Suprainhibitory Concentrations Research Articles

Bactericidal activity of lomefloxacin SC 47111 (NY-198) and ciprofloxacin against selected pathogens

The bactericidal activity of lomefloxacin and ciprofloxacin against selected pathogens was compared using kill-kinetic methods to assess inhibitory (1 × MIC) and suprainhibitory (4 × MIC) concentrations. Five strains each of the following microorganisms were studied: Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. We found that lomefloxacin was 8- to 16-fold less active than ciprofloxacin as measured by MICs. However, the bactericidal activities of both lomefloxacin and ciprofloxacin were comparable when concentrations × MIC and 4 × MIC were tested. For many of the isolates tested, such concentrations would be achieved clinically. The low MICs seen for the Gramnegative bacilli did not correlate with killing ability for either drug: concentrations 8–16 × MIC were needed for 99.9% killing of the final inoculum. Although higher concentrations of lomefloxacin are needed for inhibitory and bactericidal activity, the improved pharmacokinetics of lomefloxacin may result in this agent being comparable to ciprofloxacin.

Comparison of the in vitro action and interaction of cefotaxime and desacetylcefotaxime against clinical isolates of Bacteroides spp.

Desacetylcefotaxime (dCTX), the in vivo metabolite of cefotaxime (CTX), possess significant in vitro antimicrobial activity similar to the parent compound against a variety of aerobic and anaerobic bacteria. In vitro susceptibility studies showed that CTX inhibited 86% of 473 strains of the Bacteroides fragilis at a concentration of 32 micrograms/ml while dCTX inhibited 91% of the test isolates at the same concentration. Strains of the B. fragilis species were significantly more susceptible to CTX than were the non-B. fragilis species. Susceptibility testing of CTX and dCTX in a 1:1 ratio produced significantly more inhibitory activity, especially against the non-B. fragilis strains. Synergy studies showed that the interaction of CTX and dCTX was either completely or partially synergistic against 85% of 92 test organisms. The presence of dCTX was also shown to lower the CTX MIC values four-fold or greater in 82% of the synergy studies. Synergy was noted against strains of the B. fragilis group, B. melaninogenicus group, B. bivius, B. disiens, and B. capillosus. Through the use of time-kill kinetics studies, the interaction of CTX and dCTX was shown to be additive at subinhibitory and inhibitory concentrations and suggestedly synergistic at suprainhibitory concentrations against strains of the B. fragilis group. These in vitro studies demonstrate that dCTX increases the inhibitory and bactericidal activity of CTX when tested in combination.

Correlation between Growth Curves and Killing Curves of <i>Escherichia coli </i>in the Presence of Fleroxacin and Ampicillin

Fleroxacin, a new long-acting quinolone, induces rapid killing and bacterial filamentation as do other quinolones. Ten strains of Escherichia coli were exposed comparatively to fleroxacin and ampicillin in order to determine the effect of sub- and supra-inhibitory concentrations of each of these two compounds on turbidimetric growth curves and viable counts. By comparing the maximal early increase in optical density (OD, PIOD) as colony-forming units per milliliter (CFU/ml) after 2 and 6 h of exposure to antibiotics, we observed a reduced number of CFU/ml in comparison with the control after the 2-hour exposure at 1/4 the minimum inhibition concentration (MIC) and after 6 h at 1/8 MIC, but a high OD value was also seen among the fleroxacin exposed bacteria. For ampicillin, PIOD rates and killing rates were slower and dose dependent. This discrepancy was due to filament formation, which increased the PIOD value to the same extent as the control curve. After exposure to fleroxacin at 1/2 MIC the PIOD decreased significantly and after 2 and 6 h E. coli killing rates of 99 and 99.9%, respectively, were observed. With exposure to 2 and 4 x MIC, both PIOD values and CFU/ml decreased substantially. Combined analysis of continuous turbidimetric monitoring and viable counts showed that subinhibitory concentrations of fleroxacin and beta-lactam had different effects on E. coli. Fleroxacin's rapid killing rate, despite filament formation, contrasted with the result obtained with ampicillin. The minimum antibiotic concentration of fleroxacin against E. coli was around 1/8 MIC.

Enhanced susceptibility of gram-negative bacteria to phagocytic killing by human polymorphonuclear leucocytes after brief exposure to aztreonam.

Brief exposure of Escherichia coli, Serratia marcescens, Klebsiella pneumoniae and Salmonella typhimurium to supra-inhibitory concentrations of aztreonam enhanced their susceptibility to phagocytic killing by human polymorphonuclear leucocytes. The effect was independent of the continuous presence of the antibiotic and required the presence of serum opsonins. Phagocytic killing of Pseudomonas aeruginosa was enhanced by prior exposure to subminimal inhibitory concentrations, and killing, relative to control bacteria, was not increased with increasing concentrations of aztreonam above minimal inhibitory concentrations. The degree of sensitization, and the range of bacteria susceptible to antibiotic modulation varied between antibiotics. Under the conditions of these experiments, gentamicin sensitized pseudomonas, but failed to sensitize E. coli, while cefotaxime failed to sensitize serratia, and varied in it's activity against E. coli and pseudomonas. Enhanced killing of aztreonam-pretreated bacteria was associated with an increase in uptake by leucocytes. Aztreonam exposure decreased the liability of the bacteria to hydrophilic interactions in an aqueous two-phase partitioning system. These observations indicate that exposure of Gram-negative bacteria to aztreonam enhances phagocytic killing through modification of cell surface structures. This may be mediated through an increase in surface hydrophobicity which enhances bacterial association with leucocyte membranes with subsequent phagocytosis and intracellular killing.

Correlation between growth curve and killing curve of Escherichia coli after a brief exposure to suprainhibitory concentrations of ampicillin and piperacillin.

Escherichia coli strains that were susceptible to multiple antibiotics were exposed to suprainhibitory concentrations of ampicillin and piperacillin. As with the majority of beta-lactam antibiotics, the growth curves showed an increase in optical density (OD) before lysis during the first hours. This increase in OD depended on the concentration of ampicillin and was independent of the concentration of piperacillin. A good correlation was found between the prelytic increase in OD and the killing curve. During the prelytic increase in OD, the number of CFU per milliliter remained constant. The decrease in the number of CFU per milliliter depended on the concentration of ampicillin and was independent of the concentration of piperacillin. pH variations gave rise to similar effects on growth curves and killing curves.

Dose-activity relationships in chemotherapy.

The in vitro antibacterial effects of subinhibitory and suprainhibitory concentrations of a number of beta-lactam antibiotics and aminoglycosides on microbial growth are presented. The type and extent of the subinhibitory activity of a drug can be well defined by means of growth curves obtained with different subinhibitory concentrations; from these values one can deduce and define the minimal active concentration (MAC) as the concentration at which morphological alterations or inhibition of growth of the bacteria can be seen. The effect of suprainhibitory concentrations can be evaluated by studying the kinetics of the bactericidal activity of a drug. Different types of bactericidal dose-activity relationships can be observed; in many cases a minimal optimal concentration (MOC) can be defined as the lowest concentration of a drug which causes no further appreciable enhancement of efficacy on increasing the concentration. Usually chemotherapy is carried out at subinhibitory drug levels--with decreasing and increasing concentrations--and at present it would appear difficult to assess these constant changes in an in vitro test. Bacteriologists should thus take into account the clinicians' demands for more precise bacteriological data on antibacterial agents.