The Rate of Killing of Escherichia coli by -Lactam Antibiotics Is Strictly Proportional to the Rate of Bacterial Growth (original) (raw)
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Antimicrobial Agents and Chemotherapy, 2010
The objectives of the study were to develop a quantitative framework for generating hypotheses for and interpreting the results of time-kill and continuous-culture experiments designed to evaluate the efficacy of antibiotics and to relate the results of these experiments to MIC data. A mathematical model combining the pharmacodynamics (PD) of antibiotics with the population dynamics of bacteria exposed to these drugs in batch and continuous cultures was developed, and its properties were analyzed numerically (using computer simulations). These models incorporate details of (i) the functional form of the relationship between the concentrations of the antibiotics and rates of kill, (ii) the density of the target population of bacteria, (iii) the growth rate of the bacteria, (iv) byproduct resources generated from dead bacteria, (v) antibiotic-refractory subpopulations, persistence, and wall growth (biofilms), and (vi) density-independent and -dependent decay in antibiotic concentrations. Each of the factors noted above can profoundly affect the efficacy of antibiotics. Consequently, if the traditional (CLSI) MICs represent the sole pharmacodynamic parameter, PK/PD indices can fail to predict the efficacy of antibiotic treatment protocols. More comprehensive pharmacodynamic data obtained with time-kill and continuous-culture experiments would improve the predictive value of these indices. The mathematical model developed here can facilitate the design and interpretation of these experiments. The validity of the assumptions behind the construction of these models and the predictions (hypotheses) generated from the analysis of their properties can be tested experimentally. These hypotheses are presented, suggestions are made about how they can be tested, and the existing statuses of these tests are briefly discussed.
F1000 - Post-publication peer review of the biomedical literature, 2010
To determine the functional relationship between the density of bacteria and the pharmacodynamics of antibiotics, and the potential consequences of this inoculum effect on the microbiological course of antibiotic treatment of Staphylococcus aureus infections. Methods: In vitro time-kill, MIC estimation and antibiotic bioassay experiments were performed with S. aureus ATCC 25923 to ascertain the functional relationship between rates of kill and the MICs of six classes of antibiotics and the density of bacteria exposed. The potential consequences of the observed inoculum effects on the microbiological course of antibiotic treatment are explored with a mathematical model. Results: Modest or substantial inoculum effects on efficacy were observed for all six antibiotics studied, such as density-dependent declines in the rate and extent of antibiotic-mediated killing and increases in MIC. Although these measures of antibiotic efficacy declined with inoculum, this density effect did not increase monotonically. At higher densities, the rate of kill of ciprofloxacin and oxacillin declined with the antibiotic concentration. For daptomycin and vancomycin, much of this inoculum effect is due to density-dependent reductions in the effective concentration of the antibiotic. For the other four antibiotics, this density effect is primarily associated with a decrease in per-cell antibiotic concentration. With parameters in the range estimated, our mathematical model predicts that the course of antibiotic treatment can be affected by cell density; treatment protocols based on conventional (density-independent) MICs can fail to clear higher density infections. Conclusions: The MICs used for pharmacokinetic/pharmacodynamic indices should be functions of the anticipated densities of the infecting population.
2019
Background: Antibiotics, and biocide antiseptic disinfectants e.g. Triclosan and Chlorhexidine are all used for their antimicrobial properties. Other commonly used drugs like Ibuprofen and Fluoxetine are routinely used by many in the industrialised world but are generally not perceived to be associated with antimicrobial activity Aims: To investigate the effects of biocides and two commonly used oral, non-antimicrobially associated drugs on the growth and susceptibilities of common pathogenic bacteria. Materials and methods: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were each plated onto different media containing Triclosan, Chlorhexidine, Ibuprofen, or Fluoxetine at different measured concentrations to investigate their antimicrobial properties. Susceptibility testing was performed on colonies grown on each media to measure its resistance levels. Results: Five of the 64 bacterial tests showed increased resistance to antibiotics after 72hrs incubation when compared to values obtained after 24hrs. In particular, Triclosan and Fluoxetine each showed inducibility of resistance in K. pneumoniae at sub-lethal concentrations. Conclusions: More research is needed into the potential antimicrobial resistance-inducing properties of commonly used biocides as well as other commonly used drugs which are not usually associated with antimicrobial resistance but may in fact also be contributing to the development of antimicrobial drug resistance in common bacterial strains, as well as microbiome perturbation.
Current Microbiology, 1998
Various environmental conditions likely to be encountered at a nidus of infection were evaluated for their effect on selected classes of antimicrobial agents. The minimum inhibitory concentration (MIC) of several aminoglycosides (apramycin, kanamycin, gentamicin, tobramycin, amikacin), tetracycline, and chloramphenicol for five strains of E. coli were unchanged by temperature (35°-39.5°C), atmosphere (aerobic to anaerobic), pH Ͼ 7, NaCl concentration (up to 150 mM), zinc concentration (up to 50 mM), and manganese (up to 10 mM). However, the aminoglycoside MICs were increased up to fivefold at pH Ͻ 6.5. Magnesium and calcium ion concentrations Ͼ10 mM and ferric iron concentrations Ն10 mM increased aminoglycoside MICs from 3.66-to 8-fold. Tetracycline MICs were increased 1.2-to 6.5-fold when the concentration of magnesium or calcium was Ն10 mM. The results of this in vitro study might provide insight into the effects of local in vivo environmental conditions on several classes of antimicrobial agents.