetracyclines, fosfomycin, and piperacillin on multidrug resistant Klebsiella pneumoniae isolates

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244673
Author(s):  
Julalak C. Ontong ◽  
Nwabor F. Ozioma ◽  
Supayang P. Voravuthikunchai ◽  
Sarunyou Chusri
Keyword(s):  
Antibacterial Activity ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Antibacterial Effects ◽  
Drug Resistant Bacteria ◽  
Multidrug Resistant Pathogens ◽  
Conventional Antibiotics ◽  
Global Health Problem

Multidrug resistant Enterobacterales have become a serious global health problem, with extended hospital stay and increased mortality. Antibiotic monotherapy has been reported ineffective against most drug resistant bacteria including Klebsiella pneumoniae, thus encouraging the use of multidrug therapies as an alternative antibacterial strategy. The present works assessed the antibacterial activity of colistin against K. pneumoniae isolates. Resistant isolates were tested against 16 conventional antibiotics alone and in combination with colistin. The results revealed that all colistin resistant isolates demonstrated multidrug resistance against the tested antibiotics except amikacin. At sub-inhibitory concentrations, combinations of colistin with amikacin, or fosfomycin showed synergism against 72.72% (8 of 11 isolates). Colistin with either of gentamicin, meropenem, cefoperazone, cefotaxime, ceftazidime, moxifloxacin, minocycline, or piperacillin exhibited synergism against 81.82% (9 of 11 isolates). Combinations of colistin with either of tobramycin or ciprofloxacin showed synergism against 45.45% (5 in 11 isolates), while combinations of colistin with imipenem or ceftolozane and tazobactam displayed 36.36% (4 of 11 isolates) and 63.64% (7 of 11 isolates) synergism. In addition, combinations of colistin with levofloxacin was synergistic against 90.91% (10 of 11 isolates). The results revealed that combinations of colistin with other antibiotics could effectively inhibit colistin resistant isolates of K. pneumoniae, and thus could be further explore for the treatment of multidrug resistant pathogens.

scholarly journals Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa.

1996 ◽  
Vol 40 (4) ◽  
pp. 904-908 ◽  
Author(s):  
R White ◽  
L Friedrich ◽  
D Burgess ◽  
D Warkentin ◽  
J Bosso
Keyword(s):  
Drug Exposure ◽  
Antimicrobial Agents ◽  
Testing Procedure ◽  
Rank Test ◽  
Time Curve ◽  
Bacterial Killing ◽  
Drug Degradation ◽  
Concentration Time ◽  
Time Kill

MICs are commonly used to assess the in vitro activities of antimicrobial agents; however, they provide minimal information on the pattern of bacterial activities. Time-kill studies with extensive sampling allow assessment of both the rate and extent of bacterial killing and regrowth. We compared imipenem and meropenem by both MIC-MBC testing and a time-kill study with P. aeruginosa 27853. In the time-kill study, concentration/MIC ratios ranging from 0.0625 to 32 times the MIC were studied. The kill rate, time to 99.9% kill, doubling time of regrowth, and area under the bacterial killing curve (AUKC) were evaluated. Degradation during the testing procedure was accounted for by assessing actual drug exposure as determined by the area under the concentration-time curve. Pharmacodynamic parameters were compared by using the Wilcoxon signed-rank test. The modal MIC and MBC for imipenem were 2 and 4 micrograms/ml, respectively, and those for meropenem were 0.25 and 0.5 microgram/ml, respectively. In the time-kill study, both agents displayed concentration-dependent activity over a range of 0.25 to 4 times the MIC. Initial killing (0 to 1 h) was faster with imipenem at the same concentration/MIC ratios (P = 0.0506). The time to 99.9% kill was approximately 5 h for both agents. When regrowth occurred, the doubling rate for imipenem, which was the same as that for the growth control, was twice as rapid as that for meropenem. At the same concentrations, the AUKCs over 24 h were lower for meropenem than for imipenem (P = 0.0280); however, when normalized by MIC, imipenem resulted in smaller AUKCs. Comparison of plots of area under the concentration-time curve versus AUKC, which accounted for drug degradation and actual drug exposure, revealed that meropenem was three times more active than imipenem, rather than the eightfold difference suggested by MICs. Time-kill curves with extensive sampling and measurement of actual drug exposure, rather than traditional MIC testing, may more accurately assess differences in the in vitro activities of antimicrobial agents.

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

2010 ◽  
Vol 54 (10) ◽  
pp. 4300-4305 ◽  
Author(s):  
Tomoyuki Homma ◽  
Toshihiko Hori ◽  
Merime Ohshiro ◽  
Hideki Maki ◽  
Yoshinori Yamano ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Streptococcus Pneumoniae ◽  
Haemophilus Influenzae ◽  
Viable Cell ◽  
Time Curve ◽  
Concentration Time ◽  
Auc Value ◽  
Two Parameters ◽  
Concentration Curves

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.

scholarly journals Twenty-four-hour area under the concentration-time curve/MIC ratio as a generic predictor of fluoroquinolone antimicrobial effect by using three strains of Pseudomonas aeruginosa and an in vitro pharmacodynamic model.

1996 ◽  
Vol 40 (3) ◽  
pp. 627-632 ◽  
Author(s):  
K J Madaras-Kelly ◽  
B E Ostergaard ◽  
L B Hovde ◽  
J C Rotschafer
Keyword(s):  
Antibacterial Effect ◽  
Antimicrobial Effect ◽  
Time Curve ◽  
Emax Model ◽  
Concentration Time ◽  
Mueller Hinton ◽  
Kill Curve ◽  
Time Kill ◽  
Mueller Hinton Broth

Several investigators have suggested that the 24-h area under the concentration-time curve (AUC)/MIC ratio (AUC/MIC24 or AUIC24) can be used to make comparisons of antimicrobial activity between fluoroquinolone antibiotics. Limited data exist regarding the generic predictive ability of AUC/MIC24 for the antimicrobial effects of fluoroquinolones. The purposes of the present investigation were to determine if the AUC/MIC24 can be used as a generic outcome predictor of fluoroquinolone antibacterial activity and to determine if a similar AUC/MIC24 breakpoint can be established for different fluoroquinolones. Using an in vitro pharmacodynamic model, 29 duplicate concentration time-kill curve experiments simulated AUC/MIC24s ranging from 52 to 508 SIT-1.h (inverse serum inhibitory titer integrated over time) with ciprofloxacin or ofloxacin against three strains of Pseudomonas aeruginosa. Each 24-h experiment was performed in cation-supplemented Mueller-Hinton broth with a starting inoculum of 10(6) CFU/ml. At timed intervals cation-supplemented Mueller-Hinton broth samples were collected for CFU and fluoroquinolone concentration determinations. Transformation of bacterial counts into the cumulative bacterial effect parameter of the 24-h area under the effect curve (AUEC24) was performed for each concentration time-kill curve. Multivariate regression analysis was used to compare pharmacodynamic predictors (AUC/MIC24, 24-h AUC, peak concentration [Cmax] to MIC ratios [Cmax:MIC], etc.) with ln AUEC24. To identify threshold breakpoint AUC/MIC24s, AUEC24s were stratified by the magnitude of AUC/MIC24 into subgroups, which were analyzed for differences in antibacterial effect. The Kruskal-Wallis test and subsequent Tukey's multiple comparison test were used to determine which AUC/MIC subgroups were significantly different. Multiple regression analysis revealed that only AUC/MIC24 (r2 = 0.65) and MIC (r2 = 0.03) were significantly correlated with antibacterial effect. At similar AUC/MIC24s, yet different MICs, Cmaxs, or elimination half-lives, the AUEC24s were similar for both fluoroquinolones. The relationship between AUC/MIC24 and ln AUEC24 was best described by a sigmoidal maximal antimicrobial effect (Emax) model (r2 = 0.72; Emax = 9.1; AUC/MIC50 = 119 SIT-1.h; S = 2.01 [S is an exponent that reflects the degree of sigmoidicity]). Ciprofloxacin-bacteria AUC/MIC24 values of < 100 SIT-1.h were significantly different (P < 0.05) from the AUC/MIC24 values of > 100 SIT-1.h. An ofloxacin AUC/MIC24 of > 100 SIT-1.h and an AUC/MIC24 of < 100 SIT-1.h exhibited a trend toward a significant difference (P > 0.05 but < 0.1). The inverse relationship between drug exposure and MIC increase postexposure was described by a sigmoidal fixed Emax model (AUC/MIC24, r2 = 0.40; AUC/MIC50 = 95 SIT-1.h; S = 1.97; Cmax:MIC, r2 = 0.41; Cmax:MIC50 = 7.3; S = 2.01). These data suggest that AUC/MIC24 may be the most descriptive measurement of fluoroquinolone antimicrobial activity against P. aeruginosa, that ofloxacin and ciprofloxacin have similar AUC/MIC24 threshold breakpoints at approximately 100 SIT-1.h, that the concentration-dependent selection of resistant organisms may parallel the threshold breakpoint of the antimicrobial effect, and that AUC/MIC24 generically describes the antibacterial effects of different fluoroquinolones.

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

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.

A Comparative Pharmacokinetic Profile of Trahydropalmatine After Oral Administration of its Monomer, Rhizoma Corydalis Alkaloid Extracts and Tong-Bi-Si-Wei-Fang to Rats

2019 ◽  
Vol 15 (4) ◽  
pp. 338-345
Author(s):  
Lijun Ni ◽  
Lu Ding ◽  
Liguo Zhang ◽  
Shaorong Luan
Keyword(s):  
Oral Administration ◽  
Panax Notoginseng ◽  
Pharmacokinetic Profile ◽  
Apparent Volume ◽  
Bone Diseases ◽  
Glycyrrhiza Uralensis ◽  
Pharmacokinetic Property ◽  
Time Curve ◽  
Concentration Time

Background: Tong-Bi-Si-Wei-Fang (TBSWF) is a candidate formula of Traditional Chinese Medicine (TCM) for treating rheumatoid bone diseases, which is composed of rhizoma corydalis alkaloids, saponins of glycyrrhiza uralensis and panax notoginseng, flavonoids of rhizoma drynariae and glycyrrhiza uralensis. </P><P> Objective: Trahydropalmatine (THP), the main active ingredient of rhizoma corydalis alkaloids, was selected to study in vivo pharmacokinetics and druggability of TBSWF. Methods: The plasma concentration-time (C-T) profiles of THP and the pharmacokinetic property parameters after oral administration of THP monomer, extract of corydalis alkaloids (ECA) and TBSWF to rats, respectively were compared by a fully-validated HPLC method. Results: Compared to the THP monomer, the THP in TBSWF is absorbed faster, resides in the plasma longer and has a similar apparent volume of distribution Vz/F (10~20 L/kg). Compared to THP monomer and THP in TBSWF, the area under the concentration-time curve AUC 0-t of THP in ECA decreases two-third; Vz/F of THP in ECA (85.02 L/kg) is significantly higher than that of THP in TBSWF(p <0.05). Unlike THP monomer and THP in ECA, double peaks are observed in the C-T profile of THP after oral administration of TBSWF. THP in TBSWF exhibits slow release to a certain degree. Conclusion: The interactions among the ingredients of TBSWF promote the adsorption and prolong the residence time of THP in vivo, and provide an explanation for the advantages of TBSWF from the point of pharmacokinetics.

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