scholarly journals Net effect of inoculum size on antimicrobial action of ampicillin-sulbactam: studies using an in vitro dynamic model.

1997 ◽  
Vol 41 (1) ◽  
pp. 7-12 ◽  
Author(s):  
A A Firsov ◽  
M Ruble ◽  
D Gilbert ◽  
D Saverino ◽  
D Savarino ◽  
...  
Keyword(s):  
Dynamic Model ◽  
Approximate Equation ◽  
Bacterial Count ◽  
Inoculum Size ◽  
Antimicrobial Action ◽  
Time Curve ◽  
Bacterial Counts ◽  
The Difference ◽  
Different Strains

To examine the predictable effect of inoculum size on the kinetics of the antimicrobial action of ampicillin-sulbactam, five TEM-1 beta-lactamase-producing Escherichia coli strains were studied in an in vitro dynamic model at two different initial inocula (N0S). All bacteria were exposed to ampicillin-sulbactam in a simulated system reflecting the pharmacokinetic profiles in human tissue after the administration of a single intravenous dose of ampicillin (2 g) plus sulbactam (1 g). Each strain was studied at low (4.0 to 5.2 log CFU/ml) and high (5.0 to 7.1 log CFU/ml) N0S. Despite pronounced differences in susceptibilities, the patterns of the killing curves observed with a given strain at different N0S were similar. As expected, viable bacterial counts increased with inoculum size. Striking visual contrasts in the respective curves for each organism were reflected by the area under the bacterial count-time curve (AUBC) but not by the difference between the N0 and the lowest bacterial counts (Nmin) at the nadir of the killing curve: the N0-associated changes in the AUBC on average were 75%, versus 2.5% for log N0--logNmin. To examine qualitative differences in antimicrobial effects at different N0S (i.e., the net effect of the inoculum), the difference in the high and low N0S was subtracted from each point on the killing curve obtained at the higher N0 for each strain. These adjusted curves were virtually superimposable on the observed killing curves obtained at the lower N0. Moreover, by using adjusted data, the AUBC values were similar at the two inocula, although slight (average, 11%) but systematic increases in the AUBC occurred at high N0S. Thus, there was only a weak net effect of inoculum size on the antibacterial effect of ampicillin-sulbactam. Due to similar slopes of the AUBC-log N0 plots, the antibacterial action at different N0S may be easily predicted by an approximate equation; the predicted AUBCs were unbiased and well correlated with the observed AUBCs (r = 0.997). Compiled data obtained with normalized AUBCs for different strains at different N0S yielded a positive correlation (r = 0.963) between the N0-normalized AUBC and the MIC of ampicillin-sulbactam. The adjustment and normalization procedure described might be a useful tool for revealing the net effect of the inoculum and to predict the inoculum effect if there are no qualitative differences in antimicrobial action at different inocula.

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 Net Effect of Inoculum Size on Antimicrobial Action of Ampicillin-Sulbactam: Studies Using an In Vitro Dynamic Model

2006 ◽  
Vol 50 (9) ◽  
pp. 3230-3230
Author(s):  
Alexander A. Firsov ◽  
Matthew Ruble ◽  
Deborah Gilbert ◽  
Daniele Saverino ◽  
Brenda Manzano ◽  
...  
Keyword(s):  
Dynamic Model ◽  
Inoculum Size ◽  
Antimicrobial Action

A dynamic model for in-vitro evaluation of antimicrobial action by simulation of the pharmacokinetic profiles of antibiotics

1989 ◽  
Vol 23 (3) ◽  
pp. 389-399 ◽  
Author(s):  
S. M. Navashin ◽  
I. P. Fomina ◽  
A. A. Firsov ◽  
V. M. Chernykh ◽  
S. Kuznetsova
Keyword(s):  
Dynamic Model ◽  
Antimicrobial Action ◽  
In Vitro Evaluation ◽  
Pharmacokinetic Profiles

scholarly journals Activities of Ciprofloxacin and Moxifloxacin against Stenotrophomonas maltophilia and Emergence of Resistant Mutants in an In Vitro Pharmacokinetic-Pharmacodynamic Model

2004 ◽  
Vol 48 (3) ◽  
pp. 946-953 ◽  
Author(s):  
Boubakar B. Ba ◽  
Hala Feghali ◽  
Corinne Arpin ◽  
Marie-Claude Saux ◽  
Claudine Quentin
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Combined Therapy ◽  
Bacterial Count ◽  
Repeated Administration ◽  
Pharmacodynamic Model ◽  
Cross Resistance ◽  
Bacterial Cells ◽  
Time Curve ◽  
Resistant Mutants

ABSTRACT A two-compartment in vitro pharmacokinetic-pharmacodynamic model, with full computer-controlled devices, was used to accurately simulate human plasma pharmacokinetic profiles after multidose oral regimens of ciprofloxacin (750 mg every 12 h) and moxifloxacin (400 mg every 24 h) during 48 h. Pharmacodynamics of these drugs was investigated against three quinolone-susceptible strains of Stenotrophomonas maltophilia (MICs of ciprofloxacin and moxifloxacin of 0.5 to 2 and 0.0625 to 0.5 μg/ml, respectively). The first dose of ciprofloxacin and moxifloxacin reduced the bacterial count by 1 and 2 log CFU/ml, respectively, prior to a bacterial regrowth that reached the plateau value of the growth control curve at 13 to 24 h versus 24 to 36 h and persisted despite repeated administration of both drugs. The surviving bacterial cells were quinolone-resistant mutants (2 to 128 times the MIC) that exhibited cross-resistance to unrelated antibiotics. Their antibiotic resistance probably resulted from the overproduction of different multidrug resistance efflux system(s). C max/MIC and area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC values were at least threefold higher for moxifloxacin than for ciprofloxacin. Moreover, integral parameters of ciprofloxacin and moxifloxacin, in particular the area under the killing and regrowth curve from 0 to 48 h (AUBC0-48, 342.3 to 401.3 versus 295.2 to 378.7 h × log CFU/ml, respectively) and the area between the control growth curve and the killing and regrowth curve from 0 to 48 h (ABBC0-48, 40.4 to 101.1 versus 72.9 to 144.7 h × log CFU/ml, respectively), demonstrated a better antibacterial effect of moxifloxacin than ciprofloxacin on S. maltophilia. However, selection of resistant mutants by both fluoroquinolones, although delayed with moxifloxacin, emphasizes the need to use maximal dosages and combined therapy in the treatment of systemic S. maltophilia infections.

scholarly journals MIC-Based Interspecies Prediction of the Antimicrobial Effects of Ciprofloxacin on Bacteria of Different Susceptibilities in an In Vitro Dynamic Model

1998 ◽  
Vol 42 (11) ◽  
pp. 2848-2852 ◽  
Author(s):  
Alexander A. Firsov ◽  
Sergey N. Vostrov ◽  
Alexander A. Shevchenko ◽  
Stephen H. Zinner ◽  
Giuseppe Cornaglia ◽  
...  
Keyword(s):  
Dynamic Model ◽  
Bacterial Species ◽  
Maximal Effect ◽  
Bacterial Strains ◽  
Time Curve ◽  
Antimicrobial Effects ◽  
E Coli ◽  
Kill Curve ◽  
Time Kill

ABSTRACT 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 (T eff), 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 ofStaphylococcus aureus, Escherichia coli11775 (I) and 204 (II), and Pseudomonas aeruginosa were 0.6, 0.013, 0.08, and 0.15 μg/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,I E (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 I E-AUC curves were fitted by an E max (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 (I E max ) and the extent of sigmoidicity (s) were not related to the MIC. BothT eff and log AUC/MIC correlated well withI E (r 2 = 0.98 in both cases) in a species-independent fashion. UnlikeT eff or log AUC/MIC, a specific relationship between I E and log AUCeff was inherent in each strain. Although each I E and log AUCeff plot was fitted by linear regression (r 2 = 0.97 to 0.99), these plots were not superimposed and therefore are bacterial species dependent. Thus, AUC/MIC and T eff 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.T eff 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.

scholarly journals Activities of Clindamycin, Daptomycin, Doxycycline, Linezolid, Trimethoprim-Sulfamethoxazole, and Vancomycin against Community-Associated Methicillin-Resistant Staphylococcus aureus with Inducible Clindamycin Resistance in Murine Thigh Infection and In Vitro Pharmacodynamic Models

2008 ◽  
Vol 52 (6) ◽  
pp. 2156-2162 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Steven N. Leonard ◽  
David R. Andes ◽  
William A. Craig ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Inoculum Size ◽  
In Vivo Model ◽  
Infection Model ◽  
Time Curve ◽  
In Vivo Models ◽  
Methicillin Resistant ◽  
Inducible Clindamycin Resistance

ABSTRACT Controversy exists about the most effective treatment options for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and about the ability of these strains to develop inducible resistance to clindamycin during therapy. Using both in vitro pharmacodynamic and murine thigh infection models, we evaluated and compared several antimicrobial compounds against CA-MRSA. Strains with inducible macrolide lincosamide-streptogramin type B (iMLSB) resistance and strains in which resistance was noninducible were evaluated. Two levels of inocula (105 and 107) were evaluated for clindamycin activity in the in vivo model. In both models, the antimicrobial evaluation was performed in triplicate, and bacterial quantification occurred over 72 h, with drug doses that were designed to simulate the free drug area-under-the-concentration-time curve values (fAUCs) obtained from human samples. When the activity of clindamycin against the iMLSB strains was evaluated, constitutive resistance was noted at 24 h (MIC of >256), and failure was noted at an inoculum of ≥106 in the in vivo models. However, at a low inoculum (105) in the murine thigh-infection model, clindamycin demonstrated modest activity, reducing the CFU/thigh count for clindamycin resistance-inducible strains at 72 h (0.45 to 1.3 logs). Overall, administration of daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin noninducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid, and trimethoprim-sulfamethoxazide (not run in the murine model) demonstrated bacteriostatic activity against clindamycin resistance-inducible isolates. This study demonstrates that clindamycin's activity against the iMLSB strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising for treating clindamycin resistance-inducible strains of CA-MRSA.

Correlation of pharmacodynamic parameters of five beta-lactam antibiotics with therapeutic efficacies in an animal model.

1996 ◽  
Vol 40 (12) ◽  
pp. 2686-2690 ◽  
Author(s):  
F Soriano ◽  
P García-Corbeira ◽  
C Ponte ◽  
R Fernández-Roblas ◽  
I Gadea
Keyword(s):  
Linear Regression Analysis ◽  
Inoculum Size ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Time Curve ◽  
Beta Lactam Antibiotics ◽  
Concentration Time ◽  
Intraperitoneal Infection ◽  
Different Doses

The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics. However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics. In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed. The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime. The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca. 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml). The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice. The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h. A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h. The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

scholarly journals Antibiofilm efficacy of focused high-energy extracorporeal shockwaves and antibiotics in vitro

2021 ◽  
Vol 10 (1) ◽  
pp. 77-84
Author(s):  
Alexander Milstrey ◽  
Steffen Rosslenbroich ◽  
Jens Everding ◽  
Michael J. Raschke ◽  
Robert Geoff Richards ◽  
...  
Keyword(s):  
Bacterial Count ◽  
High Energy ◽  
Antibiotic Administration ◽  
Bacterial Counts ◽  
Shockwave Therapy ◽  
Combined Application ◽  
Fold Reduction ◽  
Fracture Nonunions ◽  
Viable Bacteria

Aims Biofilm formation is one of the primary reasons for the difficulty in treating implant-related infections (IRIs). Focused high-energy extracorporeal shockwave therapy (fhESWT), which is a treatment modality for fracture nonunions, has been shown to have a direct antibacterial effect on planktonic bacteria. The goal of the present study was to investigate the effect of fhESWT on Staphylococcus aureus biofilms in vitro in the presence and absence of antibiotic agents. Methods S. aureus biofilms were grown on titanium discs (13 mm × 4 mm) in a bioreactor for 48 hours. Shockwaves were applied with either 250, 500, or 1,000 impulses onto the discs surrounded by either phosphate-buffered saline or antibiotic (rifampin alone or in combination with nafcillin). The number of viable bacteria was determined by quantitative culture after sonication. Representative samples were taken for scanning electron microscopy. Results The application of fhESWT led to a ten-fold reduction in bacterial counts on the metal discs for all impulse numbers compared to the control (p < 0.001). Increasing the number of impulses did not further reduce bacterial counts in the absence of antibiotics (all p > 0.289). Antibiotics alone reduced the number of bacteria on the discs; however, the combined application of the fhESWT and antibiotic administration further reduced the bacterial count compared to the antibiotic treatment only (p = 0.032). Conclusion The use of fhESWT significantly reduced the colony-forming unit (CFU) count of a S. aureus biofilm in our model independently, and in combination with antibiotics. Therefore, the supplementary application of fhESWT could be a helpful tool in the treatment of IFIs in certain cases, including infected nonunions. Cite this article: Bone Joint Res 2021;10(1):77–84.

scholarly journals Efficacy of Daptomycin in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcusaureus

2003 ◽  
Vol 47 (5) ◽  
pp. 1714-1718 ◽  
Author(s):  
George Sakoulas ◽  
George M. Eliopoulos ◽  
Jeff Alder ◽  
Claudie Thauvin- Eliopoulos
Keyword(s):  
Subcutaneous Administration ◽  
Phase Iii ◽  
Methicillin Resistant ◽  
Bacterial Counts ◽  
Phase Iii Clinical Trials ◽  
Viable Bacteria ◽  
The Mean ◽  
The Difference ◽  
Lipopeptide Antibiotic

ABSTRACT Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 μg/ml), vancomycin (MIC = 0.5 μg/ml), and rifampin (MIC = 0.5 μg/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 μg/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log10 number of CFU per gram ± the standard deviation) in untreated controls reached 10.6 ± 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 ± 2.5; daptomycin at 25 mg/kg, 5.5 ± 1.7; daptomycin at 40 mg/kg, 4.2 ± 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P = 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 ± 1.6; rifampin, 3.6 ± 1.3; vancomycin plus rifampin, 3.3 ± 1.1; daptomycin plus rifampin, 2.9 ± 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P = 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.

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.

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