Comparison of in-vitro pharmacodynamics of once and twice daily ciprofloxacin.

The pharmacodynamics of ciprofloxacin were explored in an in-vitro continuous bacterial culture model of infection, by simulating two oral dosing regimens; 0.5 g 12-hourly (bd) and 1 g 24-hourly (od). Three strains of Escherichia coli (ciprofloxacin MICs 0.03, 0.5 and 2 mg/L); two strains of Pseudomonas aeruginosa (MICs 0.09 and 1.5 mg/L), two strains of Staphylococcus aureus (MICs 0.12 and 1 mg/L) and two strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L) were used. Three pharmacodynamic parameters, T > MIC, C(max)/MIC and AUC/MIC (T = time, C(max) = peak serum concentration, AUC = area under the curve), were compared with area under the bacterial-kill curve (AUBKC) (after transformation of the AUBKC) using a simple E(max) or sigmoidal E(max) model. AUBKC was taken to be the main antibacterial effect measure. The models were compared by inspection of residuals and Akaike information criterion. E(max) models adequately described the relationship between AUC/MIC and AUBKC and between C(max)/MIC and AUBKC, but not between T> MIC and AUBKC. All three pharmacodynamic parameters are related to each other but multiple regression analysis indicated that AUC/MIC was the best individual predictor of AUBKC. Despite this, comparison of od and bd regimens indicates some advantage to od in terms of early antibacterial effect. Serum concentration-time curve shape has some importance in determining antibacterial effect. These data indicate that for ciprofloxacin AUC/MIC ratio is not the sole determinant of antibacterial effect.     

Penicillin pharmacodynamics in four experimental pneumococcal infection models

Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates of Streptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 microg/ml and the other for which the penicillin MIC was 1.0 microg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (C(max)s) and times that the concentrations were greater than the MIC (T(>MIC)s). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T(>MIC) and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (approximately 6 log10 CFU/ml), followed by the thigh (approximately 3 log10 CFU/thigh), and being the lowest in the lung (approximately 1 log10 CFU/lung). In the rabbit model the maximal effect was approximately 6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T(>MIC) was > or =65% of the experimental time and C(max) was > or =15 times the MIC, and in the rabbit model bactericidal activity became marked when T(>MIC) was > or =35%, Cmax was > or =5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio and T(>MIC), the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.     

The antibacterial efficacy of levofloxacin and ciprofloxacin against Pseudomonas aeruginosa assessed by combining antibiotic exposure and bacterial susceptibility

Ciprofloxacin has a four-fold greater in-vitro activity than levofloxacin against Pseudomonas aeruginosa, but levofloxacin has a four-fold higher area under the serum concentration-time curve (AUC) for an equivalent dose. It has been proposed that the AUC/MIC ratio is a general predictor of antibacterial efficacy for quinolones. Using an in-vitro kill curve technique, performed in quadruplicate, with nine antibiotic concentrations and three strains of P. aeruginosa with varying quinolone susceptibility, we constructed sigmoidal dose-response curves for AUC(0-6.5)/MIC and area under the bacterial kill curve (AUBKC) or AUC(0-24)/MIC and log change in viable count at 24 h (delta24). For levofloxacin the log AUC(0-6.5)/MIC ratio to produce 50% of the maximal effect was 0.74 +/- 0.13 (r2 = 0.9435) for levofloxacin and 0.82 +/- 0.06 (r2 = 0.7935) for ciprofloxacin. The log AUC(0-24)/MIC ratio to produce 50% maximal effect was 1.58 +/- 0.13 (r2 = 0.7788) for levofloxacin and 1.37 +/- 0.12 (r2 = 0.7207) for ciprofloxacin. An AUC(0-24)/MIC ratio of 125 produced 85.4% of the maximal response with levofloxacin and 81.5% with ciprofloxacin. These data suggest that levofloxacin and ciprofloxacin have equivalent activity against P. aeruginosa at equivalent AUC/MIC ratios.     

Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae

The susceptibility and pharmacodynamic activity of ciprofloxacin and new fluoroquinolones were studied against low-level (MIC 4 mg/L) and high-level (MIC 16 mg/L) ciprofloxacin-resistant Streptococcus pneumoniae. An in vitro pharmacodynamic model simulating free fluoroquinolone (protein unbound) serum concentrations, using Cp(max) and AUC(0-24) achieved (in healthy volunteers) after standard oral doses that are used for community-acquired respiratory infections, was used to compare bacterial killing by five fluoroquinolones against six ciprofloxacin-resistant S. pneumoniae isolates (four different resistance mutant phenotypes: ParC, efflux, ParC with efflux, and ParC and GyrA) obtained from an ongoing Canadian respiratory organism surveillance study. The potency (MIC only) of fluoroquinolones was gemifloxacin > moxifloxacin > gatifloxacin > levofloxacin > ciprofloxacin. Ciprofloxacin (free AUC(0-24)/MIC 0.9-3.5) produced no reduction of growth at 6, 24 or 48 h compared with the initial inoculum in all six strains. Levofloxacin (free AUC(0-24)/MIC 18-35) was bactericidal (> or = 3 log(10) killing) at 6, 24 and 48 h for the ParC as well as the efflux mutants, but only bactericidal at 24 h for the ParC with efflux strain. Levofloxacin (free AUC(0-24)/MIC 4.4) demonstrated no reduction of growth relative to the initial inoculum against the ParC and GyrA mutants. Gatifloxacin and moxifloxacin (free AUC(0-24)/MIC 48 and 60, respectively) were bactericidal at 6, 24 and 48 h against the ParC, efflux, and ParC with efflux mutants, but demonstrated little to no growth reduction (free AUC(0-24)/MIC 6 and 7.5, respectively) in ParC and GyrA mutants. Gemifloxacin (free AUC(0-24)/MIC 67-133) was bactericidal (> or = 3 log(10) killing) at 6, 24 and 48 h in all low-level ciprofloxacin-resistant S. pneumoniae mutants. Against two of the ParC and GyrA mutants, gemifloxacin (free AUC(0-24)/MIC 32) was bactericidal at 6, 24 and 48 h but against one ParC and GyrA mutant (free AUC(0-24)/MIC 16) gemifloxacin demonstrated reduced activity with initial killing at 24 h but with subsequent regrowth. These data indicate that ciprofloxacin produces no inhibition of growth of low- or high-level ciprofloxacin-resistant S. pneumoniae, whereas gatifloxacin, levofloxacin and moxifloxacin (moxifloxacin>gatifloxacin>levofloxacin) were bactericidal for low-level resistant strains but produced little or no inhibition of high-level resistant strains. Gemifloxacin at simulated free AUC(0-24)/MIC > or = 32, was bactericidal against low- and high-level resistant strains. When simulated free AUC(0-24)/ MIC was <16, gemifloxacin allowed regrowth of high-level ciprofloxacin-resistant strains.     

In vitro characterization of fluoroquinolone concentration/MIC antimicrobial activity and resistance while simulating clinical pharmacokinetics of levofloxacin, ofloxacin, or ciprofloxacin against Streptococcus pneumoniae

The relationship between antibacterial effect, resistance, and concentration/MIC parameters with S. pneumoniae was studied. Thirty duplicate bacterial concentration-time-kill curve (TKC) experiments were performed with an in vitro model. TKC with levofloxacin (LVX), Ofloxacin (OFX), and ciprofloxacin (CIP) were studied against six S. pneumoniae isolates. Experiments simulated variable peak serum concentrations, but clinically relevant half-lives and dosing intervals. TKC were performed in Mueller-Hinton Broth supplemented with horse blood (SMHB) at 10(7) CFU/ml. Susceptibility was assessed on colonies recovered post TKC. Multiple regression tested association of pharmacodynamic variables with antimicrobial effect, and logistic regression with resistance post TKC. Only drug (r(2) = 0.27; p < 0.0001) and AUC/MIC(24) (r(2) = 0.15; p < 0.001) were significant variables predictive of antibacterial effect. LVX AUC/MIC(24) of 相似文献   

Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations

BACKGROUND: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. MATERIALS AND METHODS: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log(10) cfu/mL versus initial inoculum). RESULTS: Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. CONCLUSION: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.     

Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease

We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (C(max)) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC(0-24)) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean C(max) of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC(0-24)/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio C(max)/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml.     

Pharmacodynamics of gemifloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model of infection

The pharmacodynamics of gemifloxacin against Streptococcus pneumoniae were investigated in a dilutional pharmacodynamic model of infection. Dose fractionation was used to simulate concentrations of gemifloxacin in human serum associated with 640 mg every 48 h (one dose), 320 mg every 24 h (two doses), and 160 mg every 12 h (four doses). Five strains of S. pneumoniae for which MICs were 0.016, 0.06, 0.1, 0.16, and 0.24 mg/liter were used to assess the antibacterial effect of gemifloxacin. An inoculum of 10(7) to 10(8) CFU/ml was used, and each experiment was performed at least in triplicate. The pharmacodynamic parameters (area under the concentration-time curve [AUC]/MIC, maximum concentration of drug in serum [C(max)]/MIC, and the time that the serum drug concentration remains higher than the MIC [T > MIC]) were related to antibacterial effect as measured by the area under the bacterial-kill curve from 0 to 48 h (AUBKC(48)) using an inhibitory sigmoid E(max) model. Weighted least-squares regression was used to predict the effect of the pharmacodynamic parameters on AUBKC(48), and Cox proportional-hazards regression was used to predict the effect of the three pharmacodynamic parameters on the time needed to kill 99.9% of the starting inoculum (T99.9). There was a clear relationship between strain susceptibility and clearance from the model. The simulations (160 mg every 12 h) were associated with slower initial clearance than were the other simulations; in contrast, bacterial regrowth occurred with the 640-mg simulation when MICs were > or =0.1 mg/liter. The percentage coefficient of variance was 19% for AUBKC(48), and the inhibitory sigmoid E(max) model best fit the relationship between AUBKC(48) and AUC/MIC. C(max)/MIC and T > MIC fit less well. The maximum response occurred at an AUC/MIC of >300 to 400. In weighted least-squares regression analysis, there was no evidence that C(max)/MIC was predictive of AUBKC(48), but both AUC/MIC and T > MIC were. A repeat analysis using only data for which the T > MIC was >75% and for which hence regrowth was minimized indicated that AUC/MIC alone was predictive of AUBKC(48). Initial univariate analysis indicated that all three pharmacodynamic parameters were predictive of T99.9, but in the multivariate model only C(max)/MIC reached significance. These data indicate that gemifloxacin is an effective antipneumococcal agent and that AUC/MIC is the best predictor of antibacterial effect as measured by AUBKC(48). However, C(max)/MIC is the best predictor of speed of kill, as measured by T99.9. T > MIC also has a role in determining AUBKC(48), especially when the dose spacing is considerable. Once-daily dosing seems most suitable for gemifloxacin.     

Pharmacokinetic and pharmacodynamic parameters for antimicrobial effects of cefotaxime and amoxicillin in an in vitro kinetic model

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 of Streptococcus 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 log(10) 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.     

Pharmacokinetics of sparfloxacin and serum bactericidal activity against pneumococci.

Sparfloxacin, a new fluorinated quinolone, exhibits higher in vitro activity against pneumococci than do ciprofloxacin and ofloxacin. Since up to 30% of cases of pneumococcal pneumonia are associated with bacteremia, and since an increasing percentage of pneumococci are resistant against penicillin, we studied the serum bactericidal activity of sparfloxacin against pneumococci in eight healthy, middle-aged volunteers. Pharmacokinetics in serum and urine after a 400-mg oral dose of sparfloxacin were comparable to those described by other authors. Inhibitory and bactericidal activities in serum were measured for four pneumococcal isolates representing penicillin-susceptible (one isolate), intermediately resistant (two isolates), and highly resistant (one isolate) strains. Geometric mean inhibitory titers ranged between 1:2.4 and 1:6.3 and bactericidal titers ranged between 1:1.3 and 1:3.6 during a time period of 1 to 6 h after drug intake. Although such titers were not sufficient to predict a clinical response based on previous pharmacodynamic studies using quinolone antibiotics, data obtained with volunteers may only partially reflect the clinical situation in which a rise of humoral antibodies directed against pneumococcal antigens may help to reinforce the bactericidal action of the antibiotic.     

Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries

Adequate penetration of antibiotics into burn tissue and maintenance of effective serum levels are essential for the treatment of patients sustaining major thermal injuries. The pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin were determined in 12 critically ill patients with burn injuries. Mean age for the 12 patients was 45 +/- 17 (range 25-82 years), total body surface area burned (TBSAB) = 38 +/- 15% and Acute Physiology and Chronic Health Evaluation (APACHE) II score = 8 +/- 6. Patients received recommended doses of ciprofloxacin, 400 mg q12h iv, for three doses beginning 72 h post-burn. Serum concentrations were measured at t = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after the first and third doses. Burn eschar biopsies were obtained after the third ciprofloxacin dose. Three of these 12 patients (25%) manifested later signs of clinical sepsis (TBSAB = 61 +/- 6% and APACHE II score = 11 +/- 3) and underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and eschar biopsy. Serum and eschar concentrations were determined by high performance liquid chromatography. Serum ciprofloxacin concentrations were comparable to those of normal volunteers (C(max) = 4.0 +/- 1 mg/L and AUC = 11.4 +/- 2 mg.h/L) during the immediate post-burn period after dose 1 (C(max1) = 4.8 +/- 3 mg/L and AUC(0-12) = 12.5 +/- 7 mg. h/L) and dose 3 (C(max3) = 4.9 +/- 2 mg/L and AUC(24-36) = 17.5 +/- 11 mg.h/L). Mean burn eschar concentration during the 72 h post-burn was significantly lower than that found during clinical sepsis (18 +/- 17 compared with 41.3 +/- 54 microg/g; P < 0.05 by t test). Similar serum concentrations were achieved in patients with clinical sepsis (C(max1) = 4.2 +/- 0.2 mg/L and AUC(0-12) = 15.0 +/- 3 mg. h/L; C(max3) = 5.0 +/- 1 mg/L and AUC(24-36) = 22.8 +/- 9 mg.h/L). A positive correlation between burn eschar concentrations and C(max) (r = 0.71, r(2) = 0.51, P = 0.01) was found by linear regression analysis. A C(max)/MIC ratio > 10 (MIC = 0.5 mg/L) and an AUC/MIC ratio > 100 SIT(-1).h (serum inhibitory titre) (MIC = 0.125 mg/L) were achieved. High burn eschar concentrations and serum levels, similar to those found in normal volunteers, can be achieved after intravenous ciprofloxacin infusion in critically ill burns patients.     

Pharmacodynamics of trovafloxacin, ofloxacin, and ciprofloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model

An in vitro pharmacokinetic model was used to simulate the pharmacokinetics of trovafloxacin, ofloxacin, and ciprofloxacin in human serum and to compare their pharmacodynamics against eight Streptococcus pneumoniae strains. The MICs of ofloxacin and ciprofloxacin ranged from 1 to 2 micrograms/ml. Trovafloxacin was 8- to 32-fold more potent, with MICs of 0.06 to 0.12 microgram/ml. Logarithmic-phase cultures were exposed to peak concentrations of trovafloxacin, ofloxacin, or ciprofloxacin achieved in human serum after 200-, 400-, and 750-mg oral doses, respectively. Trovafloxacin was dosed at 0 and 24 h, and ofloxacin and ciprofloxacin were dosed at 0, 12, and 24 h. Human elimination pharmacokinetics were simulated, and viable bacterial counts were measured at 0, 2, 4, 6, 8, 12, 24, and 36 h. Trovafloxacin was rapidly and significantly bactericidal against all eight strains evaluated, with viable bacterial counts decreasing at least 5 logs to undetectable levels. Times to 99.9% killing were only 1 to 3 h. Although the rate of killing with ofloxacin was substantially slower than that with trovafloxacin, ofloxacin was also able to eradicate all eight strains from the model, despite a simulated area under the inhibitory curve/MIC ratio (AUC/MIC) of only 49. In contrast, ciprofloxacin eradicated only five strains (AUC/MIC = 44) from the model. Against the other three strains (AUC/MIC = 22), the antibacterial activity of ciprofloxacin was substantially diminished. These data corroborate clinical data and suggest that trovafloxacin has a pharmacodynamic advantage over ciprofloxacin and ofloxacin against S. pneumoniae in relation to its enhanced antipneumococcal activity.     

Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration

OBJECTIVES: To evaluate the mutant prevention concentrations (MPCs) of ciprofloxacin for two susceptible and one first-step gyrA resistant mutant Escherichia coli strains in an in vitro kinetic model and to identify the pharmacodynamic index that best predicts prevention of resistance emergence. METHODS: An in vitro kinetic model was used to measure MPC with static antibiotic concentrations and to test different dosing profiles to study pharmacokinetics/pharmacodynamics indices important to prevent the growth of resistant mutants. In one set of kinetic experiments the starting concentration was equal to the MPC and the T > MPC was varied before antibiotic dilution was begun. In a second set of kinetic experiments C(max) was varied and dilution of the antibiotic was started at time zero. RESULTS: From the static experiments we calculated MPC values of 0.128 mg/L for both the susceptible strains (16x MIC) and 0.188 mg/L (4x MIC) for the first-step resistant (gyrA) strain. The kinetic experiments showed that the T > MPC needed to prevent the growth of resistant bacteria was shorter with an increased C(max). When resistance was selected, several subpopulations with different levels of susceptibility to ciprofloxacin emerged. CONCLUSIONS: Neither T > MPC nor C(max) proved to be single correlates for preventing resistance development. For the two investigated wild-type strains, an AUC/MPC ratio of > or =22 was the single pharmacodynamic index that predicted prevention of resistant mutant development.     

Study of comparative antipneumococcal activities of penicillin G, RP 59500, erythromycin, sparfloxacin, ciprofloxacin, and vancomycin by using time-kill methodology.

Time-kill studies were used to examine the in vitro activities of penicillin G, RP 59500, erythromycin, ciprofloxacin, sparfloxacin, and vancomycin against 10 pneumococci expressing various degrees of susceptibility to penicillin and erythromycin. RP 59500 MICs for all strains were 0.5 to 2.0 micrograms/ml, while erythromycin MICs were 0.008 to 0.06 microgram/ml for erythromycin-susceptible strains and 32.0 to 64.0 micrograms/ml for erythromycin-resistant strains. Strains were more susceptible to sparfloxacin (0.125 to 0.5 microgram/ml) than to ciprofloxacin (0.5 to 4.0 micrograms/ml), and all were inhibited by vancomycin at MICs of 0.25 to 0.5 microgram/ml. Time-kill studies showed that antibiotic concentrations greater than the MIC were bactericidal for each strain, with the following exceptions. Erythromycin was bactericidal for one penicillin-resistant strain at 6 h, with regrowth after 12 and 24 h. Three penicillin-susceptible strains were bacteriostatically inhibited by erythromycin at concentrations greater than or equal to the MIC by 6 h. One penicillin-susceptible strain (penicillin MIC, 0.06 microgram/ml) was bacteriostatically inhibited by penicillin G at 24 h at the MIC or at one-half the MIC; a bactericidal effect was found only with penicillin G at concentrations of > or = 0.25 microgram/ml. At 10 min after inoculation a 1- to 3-log10-unit reduction (90 to 99.9%) in the original inoculum was seen for 6 of 10 strains with RP 59500 at concentrations greater than or equal to the MIC. This effect was not found with any of the other compounds tested. A bactericidal effect was found at > or = 6 h with RP 59500 at concentrations of one-half to one-quarter the MIC in 7 of 10 strains, and a bacteriostatic effect was found in 3 or 10 strains, with regrowth at 24 h. One penicillin-resistant strain was examined by the time-kill methodology at 0, 1, 2, and 3 h. RP 59500 at a concentration equal to the MIC was bactericidal within 1 h, and at a concentration of one-half the MIC it was bactericidal within 3 h. This phenomenon was not seen with the other antimicrobial agents tested. Regrowth of strains at ciprofloxacin concentrations equal to the MIC or at a one-half to one-quarter the MIC was found. For sparfloxacin, three of the four penicillin-susceptible strains and two of four penicillin-resistant strains were bacteriostatically inhibited by 6 h. Bactericidal effects were found at 6, 12, and 24 h with both intermediate-resistant, one penicillin-susceptible, and two penicillin-resistant strains. Complete killing was observed with vancomycin at concentrations greater than MIC. Of the new compounds tested, RP 59500 and sparfloxacin show promise for the treatment of infections caused by penicillin-susceptible and -resistant pneumococci. The clinical significance of rapid killing by RP 59500 remains to be determined.     

Comparative in vitro activity of older and newer fluoroquinolones against respiratory tract pathogens

The aim of this study was to evaluate the antibacterial activity of older (ciprofloxacin and ofloxacin) and newer (moxifloxacin, grepafloxacin, sparfloxacin and levofloxacin) fluoroquinolones. Minimal inhibitory concentrations (MICs) were determined, according to the NCCLS guidelines, against the following respiratory tract pathogens: penicillin-susceptible and -resistant Streptococcus pneumoniae, beta-lactamase-positive and beta-lactamase-negative Haemophilus influenzae and beta-lactamase-positive Moraxella catarrhalis. In addition, we evaluated the minimal bactericidal concentrations of the same antibiotics against all the pneumococci and the haemophili. Finally, the activity of ciprofloxacin, ofloxacin, sparfloxacin and moxifloxacin against 15 pneumococci were investigated by time-kill analysis. All fluoroquinolones tested exhibited a similar, good activity against H. influenzae and M. catarrhalis. Against S. pneumoniae, irrespective of penicillin susceptibility, moxifloxacin, grepafloxacin, sparfloxacin and levofloxacin exhibited excellent activity, better than ciprofloxacin and ofloxacin. Time-kill analysis showed that 99.9% killing of all strains was obtained after 24 h with moxifloxacin at 2 x MIC, whereas other antimicrobials obtained similar results at 4 x MIC. Moxifloxacin is characterized by an improved activity against respiratory pathogens, including penicillin-resistant and -susceptible S. pneumoniae. Its activity is not influenced by beta-lactamase production. These results suggest that moxifloxacin represents a promising alternative for treatment of respiratory tract infections.     

In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model

Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC(0-24)] to the MIC, and the ratio of the maximum serum drug concentration [C(max)] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C(max)/MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C(max)/MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 microg/ml) to determine if similar C(max)/MIC and AUC(0-24)/MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.     

Bactericidal effect and pharmacodynamics of cethromycin (ABT-773) in a murine pneumococcal pneumonia model

Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae. The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin. Eight (two macrolide susceptible, six macrolide resistant) clinical isolates of S. pneumoniae were investigated. Cyclophosphamide administration rendered ICR mice transiently neutropenic prior to intratracheal inoculation with 0.05 ml of an S. pneumoniae suspension containing 10(7) to 10(8) CFU/ml. Oral cethromycin was initiated 12 to 14 h postinoculation over a dosage range of 0.1 to 800 mg/kg of body weight/day. Lungs from seven to eight mice per treatment and control groups were collected at 0 and 24 h posttherapy to assess bacterial density. The cumulative mortality (n = 12 to 13) was assessed at 120 h (end of therapy) and at 192 h (3 days posttherapy). Recovery of pneumococci from the lungs of infected animals prior to the initiation of therapy ranged from 4.6 to 7.2 log(10) CFU. Growth in untreated control animals over a 24-h study period increased 0.3 to 2.7 log(10) CFU. Cethromycin demonstrated a substantial bactericidal effect, regardless of macrolide susceptibility. Correlation between changes in bacterial density (24 h) and survival over both 120 and 192 h were statistically significant. All three PD parameters demonstrated a significant correlation with changes in log(10) CFU/lung (Spearman's correlation coefficient, P < 0.001); however, the goodness of fit as assessed with the maximum effect (E(max)) model revealed that the maximum concentration of free drug in serum (C(max free))/MIC and the area under the free drug concentration-time curve (AUC(free))/MIC best explained the relationship between drug exposure and reductions in viable bacterial counts. These data reveal that an approximate cethromycin AUC(free)/MIC of 50 or C(max free)/MIC of 1 results in bacteriostatic effects, while higher values (twofold) maximize survival.     

Pharmacodynamic activity of telithromycin at simulated clinically achievable free-drug concentrations in serum and epithelial lining fluid against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae for which telithromycin MICs vary

The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 microg/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [C(max)] in serum, 0.7 microg/ml; half-life [t(1/2)], 10 h; free-drug C(max) in ELF, 6.0 microg/ml; t(1/2), 10 h). Starting inocula were 10(6) CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log(10) CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were C(max) 0.9 +/- 0.08 microg/ml, area under the curve to MIC (AUC(0-24 h)) 6.4 +/- 1.5 microg . h/ml, and t(1/2) of 10.6 +/- 0.6 h. Telithromycin-free ELF concentrations achieved in the model were C(max) 6.6 +/- 0.8 microg/ml, AUC(0-24 h) 45.5 +/- 5.5 microg . h/ml, and t(1/2) of 10.5 +/- 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 microg/ml and 1 microg/ml, respectively. Free-telithromycin S and ELF concentrations simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C(max)/MIC > or = 1.8 and AUC(0-24 h)/MIC > or = 12.5 were bacteriostatic (0.1 to 0.2 log(10) killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h.     

Anti-pneumococcal activity of gatifloxacin compared with other quinolone and non-quinolone agents.

An agar dilution MIC method was used to test the activity of gatifloxacin, a new broad-spectrum fluoroquinolone, compared with ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, amoxycillin, cefuroxime, ceftriaxone and clarithromycin against 71 penicillin-susceptible, 81 penicillin-intermediate and 55 penicillin-resistant pneumococci. Quinolone activity was unaffected by penicillin susceptibility, with MIC50/MIC90s (mg/L) of 0.25/0.5 for gatifloxacin; 1/2 for ciprofloxacin; 1/2 for levofloxacin; 0.25/0.5 for sparfloxacin; 0.125/0.25 for trovafloxacin. beta-Lactam and clarithromycin MICs rose with those of penicillin G; MIC50/MIC90 values (mg/L) for penicillin-susceptible, -intermediate and -resistant strains were: 0.03/0.06, 0.25/1, 2/4 for penicillin G; 0.03/0.03, 0.125/1, 2/4 for amoxycillin; 0.03/0.125, 0.5/4, 8/16 for cefuroxime; 0.03/0.03, 0.25/0.5, 2/4 for ceftriaxone; 0.03/0.06, 0.03/>64, 1/>64 for clarithromycin. Time-kill testing of four penicillin-susceptible, four -intermediate and four -resistant strains showed that levofloxacin at the MIC, gatifloxacin and sparfloxacin at 2 x MIC, and trovafloxacin and ciprofloxacin at 4 x MIC, were bactericidal (99.9% killing) for all strains after 12 h and 24 h. By contrast, amoxycillin, cefuroxime and ceftriaxone showed bactericidal activity after 24 h against all strains at 4, 8 and 4 x MIC, respectively. Against ten organisms with clarithromycin MICs of 0.03-4.0 mg/L, clarithromycin was bactericidal against seven strains at 8 x MIC after 24 h. Quinolones showed more rapid killing at lower concentrations and earlier time periods than did beta-lactams and clarithromycin.     

MIC and time-kill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible and -resistant pneumococci.

MIC and time-kill methods were used to test the activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible, -intermediate, and -resistant pneumococci. The MIC of penicillin for penicillin-susceptible strains was 0.016 micrograms/ml, those for intermediate strains were 0.25 to 1.0 microgram/ml, and those for resistant strains were 2.0 to 4.0 micrograms/ml. Of the four quinolones tested, DU-6859a had the lowest MIC (0.064 micrograms/ml), followed by sparfloxacin (0.25 to 0.5 micrograms/ml) and levofloxacin and ciprofloxacin (both 1.0 to 4.0 micrograms/ml). Vancomycin inhibited all strains at MICs of 0.25 to 0.5 micrograms/ml. The MICs of imipenem and cefotaxime for penicillin-susceptible, -intermediate, and -resistant strains were 0.004 to 0.008, 0.008 to 0.032, and 0.25 micrograms/ml and 0.016, 0.125 to 0.5, and 2.0 micrograms/ml, respectively. DU-6859a was bactericidal at eight times the MICs (0.5 micrograms/ml) for seven of the nine strains after 4 h and bactericidal for all nine strains after 6 h at eight times the MICs and after 12 h at two times the MICs. By comparison, sparfloxacin, the next most active quinolone, was uniformly bactericidal at two times the MICs only after 24 h, with little activity after 2 h. Levofloxacin and ciprofloxacin were bactericidal against all strains after 12 h at eight times the MICs and against all strains at 24 h at four times the MICs. Imipenem was bactericidal against all strains, at concentrations exceeding the MICs, after 24 h. Cefotaxime was also uniformly bactericidal only after 24 h of incubation at two times the MICs. Vancomycin, despite having uniformly low MICs for all strains irrespective of their penicillin susceptibility, was uniformly bactericidal only at two times the MICs after 24 h.