The antistaphylococcal pharmacodynamics of linezolid alone and in combination with doxycycline in an in vitro dynamic model.

To delineate the possible advantages of linezolid/doxycycline combinations over either drug alone, the in vitro pharmacodynamics of linezolid, doxycycline and linezolid plus doxycycline were studied with Staphylococcus aureus.S. aureus ATCC 43300 and a clinical isolate S. aureus 479 were exposed to twice-daily linezolid and once-daily doxycycline, alone and in combination, for five consecutive days. Three dosing regimens were simulated with each drug alone: linezolid (AUC(24)/MIC 30, 60 and 200 h-L30, L60 and L200, respectively) and doxycycline (AUC(24)/MIC 90, 180 and 520 h - D90, D180 and D520, respectively) and in combination: linezolid plus doxycycline (L30+D90; L60+D180 and L200+D520).With both S. aureus ATCC 43300 and S. aureus 479 exposed to linezolid or doxycycline, the area between the line crossing each time-kill curve at the level of 10(8) CFU/mL and the respective time-kill curve (I(E)) increased with increasing simulated AUC(24)/MIC ratios. Each of the combined treatments produced greater I(E)s than the sum of linezolid and doxycycline I(E)s observed in the respective single drug treatments.This study suggests that linezolid combinations with doxycycline may be synergistic in treating staphylococcal infections.

Simulated in vitro quinolone pharmacodynamics at clinically achievable AUC/MIC ratios: advantage of I E over other integral parameters.

To compare the antimicrobial effects of clinically achievable ratios of area under the curve (AUC) to MIC, a clinical isolate of Moraxella catarrhalis was selected with MICs corresponding to the MIC(50)s of four quinolones. Monoexponentially declining concentrations observed in human plasma after oral administration of 1,000 mg of ciprofloxacin (as two 500-mg doses at a 12-hour interval), 320 mg gemifloxacin, 500 mg levofloxacin or 400 mg moxifloxacin (each as a single dose) and were simulated in an in vitro dynamic model. The respective half-lives were 4, 7.4, 6.8 and 12.1 h, and the AUC/MICs were 730, 1,130, 920 and 690 h. The time-kill/regrowth curves yielded similar patterns with the four quinolones: a rapid reduction in bacterial numbers followed by bacterial regrowth that occurred later with moxifloxacin than with ciprofloxacin, gemifloxacin, and levofloxacin. The total antimicrobial effect of moxifloxacin as expressed by the I(E) parameter (area between the control growth and time- kill curves from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of antimicrobial) was 30, 55, and 120% greater than gemifloxacin, levofloxacin and ciprofloxacin, respectively. Unlike I(E), the other integral indices determined over a fixed time (24 h) - the area between the control growth and time-kill curves, area above the time-kill curve and area under the time-kill curve were similar for the four fluoroquinolones, thus precluding their differentiation.

The pharmacodynamics of gatifloxacin and ciprofloxacin for pneumococci in an in vitro dynamic model: prediction of equiefficient doses.

Enhanced activity against Streptococcus pneumoniae is one of the putative advantages of gatifloxacin over older fluoroquinolones such as ciprofloxacin. This study examined ciprofloxacin and gatifloxacin pharmacodynamics against two differentially susceptible clinical isolates of S. pneumoniae (gatifloxacin MIC, 0.125 and 2 mg/L; ciprofloxacin MIC, 1 and 32 mg/L). The pharmacokinetics of gatifloxacin (single dose) and ciprofloxacin (two 12 hourly doses) with half-lives of 6 and 5 h, respectively, were simulated using a two-compartment dynamic model. The AUC/MIC ratios in the peripheral compartments that contain bacterial cultures varied over a four- to five-fold range, from 11 to 48 h with ciprofloxacin and from 15 to 78 h with gatifloxacin. The intensity of the antimicrobial effect (IE) increased with increasing AUC/MIC ratios in a strain-independent fashion, although different relationships of IE to log AUC/MIC were inherent for each drug (r2 0.73 for gatifloxacin and r2 0.94 for ciprofloxacin). Subsequently, the respective dose-response relationships of gatifloxacin and ciprofloxacin for a hypothetical strain of S. pneumoniae with MIC equal to the MIC50 were modelled. Based on these relationships, the equiefficient doses of gatifloxacin and ciprofloxacin were predicted for MIC50S of 0.4 and 1 mg/L, respectively. Gatifloxacin 400 mg was predicted to be equiefficient to ciprofloxacin 1400 mg. To provide the same anti-pneumococcal effect as the usual 1000 mg daily dose of ciprofloxacin, the respective daily dose of gatifloxacin could be as low as 180 mg. This in vitro study demonstrates advantages of gatifloxacin relative to ciprofloxacin in terms of the dose-dependent total antimicrobial effect.

Comparative anti-staphylococcal effects of gemifloxacin and trovafloxacin in an in vitro dynamic model in terms of AUC/MIC and dose relationships.

To compare the antimicrobial effects of gemifloxacin and trovafloxacin on Staphylococcus aureus, their pharmacodynamics were studied in an in vitro dynamic model. A series of pharmacokinetic profiles of gemifloxacin and trovafloxacin with half-lives of 7.4 and 9.2 h, respectively, were simulated in vitro over an eightfold range of area under the curve (AUC)-to-MIC ratio, from 58 to 466 h. The relationships observed between the intensity of antimicrobial effect (I(E)) and log AUC/MIC were linear, species- and strain-independent and were distinct (not superimposed) for both gemifloxacin and trovafloxacin (r(2) = 0.99 in both cases). At AUC/MICs > 100 h, trovafloxacin had greater effects than gemifloxacin. For example, at an AUC/MIC of 250 h, the antimicrobial effect of trovafloxacin was 17% higher than gemifloxacin. However, due to its higher intrinsic activity, gemifloxacin may be as efficient as trovafloxacin at their clinical doses (320 and 200 mg, respectively): the I(E)s on a hypothetical strain of S. aureus with gemifloxacin's and trovafloxacin's MICs corresponding to the MIC(50)s were similar-290 and 310 (log CFU/mL)x h, respectively. This analysis suggests that both AUC/MIC and dose relationships of the antimicrobial effect are needed for comprehensive comparisons of fluoroquinolone pharmacodynamics.

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.

Most integral endpoints of the antimicrobial effect are determined over an arbitrarily chosen time period, such as the dosing interval (tau), regardless of the actual effect duration. Unlike the tau-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 of Staphylococcus 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 tau-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 tau = 24 h. Unlike the I(E), which displayed pseudolinear relationships with the AUC/MIC ratio; each tau-related endpoint showed a distinct saturation at potentially therapeutic AUC/MIC ratios (116 to 466 h) when the antimicrobial effect persisted longer than tau. 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 tau-related endpoints as indices of the total antimicrobial effect. Since all of them respond to AUC/MIC ratio changes less than the I(E), the latter is preferable in comparative pharmacodynamic studies.

Gemifloxacin and ciprofloxacin pharmacodynamics in an in-vitro dynamic model: prediction of the equivalent AUC/MIC breakpoints and doses.

To compare the antimicrobial effects (AMEs) of gemifloxacin (GEM) and ciprofloxacin (CIP) on Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, a series of pharmacokinetic profiles of GEM (a single dose with the half-life (T(1/2)) of 7.4 h and CIP (two 12 h doses with T(1/2) of 4 h) were simulated in vitro over eight-fold ranges of the AUC/MIC ratio. Species- and strain-independent linear relationships observed between the intensity of AME (I(E)) and log AUC/MIC were not superimposed for GEM and CIP (r(2)=0.99 and 0.98, respectively). The predicted ratio for GEM that might be equivalent to a clinically established breakpoint value of AUC/MIC=125 (mg h/l)/(mg/l) for CIP was estimated at 110 (mg h/l)/(mg/l). It was calculated, that a daily dose of CIP that might provide the same AME as a clinical dose of GEM (320 mg) on a hypothetical strain of S. aureus with MICs=MIC(50)s would be as high as 2 x 3200 mg.

Comparative pharmacodynamics of moxifloxacin and levofloxacin in an in vitro dynamic model: prediction of the equivalent AUC/MIC breakpoints and equiefficient doses.

To demonstrate the impact of the different pharmacokinetics of moxifloxacin and levofloxacin on their antimicrobial effects (AMEs), killing and regrowth kinetics of two clinical isolates of Staphylococcus aureus and one each of Escherichia coli and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of single doses of moxifloxacin (T:1/2 = 12.1 h) and levofloxacin (T:(1/2) = 6.8 h) were simulated. The respective eight-fold ranges of the ratios of area under the concentration-time curve (AUC) to the MIC were 58-475 and 114-934. Species- and strain-independent linear relationships observed between the intensity of AME (I:(E)) and log AUC/MIC were not superimposed for moxifloxacin and levofloxacin (r(2) = 0.99 in both cases). The predicted AUC/MIC ratios for moxifloxacin and levofloxacin that might be equivalent to Schentag's AUC/MIC breakpoint for ciprofloxacin (125) were estimated at 80 and 130, respectively. The respective equivalent MIC breakpoints were 0.41 mg/L (for a 400 mg dose of moxifloxacin) and 0.35 mg/L (for a 500 mg dose of levofloxacin). Based on the I:(E)-log AUC/MIC relationships, equiefficient 24 h doses (D:(24)s) of moxifloxacin and levofloxacin were calculated for hypothetical strains of S. aureus, E. coli and K. pneumoniae with MICs equal to the respective MIC50s (weighted geometric means of reported values). To provide an 'acceptable' I:(E) = 200 (log cfu/mL)*h, the D:(24)s of moxifloxacin for all three organisms were much lower (150, 30 and 60 mg, respectively) than the clinically proposed 400 mg dose. Although the usual dose of levofloxacin (500 mg) would be in excess for E. coli and K. pneumoniae (D:(24) = 36 and 220 mg, respectively), it might be insufficient for S. aureus (the estimated D:(24) = 850 mg). Moreover, to provide the same effect as a 400 mg D:(24) of moxifloxacin against staphylococci, levofloxacin would have to be given in a 5000 mg D:(24), which is 10-fold higher than its clinically accepted dose. The described method of generalization of data obtained with specific organisms to other representatives of the same species might be useful to predict the AMEs of new quinolones.

New pathogens in neutropenic patients with cancer: an update for the new millennium.

As patients with malignant diseases are treated with increasingly potent agents it is likely that they will be subject to infection with an ever broadening array of microorganisms. As a result of the prompt institution of empirical antibiotics at the onset of fever in neutropenic patients, mortality has been reduced but new problems have emerged. First, there has been a shift in the type of infecting organisms responsible for bacteraemia in these patients from predominantly Gram-negative organisms to Gram-positive cocci. Secondly, perhaps as a consequence of the effectiveness of antibiotics, there is increasing concern about infections with antibiotic-resistant organisms. As an example, viridans streptococci are becoming increasingly resistant to penicillin. Thirdly, organisms previously thought to be non pathogens or 'commensals' are now being reported as agents of serious invasive infections in neutropenic patients with cancer. This review will highlight these changes and discuss 'new' pathogens in these patients.

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.

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 (microg. h/ml)/(microg/ml). The species- and strain-independent linear relationships observed between the intensity of AME (I(E)) 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 (microg. h/ml)/(microg/ml). The respective MIC breakpoints were 0.32 microg/ml (for a 400-mg dose of GA) and 0.18 microg/ml (for two 500-mg doses of CI). On the basis of the I(E)-log AUC/MIC relationships, equiefficient 24-h doses (D(24h)s) of GA and CI were calculated for hypothetical strains of S. aureus, E. coli, and K. pneumoniae for which the MICs were equal to the MICs at which 50% of isolates are inhibited. To provide an "acceptable" I(E) equal to 200 (log CFU/ml). h, i.e., the I(E) provided by AUC/MIC of 125 (microg. h/ml)/(microg/ml) for ciprofloxacin, the D(24h)s 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.

Comparative activities of ciprofloxacin and levofloxacin against Streptococcus pneumoniae in an In vitro dynamic model.

The activities of levofloxacin (500 mg every 24 h) and ciprofloxacin (750 mg every 12 h) against six pneumococcal isolates in an in vitro dynamic model were compared. For one strain, levofloxacin reduced the inoculum by over 4 log CFU/ml and ciprofloxacin reduced the inoculum by over 2 log CFU/ml. For four isolates, both drugs reduced inocula by 4 log CFU/ml within 6 h, suggesting that this dose of ciprofloxacin should be as effective as levofloxacin against these pneumococci.

In vitro dynamic model for determining the comparative pharmacology of fluoroquinolones.

An in vitro model for determining the comparative pharmacology of fluoroquinolones is presented. The true therapeutic potential of fluoroquinolones against bacterial pathogens may be best understood before clinical testing with the use of in vitro dynamic models. These models simulate pharmacokinetics in humans and can be used to compare different drugs in the same class over a wide range of dosages with respect to the antimicrobial effect (AME). Two models for evaluating AME are described. In one (a two-compartment model), a simple bacterial killing curve is generated after exposure to simulated clinical doses of antimicrobial. In the other (a one-compartment model), AME is defined as the area between the control bacterial growth curve in the absence of drug and the curve that represents bacterial killing and regrowth. This area can be readily measured and is referred to as the intensity of the effect (I(e)). In general, AME is correlated with drug exposure, as simulated in the model at different ratios of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC) for the organism under study. With this in vitro dynamic model, several fluoroquinolones were tested over a range of AUC/MIC ratios for their AMEs against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. The data generated illustrate the usefulness of in vitro dynamic models for comparing AMEs of different fluoroquinolones. Because the model incorporates pharmacokinetic variables, it provides a method for comparing various dosage regimens or schedules of administration and is useful in preclinical drug development.

Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria.

Over the past 3 decades, considerable changes have occurred in the types of bacteria causing infection in febrile patients with neutropenia and cancer. Twenty years ago, gram-negative bacteria caused approximately 70% of bloodstream infections. As a probable consequence of long-dwelling intravascular devices, fluoroquinolone prophylaxis, and high-dose chemotherapy-induced mucositis, there has been a shift toward gram-positive coccal bacteremia. In most centers today, approximately 70% of bacteremic isolates are gram-positive cocci. Of potential concern is that antimicrobial-resistant gram-positive organisms are becoming increasingly frequent in patients with neutropenia. Fluoroquinolone-resistant Escherichia coli are being isolated from several cancer centers. Several "new" organisms, such as Stomatococcus mucilaginosus, Bacillus cereus, Leuconostoc species, Corynebacterium jeikeium, Rhodococcus species, Stenotrophomonas maltophilia, Moraxella catarrhalis, Burkholderia cepacia, and Bartonella species, now cause infections in these patients. Careful application of infection-control principles, judicious prophylaxis, appropriate evaluation of new antibiotics, and prompt effective therapy will maximize benefits for these patients.

Prediction of the antimicrobial effects of trovafloxacin and ciprofloxacin on staphylococci using an in-vitro dynamic model.

To compare the pharmacodynamics of trovafloxacin and ciprofloxacin, three clinical isolates of Staphylococcus aureus with different MICs (0.03, 0.15, 0.6 and 0.1, 0.25, 1.25 mg/L, respectively) were exposed to decreasing concentrations of the quinolones according to their half-lives of 9.25 and 4 h, respectively. With each organism, single doses of trovafloxacin and twice-daily doses of ciprofloxacin were designed to provide 8-fold ranges of the ratio of area under the concentration-time curve (AUC) to the MIC, 58-466 and 116-932 (mg x h/L)/(mg/L), respectively. The antimicrobial effect was expressed by its intensity: the area between the control growth in the absence of antibiotics and the antibiotic-induced time-kill/regrowth curves (I(E)). Linear relationships established between I(E) and log AUC/MIC were bacterial strain-independent but specific for the quinolones (r2 = 0.99 in both cases). At a given AUC/MIC ratio, the I(E)s of trovafloxacin were greater than those of ciprofloxacin, suggesting that the antimicrobial effect of trovafloxacin compared with ciprofloxacin against staphylococci may be even greater than might be expected from the difference in their MICs. These data were combined with previous results obtained with three Gram-negative bacteria. Again, I(E) correlated well with the log AUC/MIC of trovafloxacin and ciprofloxacin in a strain- and species-independent fashion (r2 = 0.94 and 0.96, respectively). On this basis, a value of the AUC/MIC of trovafloxacin which might be equivalent to Schentag's AUC/MIC = 125 (mg x h/L)/(mg/L) reported as the breakpoint value for ciprofloxacin was estimated at 71 (mg x h/L)/(mg/L) with the respective MIC breakpoint of 0.27 mg/L. Based on the I(E)-log AUC/MIC relationships, the I(E)s were plotted against the logarithm of trovafloxacin and ciprofloxacin dose (D) for hypothetical representatives of S. aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa with MICs corresponding to the MIC50s. These I(E)-log D relationships allow prediction of the effect of a given quinolone on a representative strain of the bacterial species.

Prediction of the effects of inoculum size on the antimicrobial action of trovafloxacin and ciprofloxacin against Staphylococcus aureus and Escherichia coli in an in vitro dynamic model.

The effect of inoculum size (N0) 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 and Escherichia coli exposed to monoexponentially decreasing concentrations of trovafloxacin (as a single dose) and ciprofloxacin (two doses at a 12-h interval) were compared at N0 = 10(6) and 10(9) CFU/ml (S. aureus) and at N0 = 10(6), 10(7), and 10(9) 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 x 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 N0 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 N0 for both organisms. The N0-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 N0 effect could not be eliminated either by simple shifting of the time-kill curves obtained at higher N0s by the difference between the higher and lowest N0 or by operating with IEs determined within the N0-adopted upper limits of bacterial numbers (IE's). By using multivariate correlation and regression analyses, linear relationships between IE and log AUC/MIC and log N0 related to the respective mean values [(log AUC/MIC)average and (log N0)average] were established for both trovafloxacin and ciprofloxacin against each of the strains (r2 = 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 N0 based on the relationship IE = a + b [(log AUC/MIC)/(log AUC/MIC)average] - c [(log N0)/(log N0)average]. Moreover, the relative impacts of AUC/MIC and N0 on IE may be evaluated. Since the c/b ratios for trovafloxacin and ciprofloxacin against E. coli were 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 beta-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.

MIC-based interspecies prediction of the antimicrobial effects of ciprofloxacin on bacteria of different susceptibilities in an in vitro dynamic model.

Multiple predictors of fluoroquinolone antimicrobial effects (AMEs) are not usually examined simultaneously in most studies. To compare the predictive potentials of the area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC), the AUC above MIC (AUCeff), and the time above MIC (Teff), the kinetics of killing and regrowth of four bacterial strains exposed to monoexponentially decreasing concentrations of ciprofloxacin were studied in an in vitro dynamic model. The MICs of ciprofloxacin for clinical isolates of Staphylococcus aureus, Escherichia coli 11775 (I) and 204 (II), and Pseudomonas aeruginosa were 0.6, 0.013, 0.08, and 0.15 microg/ml, respectively. The simulated values of AUC were designed to provide similar 1,000-fold (S. aureus, E. coli I, and P. aeruginosa) or 2, 000-fold (E. coli II) ranges of the AUC/MIC. In each case except for the highest AUC/MIC ratio, the observation periods included complete regrowth in the time-kill curve studies. The AME was expressed by its intensity, IE (the area between the control growth and time-kill and regrowth curves up to the point where the viable counts of regrowing bacteria are close to the maximum values observed without drug). For most AUC ranges the IE-AUC curves were fitted by an Emax (maximal effect) model, whereas the effects observed at very high AUCs were greater than those predicted by the model. The AUCs that produced 50% of maximal AME were proportional to the MICs for the strains studied, but maximal AMEs (IEmax) and the extent of sigmoidicity (s) were not related to the MIC. Both Teff and log AUC/MIC correlated well with IE (r2 = 0.98 in both cases) in a species-independent fashion. Unlike Teff or log AUC/MIC, a specific relationship between IE and log AUCeff was inherent in each strain. Although each IE and log AUCeff plot was fitted by linear regression (r2 = 0.97 to 0.99), these plots were not superimposed and therefore are bacterial species dependent. Thus, AUC/MIC and Teff were better predictors of ciprofloxacin's AME than AUCeff. This study suggests that optimal predictors of the AME produced by a given quinolone (intraquinolone predictors) may be established by examining its AMEs against bacteria of different susceptibilities. Teff was shown previously also to be the best interquinolone predictor, but unlike AUC/MIC, it cannot be used to compare different quinolones. AUC/MIC might be the best predictor of the AME in comparisons of different quinolones.

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.

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 (microg . h/ml)/(microg/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 [IE]). 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 IE and log AUC/MIC were established for TR and CI against three bacteria: Escherichia coli (MIC of TR [MICTR] = 0.25 microg/ml; MIC of CI [MICCI] = 0.12 microg/ml), Pseudomonas aeruginosa (MICTR = 0.3 microg/ml; MICCI = 0.15 microg/ml), and Klebsiella pneumoniae (MICTR = 0.25 microg/ml; MICCI = 0.12 microg/ml). The slopes and intercepts of these relationships differed for TR and CI, and the IE-log AUC/MIC plots were not superimposed, although they were similar for all bacteria with a given antibiotic. By using the relationships between IE 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 (microg . h/ml)/(microg/ml)] was approximately twofold lower than that for CI. Based on the IE-log AUC/MIC relationships, the respective dose (D)-response relationships were reconstructed. Like the IE-log AUC/MIC relationships, the IE-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 IE 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.

Inter- and intraquinolone predictors of antimicrobial effect in an in vitro dynamic model: new insight into a widely used concept.

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 (microg x h/ml)/(microg/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 (Teff). Specific and nonsuperimposed IE versus log AUC/MIC or log AUCeff relationships were inherent in each of the treatments: TRO given q.d. (r2 = 0.97 and 0.96), CIP given q.d. (r2 = 0.98 and 0.96), and CIP given b.i.d. (r2 = 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-Teff relationships plotted for the different quinolones and dosing regimens were nonspecific and virtually superimposed (r2 = 0.95). Hence, AUC/MIC, AUCeff and Teff were equally good predictors of the AME of each of the quinolones and each dosing regimen taken separately, whereas Teff 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 Teff 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 (Teff). Teff may be able to accurately predict the AME of one quinolone on the basis of the data obtained for another quinolone.