scholarly journals Comparative Pharmacodynamics of Gatifloxacin and Ciprofloxacin in an In Vitro Dynamic Model: Prediction of Equiefficient Doses and the Breakpoints of the Area under the Curve/MIC Ratio

2000 ◽  
Vol 44 (4) ◽  
pp. 879-884 ◽  
Author(s):  
Sergey N. Vostrov ◽  
Olga V. Kononenko ◽  
Irene Y. Lubenko ◽  
Stephen H. Zinner ◽  
Alexander A. Firsov
Keyword(s):  
Present Report ◽  
Area Under The Curve ◽  
Antimicrobial Effect ◽  
Time Curve ◽  
E Coli ◽  
Clinical Dose ◽  
Linear Relationships ◽  
New Quinolones ◽  
The Impact

ABSTRACT To demonstrate the impact of the pharmacokinetics of gatifloxacin (GA) relative to those of ciprofloxacin (CI) on the antimicrobial effect (AME), the killing and regrowth kinetics of two differentially susceptible clinical isolates each of Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of GA (half-life [t 1/2], 7 h) and CI (t 1/2 = 4 h) were simulated to mimic different single doses of GA and two 12-h doses of CI. The respective eightfold ranges of the ratios of the area under the concentration-time curve (AUC) to the MIC were 58 to 466 and 116 to 932 (μg · h/ml)/(μg/ml). The species- and strain-independent linear relationships observed between the intensity of AME (IE ) and log AUC/MIC were not superimposed for GA and CI (r 2 = 0.99 in both cases). The predicted AUC/MIC ratio for GA that might be equivalent to a clinically relevant AUC/MIC breakpoint for CI was estimated to be 102 rather than 125 (μg · h/ml)/(μg/ml). The respective MIC breakpoints were 0.32 μg/ml (for a 400-mg dose of GA) and 0.18 μg/ml (for two 500-mg doses of CI). On the basis of the IE -log AUC/MIC relationships, equiefficient 24-h doses (D 24hs) of GA and CI were calculated for hypothetical strains of S. aureus, E. coli, andK. pneumoniae for which the MICs were equal to the MICs at which 50% of isolates are inhibited. To provide an “acceptable”IE equal to 200 (log CFU/ml) · h, i.e., the IE provided by AUC/MIC of 125 (μg · h/ml)/(μg/ml) for ciprofloxacin, theD 24hs of GA for all three organisms were much lower (115, 30, and 60 mg) than the clinically proposed 400-mg dose. Although the usual dose of CI (two doses of 500 mg) would be in excess for E. coli and K. pneumoniae(D 24h = two doses of 40 mg and two doses of 115 mg, respectively), even the highest clinical dose of CI (two doses of 750 mg) might be insufficient for S. aureus(D 24h, > two doses of 1,000 mg). The method of generalization of data obtained with specific organisms to other representatives of the same species described in the present report might be useful for prediction of the AMEs of new quinolones.

scholarly journals Relationships of the Area under the Curve/MIC Ratio to Different Integral Endpoints of the Antimicrobial Effect: Gemifloxacin Pharmacodynamics in an In Vitro Dynamic Model

2001 ◽  
Vol 45 (3) ◽  
pp. 927-931 ◽  
Author(s):  
Alexander A. Firsov ◽  
Irene Y. Lubenko ◽  
Yury A. Portnoy ◽  
Stephen H. Zinner ◽  
Sergey N. Vostrov
Keyword(s):  
Area Under The Curve ◽  
Antimicrobial Effect ◽  
Time Curve ◽  
Marginal Value ◽  
Actual Effect ◽  
Control Growth ◽  
Effect Duration ◽  
Kill Curve ◽  
Time Kill

ABSTRACT Most integral endpoints of the antimicrobial effect are determined over an arbitrarily chosen time period, such as the dosing interval (τ), regardless of the actual effect duration. Unlike the τ-related endpoints, the intensity of the antimicrobial effect (I E) does consider its duration—from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of the antimicrobial. To examine the possible impact of this fundamental difference on the relationships of the antimicrobial effect to the ratio of the area under the concentration-time curve (AUC) to the MIC, a clinical isolate ofStaphylococcus aureus was exposed to simulated gemifloxacin pharmacokinetics over a 40-fold range of AUC/MIC ratios, from 11 to 466 h. In each run, I E and four τ-related endpoints, including the area under the time-kill curve (AUBC), the area above the curve (AAC), the area between the control growth and time-kill curves (ABBC), and the ABBC related to the area under the control growth curve (AUGC), were calculated for τ = 24 h. Unlike the I E, which displayed pseudolinear relationships with the AUC/MIC ratio; each τ-related endpoint showed a distinct saturation at potentially therapeutic AUC/MIC ratios (116 to 466 h) when the antimicrobial effect persisted longer than τ. This saturation results from the underestimation of the true effect and may be eliminated if ABBC, AAC, and AUBC (but not AUGC) are modified and determined in the same manner as the I E to consider the actual effect duration. These data suggest a marginal value of the τ-related endpoints as indices of the total antimicrobial effect. Since all of them respond to AUC/MIC ratio changes less than theI E, the latter is preferable in comparative pharmacodynamic studies.

Prediction of the Effects of Inoculum Size on the Antimicrobial Action of Trovafloxacin and Ciprofloxacin againstStaphylococcus aureus and Escherichia coli in an In Vitro Dynamic Model

1999 ◽  
Vol 43 (3) ◽  
pp. 498-502 ◽  
Author(s):  
Alexander A. Firsov ◽  
Sergey N. Vostrov ◽  
Olga V. Kononenko ◽  
Stephen H. Zinner ◽  
Yury A. Portnoy
Keyword(s):  
Escherichia Coli ◽  
Dynamic Models ◽  
Antimicrobial Effect ◽  
Inoculum Size ◽  
Antimicrobial Action ◽  
Time Curve ◽  
Mean Values ◽  
E Coli ◽  
Inoculum Effect

ABSTRACT The effect of inoculum size (N 0) on antimicrobial action has not been extensively studied in in vitro dynamic models. To investigate this effect and its predictability, killing and regrowth kinetics of Staphylococcus aureus andEscherichia coli exposed to monoexponentially decreasing concentrations of trovafloxacin (as a single dose) and ciprofloxacin (two doses at a 12-h interval) were compared atN 0 = 106 and 109 CFU/ml (S. aureus) and at N 0 = 106, 107, and 109 CFU/ml (E. coli). A series of pharmacokinetic profiles of trovafloxacin and ciprofloxacin with respective half-lives of 9.2 and 4 h were simulated at different ratios of area under the concentration-time curve (AUC) to MIC (in [micrograms × hours/milliliter]/[micrograms/milliliter]): 58 to 466 with trovafloxacin and 116 to 932 with ciprofloxacin for S. aureus and 58 to 233 and 116 to 466 for E. coli, respectively. Although the effect of N 0 was more pronounced for E. coli than for S. aureus, only a minor increase in minimum numbers of surviving bacteria and an almost negligible delay in their regrowth were associated with an increase of the N 0 for both organisms. TheN 0-induced reductions of the intensity of the antimicrobial effect (IE , area between control growth and the killing-regrowth curves) were also relatively small. However, the N 0 effect could not be eliminated either by simple shifting of the time-kill curves obtained at higherN 0s by the difference between the higher and lowest N 0 or by operating withIE s determined within theN 0-adopted upper limits of bacterial numbers (IE ′s). By using multivariate correlation and regression analyses, linear relationships betweenIE and log AUC/MIC and logN 0 related to the respective mean values [(log AUC/MIC)average and (logN 0)average] were established for both trovafloxacin and ciprofloxacin against each of the strains (r 2 = 0.97 to 0.99). The antimicrobial effect may be accurately predicted at a given AUC/MIC of trovafloxacin or ciprofloxacin and at a given N 0 based on the relationship IE = a + b [(log AUC/MIC)/(log AUC/MIC)average] − c [(logN 0)/(logN 0)average]. Moreover, the relative impacts of AUC/MIC and N 0 onIE may be evaluated. Since the c/bratios for trovafloxacin and ciprofloxacin against E. coliwere much lower (0.3 to 0.4) than that for ampicillin-sulbactam as examined previously (1.9), the inoculum effect with the quinolones may be much less pronounced than with the β-lactams. The described approach to the analysis of the inoculum effect in in vitro dynamic models might be useful in studies with other antibiotic classes.

scholarly journals Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

2005 ◽  
Vol 49 (7) ◽  
pp. 2642-2647 ◽  
Author(s):  
Alexander A. Firsov ◽  
Irene Y. Lubenko ◽  
Sergey N. Vostrov ◽  
Yury A. Portnoy ◽  
Stephen H. Zinner
Keyword(s):  
In Vitro Model ◽  
Therapeutic Potential ◽  
Area Under The Curve ◽  
Antimicrobial Effect ◽  
Clinical Isolates ◽  
Clinical Settings ◽  
Time Curve ◽  
Concentration Time ◽  
Vitro Model

ABSTRACT Prediction of the relative efficacies of different fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC50 or the MIC90 and with the assumption of antibiotic-independent patterns of the AUC/MIC-response relationships. To ascertain whether this assumption is correct, the pharmacodynamics of seven pharmacokinetically different quinolones against two clinical isolates of Staphylococcus aureus were studied by using an in vitro model. Two differentially susceptible clinical isolates of S. aureus were exposed to two 12-h doses of ciprofloxacin (CIP) and one dose of gatifloxacin (GAT), gemifloxacin (GEM), grepafloxacin (GRX), levofloxacin (LVX), moxifloxacin (MXF), and trovafloxacin (TVA) over similar AUC/MIC ranges from 58 to 932 h. A specific bacterial strain-independent AUC/MIC relationship with the antimicrobial effect (IE ) was associated with each quinolone. Based on the IE -log AUC/MIC relationships, breakpoints (BPs) that are equivalent to a CIP AUC/MIC ratio of 125 h were predicted for GRX, MXF, and TVA (75 to 78 h), GAT and GEM (95 to 103 h) and LVX (115 h). With GRX and LVX, the predicted BPs were close to those established in clinical settings (no clinical data on other quinolones are available in the literature). To determine if the predicted AUC/MIC BPs are achievable at clinical doses, i.e., at the therapeutic AUCs (AUCthers), the AUCther/MIC50 ratios were studied. These ratios exceeded the BPs for GAT, GEM, GRX, MXF, TVA, and LVX (750 mg) but not for CIP and LVX (500 mg). AUC/MIC ratios above the BPs can be considered of therapeutic potential for the quinolones. The highest ratios of AUCther/MIC50 to BP were achieved with TVA, MXF, and GEM (2.5 to 3.0); intermediate ratios (1.5 to 1.6) were achieved with GAT and GRX; and minimal ratios (0.3 to 1.2) were achieved with CIP and LVX.

scholarly journals A New Approach to In Vitro Comparisons of Antibiotics in Dynamic Models: Equivalent Area under the Curve/MIC Breakpoints and Equiefficient Doses of Trovafloxacin and Ciprofloxacin against Bacteria of Similar Susceptibilities

1998 ◽  
Vol 42 (11) ◽  
pp. 2841-2847 ◽  
Author(s):  
Alexander A. Firsov ◽  
Sergey N. Vostrov ◽  
Alexander A. Shevchenko ◽  
Yury A. Portnoy ◽  
Stephen H. Zinner
Keyword(s):  
Antimicrobial Agents ◽  
Dynamic Models ◽  
Area Under The Curve ◽  
Time Curve ◽  
Linear Relationships ◽  
Control Growth ◽  
Wide Range ◽  
Equivalent Area ◽  
Time Kill

ABSTRACT Time-kill studies, even those performed with in vitro dynamic models, often do not provide definitive comparisons of different antimicrobial agents. Also, they do not allow determinations of equiefficient doses or predictions of area under the concentration-time curve (AUC)/MIC breakpoints that might be related to antimicrobial effects (AMEs). In the present study, a wide range of single doses of trovafloxacin (TR) and twice-daily doses of ciprofloxacin (CI) were mimicked in an in vitro dynamic model. The AMEs of TR and CI against gram-negative bacteria with similar susceptibilities to both drugs were related to AUC/MICs that varied over similar eight-fold ranges [from 54 to 432 and from 59 to 473 (μg · h/ml)/(μg/ml), respectively]. The observation periods were designed to include complete bacterial regrowth, and the AME was expressed by its intensity (the area between the control growth in the absence of antibiotics and the antibiotic-induced time-kill and regrowth curves up to the point where viable counts of regrowing bacteria equal those achieved in the absence of drug [I E]). In each experiment monoexponential pharmacokinetic profiles of TR and CI were simulated with half-lives of 9.2 and 4.0 h, respectively. Linear relationships between I E and log AUC/MIC were established for TR and CI against three bacteria: Escherichia coli (MIC of TR [MICTR] = 0.25 μg/ml; MIC of CI [MICCI] = 0.12 μg/ml), Pseudomonas aeruginosa (MICTR = 0.3 μg/ml; MICCI = 0.15 μg/ml), and Klebsiella pneumoniae(MICTR = 0.25 μg/ml; MICCI = 0.12 μg/ml). The slopes and intercepts of these relationships differed for TR and CI, and the I E-log AUC/MIC plots were not superimposed, although they were similar for all bacteria with a given antibiotic. By using the relationships betweenI E and log AUC/MIC, TR was more efficient than CI. The predicted value of the AUC/MIC breakpoint for TR [mean for all three bacteria, 63 (μg · h/ml)/(μg/ml)] was approximately twofold lower than that for CI. Based on theI E-log AUC/MIC relationships, the respective dose (D)-response relationships were reconstructed. Like the I E-log AUC/MIC relationships, theI E-log D plots showed TR to be more efficient than CI. Single doses of TR that are as efficient as two 500-mg doses of CI (500 mg given every 12 h) were similar for the three strains (199, 226, and 203 mg). This study suggests that in vitro evaluation of the relationships between I E and AUC/MIC or D might be a reliable basis for comparing different fluoroquinolones and that the results of such comparative studies may be highly dependent on their experimental design and datum quantitation.

scholarly journals Pharmacokinetic and Pharmacodynamic Parameters for Antimicrobial Effects of Cefotaxime and Amoxicillin in an In Vitro Kinetic Model

2001 ◽  
Vol 45 (9) ◽  
pp. 2436-2440 ◽  
Author(s):  
I. Gustafsson ◽  
E. Löwdin ◽  
I. Odenholt ◽  
O. Cars
Keyword(s):  
Kinetic Model ◽  
Streptococcus Pyogenes ◽  
Elimination Rate ◽  
Antimicrobial Effect ◽  
Drug Elimination ◽  
Time Curve ◽  
Initial Concentration ◽  
E Coli ◽  
Concentration Time

ABSTRACT An in vitro kinetic model was used to study the relation between pharmacokinetic and pharmacodynamic (PK-PD) parameters for antimicrobial effect, e.g., the time above MIC (T>MIC), maximum concentration in serum (C max), and area under the concentration-time curve (AUC). Streptococcus pyogenes and Escherichia coli were exposed to cefotaxime, and the activity of amoxicillin against four strains ofStreptococcus pneumoniae with different susceptibilities to penicillin was studied. The drug elimination rate varied so that the T>MIC ranged from 20 to 100% during 24 h, while the AUC and/or the initial concentration (C max) were kept constant. For S. pyogenes and E. coli, the maximal antimicrobial effect (E max) at 24 h occurred when the antimicrobial concentration exceeded the MIC for 50 and 80% of the strains tested, respectively. The penicillin-susceptible pneumococci (MIC, 0.03 mg/liter) and the penicillin-intermediate strain (MIC, 0.25 mg/liter) showed maximal killing by amoxicillin at a T>MIC of 50%. For a strain for which the MIC was 2 mg/liter, C max needed to be increased to achieve the E max. Under the condition that C max was 10 times the MIC,E max was obtained at a T>MIC of 60%, indicating that C max, in addition to T>MIC, may be an important parameter for antimicrobial effect on moderately penicillin-resistant pneumococci. For the strain for which the MIC was 4 mg/liter, the reduction of bacteria varied from −0.4 to −3.6 log10 CFU/ml at a T>MIC of 100%, despite an initial antimicrobial concentration of 10 times the MIC. Our studies have shown that the in vitro kinetic model is a useful complement to animal models for studying the PK-PD relationship for antimicrobial effect of antibiotics.

scholarly journals Inter- and Intraquinolone Predictors of Antimicrobial Effect in an In Vitro Dynamic Model: New Insight into a Widely Used Concept

1998 ◽  
Vol 42 (3) ◽  
pp. 659-665 ◽  
Author(s):  
Alexander A. Firsov ◽  
Alexander A. Shevchenko ◽  
Sergey N. Vostrov ◽  
Stephen H. Zinner
Keyword(s):  
Dynamic Model ◽  
Half Life ◽  
Antimicrobial Effect ◽  
Data Sets ◽  
Time Curve ◽  
Linear Relationships ◽  
Control Growth ◽  
Dosing Regimens ◽  
Time Kill

ABSTRACT Earlier efforts to search for pharmacokinetic and bacteriological predictors of fluoroquinolone antimicrobial effects (AMEs) have resulted in conflicting findings. To elucidate whether these conflicts are real or apparent, several predictors of the AMEs of two pharmacokinetically different antibiotics, trovafloxacin (TRO) and ciprofloxacin (CIP), as well as different dosing regimens of CIP were examined. The AMEs of TRO given once daily (q.d.) and CIP given q.d. and twice daily (b.i.d.) against Escherichia coli,Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied in an in vitro dynamic model. Different monoexponential pharmacokinetic profiles were simulated with a TRO half-life of 9.2 h and a CIP half-life of 4.0 h to provide similar eightfold ranges of the area under the concentration-time curve (AUC)-to-MIC ratios, from 54 to 432 and from 59 to 473 (μg · h/ml)/(μg/ml), respectively. In each case the observation periods were designed to incorporate full-term regrowth phases in the time-kill curves, and the AME was expressed by its intensity (IE ; the area between the control growth and time-kill and regrowth curves up to the point at which the viable counts of regrowing bacteria are close to the maximum values observed without drug). Species-independent linear relationships were established between IE and log AUC/MIC, log AUC above MIC (log AUCeff), and time above the MIC (T eff). Specific and nonsuperimposedIE versus log AUC/MIC or log AUCeffrelationships were inherent in each of the treatments: TRO given q.d. (r 2 = 0.97 and 0.96), CIP given q.d. (r 2 = 0.98 and 0.96), and CIP given b.i.d. (r 2 = 0.95 and 0.93). This suggests that in order to combine data sets obtained with individual quinolones to examine potential predictors, one must be sure that these sets may be combined. Unlike AUC/MIC and AUCeff, the IE -T effrelationships plotted for the different quinolones and dosing regimens were nonspecific and virtually superimposed (r 2 = 0.95). Hence, AUC/MIC, AUCeff, and T eff were equally good predictors of the AME of each of the quinolones and each dosing regimen taken separately, whereas T eff was also a good predictor of the AMEs of the quinolones and their regimens taken together. However, neither the quinolones nor the dosing regimens could be distinguished solely on the basis of T eff, whereas they could be distinguished on the basis of AUC/MIC or AUCeff. Thus, two types of predictors of the quinolone AME may be identified: intraquinolone and/or intraregimen predictors (AUC/MIC, AUCeff and Teff) and an interquinolone and interregimen predictor (T eff). T eff may be able to accurately predict the AME of one quinolone on the basis of the data obtained for another quinolone.

scholarly journals In Vitro Coliform Resistance to Bioactive Compounds in Urinary Infection, Assessed in a Lab Catheterization Model

2021 ◽  
Vol 11 (9) ◽  
pp. 4315
Author(s):  
Emanuel Vamanu ◽  
Laura Dorina Dinu ◽  
Cristina Mihaela Luntraru ◽  
Alexandru Suciu
Keyword(s):  
Urinary Tract ◽  
Bioactive Compounds ◽  
Urinary Tract Infections ◽  
Antimicrobial Effect ◽  
Biologically Active ◽  
Bacterial Strains ◽  
E Coli ◽  
Functional Product ◽  
Tract Infections

Bioactive compounds and phenolic compounds are viable alternatives to antibiotics in recurrent urinary tract infections. This study aimed to use a natural functional product, based on the bioactive compounds’ composition, to inhibit the uropathogenic strains of Escherichia coli. E. coli ATCC 25922 was used to characterize the IVCM (new in vitro catheterization model). As support for reducing bacterial proliferation, the cytotoxicity against a strain of Candida albicans was also determined (over 75% at 1 mg/mL). The results were correlated with the analysis of the distribution of biologically active compounds (trans-ferulic acid-268.44 ± 0.001 mg/100 g extract and an equal quantity of Trans-p-coumaric acid and rosmarinic acid). A pronounced inhibitory effect against the uropathogenic strain E. coli 317 (4 log copy no./mL after 72 h) was determined. The results showed a targeted response to the product for tested bacterial strains. The importance of research resulted from the easy and fast characterization of the functional product with antimicrobial effect against uropathogenic strains of E. coli. This study demonstrated that the proposed in vitro model was a valuable tool for assessing urinary tract infections with E. coli.

scholarly journals Activity of Ceftazidime-Avibactam against Fluoroquinolone-Resistant Enterobacteriaceae and Pseudomonas aeruginosa

2015 ◽  
Vol 59 (6) ◽  
pp. 3059-3065 ◽  
Author(s):  
C. Pitart ◽  
F. Marco ◽  
T. A. Keating ◽  
W. W. Nichols ◽  
J. Vila
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistant Mutant ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
Content Type ◽  
E Coli ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
The Impact

ABSTRACTCeftazidime-avibactam and comparator antibiotics were tested by the broth microdilution method against 200Enterobacteriaceaeand 25Pseudomonas aeruginosastrains resistant to fluoroquinolones (including strains with the extended-spectrum β-lactamase [ESBL] phenotype and ceftazidime-resistant strains) collected from our institution. The MICs and mechanisms of resistance to fluoroquinolone were also studied. Ninety-nine percent of fluoroquinolone-resistantEnterobacteriaceaestrains were inhibited at a ceftazidime-avibactam MIC of ≤4 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference). Ceftazidime-avibactam was very active against ESBLEscherichia coli(MIC90of 0.25 mg/liter), ESBLKlebsiella pneumoniae(MIC90of 0.5 mg/liter), ceftazidime-resistant AmpC-producing species (MIC90of 1 mg/liter), non-ESBLE. coli(MIC90of ≤0.125 mg/liter), non-ESBLK. pneumoniae(MIC90of 0.25 mg/liter), and ceftazidime-nonresistant AmpC-producing species (MIC90of ≤0.5 mg/liter). Ninety-six percent of fluoroquinolone-resistantP. aeruginosastrains were inhibited at a ceftazidime-avibactam MIC of ≤8 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference), with a MIC90of 8 mg/liter. Additionally, fluoroquinolone-resistant mutants from each species tested were obtainedin vitrofrom two strains, one susceptible to ceftazidime and the other a β-lactamase producer with a high MIC against ceftazidime but susceptible to ceftazidime-avibactam. Thereby, the impact of fluoroquinolone resistance on the activity of ceftazidime-avibactam could be assessed. The MIC90values of ceftazidime-avibactam for the fluoroquinolone-resistant mutant strains ofEnterobacteriaceaeandP. aeruginosawere ≤4 mg/liter and ≤8 mg/liter, respectively. We conclude that the presence of fluoroquinolone resistance does not affectEnterobacteriaceaeandP. aeruginosasusceptibility to ceftazidime-avibactam; that is, there is no cross-resistance.

scholarly journals In VivoTransmission of an IncA/C Plasmid in Escherichia coli Depends on Tetracycline Concentration, and Acquisition of the Plasmid Results in a Variable Cost of Fitness

2015 ◽  
Vol 81 (10) ◽  
pp. 3561-3570 ◽  
Author(s):  
Timothy J. Johnson ◽  
Randall S. Singer ◽  
Richard E. Isaacson ◽  
Jessica L. Danzeisen ◽  
Kevin Lang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Dose ◽  
Broad Host Range ◽  
Antibiotic Administration ◽  
Dose Administration ◽  
Content Type ◽  
E Coli ◽  
The Impact ◽  
Selection Of

ABSTRACTIncA/C plasmids are broad-host-range plasmids enabling multidrug resistance that have emerged worldwide among bacterial pathogens of humans and animals. Although antibiotic usage is suspected to be a driving force in the emergence of such strains, few studies have examined the impact of different types of antibiotic administration on the selection of plasmid-containing multidrug resistant isolates. In this study, chlortetracycline treatment at different concentrations in pig feed was examined for its impact on selection and dissemination of an IncA/C plasmid introduced orally via a commensalEscherichia colihost. Continuous low-dose administration of chlortetracycline at 50 g per ton had no observable impact on the proportions of IncA/C plasmid-containingE. colifrom pig feces over the course of 35 days. In contrast, high-dose administration of chlortetracycline at 350 g per ton significantly increased IncA/C plasmid-containingE. coliin pig feces (P< 0.001) and increased movement of the IncA/C plasmid to other indigenousE. colihosts. There was no evidence of conjugal transfer of the IncA/C plasmid to bacterial species other thanE. coli.In vitrocompetition assays demonstrated that bacterial host background substantially impacted the cost of IncA/C plasmid carriage inE. coliandSalmonella.In vitrotransfer and selection experiments demonstrated that tetracycline at 32 μg/ml was necessary to enhance IncA/C plasmid conjugative transfer, while subinhibitory concentrations of tetracyclinein vitrostrongly selected for IncA/C plasmid-containingE. coli. Together, these experiments improve our knowledge on the impact of differing concentrations of tetracycline on the selection of IncA/C-type plasmids.

scholarly journals Lysine Acetylation Regulates Alanyl-tRNA Synthetase Activity in Escherichia coli

Genes ◽  
2018 ◽  
Vol 9 (10) ◽  
pp. 473 ◽  
Author(s):  
Takuya Umehara ◽  
Saori Kosono ◽  
Dieter Söll ◽  
Koji Tamura
Keyword(s):  
Escherichia Coli ◽  
Trna Synthetase ◽  
Synthetase Activity ◽  
Lysine Acetylation ◽  
Trna Synthetases ◽  
E Coli ◽  
Domains Of Life ◽  
The Impact

Protein lysine acetylation is a widely conserved posttranslational modification in all three domains of life. Lysine acetylation frequently occurs in aminoacyl-tRNA synthetases (aaRSs) from many organisms. In this study, we determined the impact of the naturally occurring acetylation at lysine-73 (K73) in Escherichia coli class II alanyl-tRNA synthetase (AlaRS) on its alanylation activity. We prepared an AlaRS K73Ac variant in which Nε-acetyl-l-lysine was incorporated at position 73 using an expanded genetic code system in E. coli. The AlaRS K73Ac variant showed low activity compared to the AlaRS wild type (WT). Nicotinamide treatment or CobB-deletion in an E. coli led to elevated acetylation levels of AlaRS K73Ac and strongly reduced alanylation activities. We assumed that alanylation by AlaRS is affected by K73 acetylation, and the modification is sensitive to CobB deacetylase in vivo. We also showed that E. coli expresses two CobB isoforms (CobB-L and CobB-S) in vivo. CobB-S displayed the deacetylase activity of the AlaRS K73Ac variant in vitro. Our results imply a potential regulatory role for lysine acetylation in controlling the activity of aaRSs and protein synthesis.

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