MIC Ratio Research Articles

Cefepime pharmacodynamics in patients with extended spectrum β-lactamase (ESBL) and non-ESBL infections

This study was designed to compare cefepime exposures with microbiological outcomes in ESBL and non-ESBL infections and determine the pharmacodynamic profiles associated with successful outcome. Cefepime pharmacodynamic exposures of unbound drug [time above MIC (fT>MIC), minimal concentration over MIC (fC(min)/MIC), and area under the curve over MIC (fAUC/MIC)] for 18 patients with ESBL and non-ESBL infections were determined by using a published population pharmacokinetic model. Classification and regression tree analysis was used to identify pharmacodynamic breakpoints that predicted eradication. A 5000-patient Monte Carlo Simulation was conducted to estimate the probability of target attainment for the goal pharmacodynamic exposures. Eradication was 80% when fT>MIC was 50% compared with 0% when T>MIC was less than 50% (p<0.05). The median fC(min)/MIC ratio for ESBL group was statistically lower than that for the non-ESBL group (1.54 versus 138, p<0.001). Regardless of ESBL production, all pathogens were eradicated when fC(min)/MIC>7.6 and only 33.3% were eradicated when fC(min)/MIC< or =7.6 (p<0.05). Pharmacodynamic exposures of 50% fT>MIC and fAUC/MIC>1654 were also predictive of eradication. While conventional dosage regimens of 2g q 12h and q 8h failed to achieve adequate target attainment, 4 g continuous infusion and 2g q 6-8h prolonged infusion could attain more than 90% of target attainment at the MIC of 2 microg/ml for the breakpoint of fCmin/MIC=7.6. Microbiological eradication in patients receiving cefepime was best predicted by fCmin/MIC ratio greater than 7.6 regardless of the presence of an ESBL. Continuous or prolonged infusion regimens provided the greatest probability of attaining this exposure.

Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model

To extend the mutant selection window (MSW) hypothesis to include antibiotics in addition to fluoroquinolones, the pharmacodynamics of daptomycin (DAP) and vancomycin (VAN) and their ability to prevent the selection of resistant Staphylococcus aureus were studied in an in vitro model that simulates antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC. Two clinical isolates of S. aureus, S. aureus 866 (MIC(DAP) 0.35, MIC(VAN) 0.7, MPC(DAP) 1.1, MPC(VAN) 2.4 mg/L) and S. aureus 10 (MIC(DAP) 1.1, MIC(VAN) 1.3, MPC(DAP) 5.5, MPC(VAN) 11 mg/L), were exposed for five consecutive days to once-daily daptomycin (half-life 9 h) and twice-daily vancomycin (half-life 6 h) at the ratio of 24 h area under the concentration-time curve (AUC24) to MIC that varied over a 16- to 30-fold range. The cumulative antimicrobial effect was expressed by its intensity (I(E)). Changes in susceptibility and numbers of surviving organisms on agar plates containing 2x and 4x MIC of daptomycin or vancomycin were monitored daily. The I(E)-log AUC24/MIC plots were bacterial strain- and antibiotic-independent. This allowed combination of data obtained with both antibiotics and both organisms. Based on the sigmoid relationship between I(E) and the AUC24/MIC (r2 = 0.9), the antistaphylococcal effect of the therapeutic doses of daptomycin (4 and 6 mg/kg) against a hypothetical S. aureus with MIC equal to the MIC90 (AUC24/MIC90 380 and 570 h, respectively) was predicted to be similar to the effect of two 1 g doses of vancomycin given at a 12 h interval (AUC24/MIC90 200 h). AUC24/MIC relationships of the final-to-initial MIC ratio and logarithm of the ratio of maximal-to-initial numbers of organisms resistant to 2x and 4x MIC of daptomycin or vancomycin were bell-shaped and bacterial strain- and antibiotic-independent. Based on these relationships, an AUC24/MIC ratio that protects against the selection of resistant mutants was predicted at > or = 200 h. This protective value is less than the AUC24/MIC90s provided by the 4 mg/kg dose and considerably less than the 6 mg/kg dose of daptomycin, but it is close to the AUC24/MIC90 provided by two 1 g doses of vancomycin. These findings support the MSW hypothesis and suggest comparable antistaphylococcal effects of clinically achievable AUC24/MIC90s of daptomycin and vancomycin but slightly better prevention against the selection of resistant S. aureus by daptomycin.

Pharmacokinetic-Pharmacodynamic Modelling of Danofloxacin in Turkeys

Colibacillosis is a systemic disease responsible for important economic losses in poultry breeding; fluoroquinolones, including danofloxacin, are used to treat diseased animals. The purpose of the present study was to estimate pharmacokinetic-pharmacodynamic (PK-PD) surrogates for bacteriostasis, bactericidal activity and bacterial elimination against Escherichia coli O78/K80, using a PK-PD approach, for danofloxacin in turkeys after oral administration. Eight healthy turkeys, breed BUT 9, were included in a two-way crossover study. The drug was administered intravenously (i.v.) and orally at a dose rate of 6 mg/kg bw. The values of the elimination half-life and the total body clearance after i.v. administration were 8.64 +/- 2.35 h and 586.76 +/- 136.67 ml kg(-1)h(-1), respectively. After oral administration, the values of the absolute bioavailability and the elimination half-life were 78.37+/- 17.35% and 9.74+/- 2.93 h, respectively. The minimum inhibitory concentration against the investigated strain in turkey serum was 0.25 microg/ml, four times higher than in broth. The lowest effective ex vivo AUC(24)/MIC ratios required for bacteriostasis, bactericidal activity, and total killing of E. coli O78/K80 were 0.416 h, 1.9 h and 6.73 h, respectively. The oral dose of 6 mg/kg used in the present study could be interpreted as being sufficient to eliminate E. coli with an MIC 0.25 microg/ml. However, considering the demand that antimicrobial resistance should be avoided by complete bacterial elimination, PK-PD considerations suggest that an even higher dose of 32 mg/kg per day or 0.7 mg/kcal per day should be evaluated in clinical trials.

Population pharmacokinetic modeling and Monte Carlo simulation of varying doses of intravenous metronidazole

Population pharmacokinetic modeling and Monte Carlo simulation (MCS) are approaches used to determine probability of target attainment (PTA) of antimicrobial therapy. The objectives of this study were 1) to determine a population pharmacokinetic model (PPM) using metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients, and 2) to determine the probability of attaining the pharmacodynamic target area under the plasma concentration (AUC)/MIC ratio ≥70 against 218 clinical isolates of Bacteroides fragilis using MCS. Eighteen healthy subjects were randomized to 3 dosages of intravenous metronidazole (500 mg every 8 h, 1000 mg day −1, 1500 mg day −1) in an open-label 3-way crossover fashion. Serial blood samples were collected over 25.5 h on the 3rd day of each study period. An additional of 8 critically ill patients received intravenous metronidazole 500 mg every 8 h. Serial blood samples were collected over 8 h after the 2nd day of dosing. Plasma metronidazole and hydroxy-metronidazole concentrations were analyzed using a high-performance liquid chromatographic assay. The 834 plasma concentrations from 62 data sets were simultaneously modeled with Non-Parametric Adaptive Grid population modeling program. A 4-compartment model with a metabolite and zero-order infusion into the central compartment was used. The mean parameter vector and covariance matrix from PPM were inserted into the simulation module of ADAPT II. A 10 000-subject MCS was performed to determine the probability of PTA for a total drug AUC to MIC ratio ≥70 against 218 isolates of B. fragilis (MIC range, 0.125–2.0 mg L −1). Mean parameter values were CL non-OH, 3.08 L h −1; V c, 35.4 L; K OH, 0.04 h −1; CL OH, 2.78 L h −1; and V OH, 9.66 L. The regression values of the observed versus predicted concentrations ( r 2) of metronidazole and hydroxy-metronidazole were 0.972 and 0.980, respectively. The PTA for metronidazole 1500 mg day −1 or 500 mg every 8 h (taken together) and 1000 mg day −1 were 99.9% and 99.8%, respectively, over the reported MIC distribution range. For an MIC of 4 mg L −1, the predicted PTA decreased to 80.0% and 28.5%, respectively. A PPM was determined by comodeling metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients. Based on this model, attainment of the target pharmacodynamic parameter (AUC/MIC ratio ≥70) against B. fragilis isolates is >99% when MICs are <2 mg L −1, irrespective of the dosing interval of 24 h.

Pharmacokinetic and pharmacodynamic aspects of antimicrobial agents for the treatment of uncomplicated urinary tract infections

Uncomplicated urinary tract infections (UTI) are treated with β-lactams, co-trimoxazole, quinolones and fosfomycin tromethamine. Due to increasing resistance of causative pathogens, antibiotics should be used by considering their pharmacodynamic and pharmacokinetic characteristics. β-lactams have time-dependent activity and should not be used once-daily. Co-trimoxazole should be restricted due to increasing chemoresistance. Fluoroquinolones play a primary role in the treatment of serious and complicated infections. Fosfomycin tromethamine is active against most urinary tract pathogens. In vitro time-kill kinetics of fosfomycin against Escherichia coli and Proteus mirabilis showed primarily concentration-dependent activity, with a prolonged post-antibiotic effect (3.4 to 4.7 h). Based on these results a single 3 g dose of fosfomycin guarantees optimal efficacy against common uropathogens with an AUC(urine)/MIC ratio of 500.

Pharmacodynamic activity of garenoxacin against ciprofloxacin-resistant Streptococcus pneumoniae

The pharmacodynamic parameter that best correlates with bacteriological eradication for fluoroquinolones is the free (f) area under the 24 h serum concentration curve (AUC24) to MIC (fAUC24/MIC) ratio. This study assessed garenoxacin fAUC24/MIC against ciprofloxacin-resistant Streptococcus pneumoniae using an in vitro pharmacodynamic model. A total of 14 S. pneumoniae including 1 fluoroquinolone-susceptible and 13 ciprofloxacin-resistant S. pneumoniae (ParC, efflux, ParC with efflux, and ParC and GyrA) were studied. The quinolone-resistance determining regions (QRDRs) of parC and gyrA were sequenced and efflux was assessed using a reserpine assay. S. pneumoniae with garenoxacin MICs (mg/L) [number of strains] studied were: 0.03 [1], 0.06 [2], 0.12 [2], 0.25 [2], 0.5 [3], 1 [2] and 2 [2]. The in vitro pharmacodynamic model was inoculated with 1 x 10(6) cfu/mL and garenoxacin was dosed once daily at 0 and 24 h to simulate fAUC24 and t1/2 obtained after standard oral doses in healthy volunteers (400 mg once daily, free AUC24 20 mg.h/L, t1/2 16 h). Sampling was performed over 48 h to assess viable growth. Garenoxacin fAUC24/MIC achieved in the model ranged from 12 to 800. Garenoxacin fAUC24/MIC 200-800 was bactericidal (> or = 3 log(10) killing) at 6, 24 and 48 h against ciprofloxacin-resistant S. pneumoniae mutants including ParC mutants only, efflux mutants only and ParC/efflux mutants. Garenoxacin fAUC24/MIC 48-96 was bactericidal (> or = 3 log(10) killing) at 24 and 48 h against all ciprofloxacin-resistant S. pneumoniae mutants. Garenoxacin fAUC24/MIC < or = 24 (against ParC and GyrA mutants) resulted in a bacteriostatic effect with regrowth at 24 and 48 h. Garenoxacin was bactericidal against ciprofloxacin-resistant S. pneumoniae at fAUC24/MIC > or = 48. Garenoxacin fAUC24/MIC < or = 24 resulted in a bacteriostatic effect with regrowth at 24 and 48 h.

In-vivo impact of the MexXY efflux system on aminoglycoside efficacy in an experimental model of Pseudomonas aeruginosa pneumonia treated with tobramycin

Aminoglycosides are of major importance in treating Pseudomonas aeruginosa pneumonia (PAP). However, their efficacy may be compromised by low-level resistance caused by the inducible MexXY multidrug efflux pump. In the present study, the impact of the MexXY efflux pump was investigated in vivo in an experimental model of PAP in rabbits treated with intravenous tobramycin. Three strains were used to induce PAP in rabbits: PAO1 (wild-type strain; MIC 1 mg/L), mutant 11B (mexX::Tn501; no expression of MexXY; MIC 0.5 mg/L) and mutant MutGR1 (MexZ null; constitutive expression of MexXY; MIC 2 mg/L). Five hours after inoculation, treatment with tobramycin (10 mg/kg) was implemented (peak serum concentration 30 mg/L). The animals were killed humanely 48 h after inoculation, and the residual pulmonary bacterial concentration was determined. Selection of bacteria expressing MexXY was determined by plating lung homogenates on agar plates containing antibiotic. Mean bacterial counts (log(10) CFU/g) for treated vs. untreated rabbits were 6.26 and 8.13 (p < 0.0001), 6.00 and 8.38 (p < 0.001), and 7.25 and 8.79 (p 0.04) for PAO1, 11B and MutGR1, respectively, with an overall mortality rate of 0% vs. 8.9% (p < 0.01). MexXY-overexpressing bacteria were recovered from three (21%) treated rabbits. The C(max)/MIC ratio was the parameter that was best associated with tobramycin efficacy. The bacteria overexpressing MexXY, recovered from lung, occurred with a C(max)/MIC window of 19-26. It was concluded that the experimental PAP model highlights poor tobramycin bacteriological efficacy in vivo, contrasting with survival gain, and that the contribution of the MexXY system to this low level of tobramycin efficacy is modest. Finally, this model appears to be suitable for the investigation of new anti-pseudomonal therapeutic strategies.

Pharmacodynamics of Levofloxacin against Pseudomonas aeruginosa with Reduced Susceptibility Due to Different Efflux Pumps: Do Elevated MICs Always Predict Reduced In Vivo Efficacy?

The Pseudomonas aeruginosa efflux pumps MexAB-OprM, MexCD-OprJ, and MexEF-OprN play an important role in susceptibility to fluoroquinolones in vitro. To determine if levofloxacin MICs arising from different levels of expression of efflux pumps result in a proportional reduction in the response to levofloxacin in vivo, isogenic strains of P. aeruginosa were tested with levofloxacin in two mouse models of infection (sepsis and neutropenic mouse thigh models). The levofloxacin 50% effective doses (ED(50)s) increased proportionally with the MICs for most strains. Similarly, the 24-h area under the concentration-time curve (AUC)/MIC ratio that resulted in 90% of the maximum bactericidal activity (90% E(max)) exceeded 75 for all strains except those with elevated MICs due to MexEF-OprN overexpression. In these strains, levofloxacin ED(50)s were 2- to 10-fold lower than the ED(50)/MIC ratios in the other strains and 90% E(max) AUC/MIC ratios were 2- to 4-fold lower than those predicted from pharmacodynamic modeling of efficacy against other strains. These data show that while the MexEF-OprN efflux pump can provide P. aeruginosa resistance to levofloxacin in vitro, it appears to be less efficient in providing resistance to levofloxacin in animal models of infection.

Garenoxacin Treatment of Experimental Endocarditis Caused by Viridans Group Streptococci

The activity of garenoxacin was compared to that of levofloxacin or penicillin in a rabbit model of Streptococcus mitis group (penicillin MIC, 0.125 microg/ml) and Streptococcus sanguinis group (penicillin MIC, 0.25 microg/ml) endocarditis. Garenoxacin and levofloxacin had MICs of 0.125 and 0.5 microg/ml, respectively, for both study isolates. Rabbits with catheter-induced aortic valve endocarditis were given no treatment, penicillin at 1.2x10(6) IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously. For both isolates tested, garenoxacin area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax)/MIC ratios were 368 and 91, respectively. Rabbits were sacrificed after 3 days of treatment; cardiac valve vegetations were aseptically removed and quantitatively cultured. For S. mitis group experimental endocarditis, all studied antimicrobial agents were more active than no treatment (P<0.001), whereas for S. sanguinis group endocarditis, no studied antimicrobial agents were more active than no treatment. We conclude that AUC/MIC and Cmax/MIC ratios may not predict activity of some quinolones in experimental viridans group endocarditis and that garenoxacin and levofloxacin may not be ideal choices for serious infections caused by some quinolone-susceptible viridans group streptococci.

Effect of heavy metals on substrate utilization pattern, biomass, and activity of microbial communities in a reclaimed mining wasteland of red soil area

The microbial biomass, basal respiration, and substrate utilization pattern in a copper mining wasteland of red soil area, southern China, were investigated, and indicated that soil microflora were obviously affected by heavy metals. Microbial biomass and basal respiration were negatively affected by comparatively high heavy metal levels. Two important microbial ecophysiological parameters, namely, the microbial biomass C ( C mic)/microbial biomass N ( N mic) ratio and the metabolic quotient ( qCO 2) were significantly correlated to heavy metal stress. There was a significant decrease in the C mic/ N mic ratio and an increase in the metabolic quotient with increasing metal concentration. Multivariate analysis of Biolog data for sole carbon source utilization pattern demonstrated that heavy metal pollution had a significant impact on microbial community structure and functional diversity. All the results showed that soil microbiological parameters could have great potential as sensitive, effective, and liable indicators of the stresses or perturbations in soils of mining ecosystems.

Effects of tree harvesting, forest floor removal, and compaction on soil microbial biomass, microbial respiration, and N availability in a boreal aspen forest in British Columbia

The effects of timber harvesting and the resultant soil disturbances (compaction and forest floor removal) on relative soil water content, microbial biomass C and N contents (C mic and N mic), microbial biomass C:N ratio (C mic-to-N mic), microbial respiration, metabolic quotient ( qCO 2), and available N content in the forest floor and the uppermost mineral soil (0–3 cm) were assessed in a long-term soil productivity (LTSP) site and adjacent mature forest stands in northeastern British Columbia (Canada). A combination of principal component analysis and redundancy analysis was used to test the effects of stem-only harvest, whole tree harvest plus forest floor removal, and soil compaction on the studied variables. Those properties in the forest floor were not affected by timber harvesting or soil compaction. In the mineral soil, compaction increased soil total C and N contents, relative water content, and N mic by 45%, 40%, 34% and 72%, respectively, and decreased C mic-to-N mic ratio by 29%. However, these parameters were not affected by stem only harvesting or whole tree harvesting plus forest floor removal, contrasting the reduction of white spruce and aspen growth following forest floor removal and soil compaction reported in an earlier study. Those results suggest that at the study site the short-term effects of timber harvesting, forest floor removal, and soil compaction are rather complex and that microbial populations might not be affected by the perturbations in the same way as trees, at least not in the short term.

Pharmacodynamic evaluation of tosufloxacin against Streptococcus pneumoniae in an in vitro model simulating serum concentration

We compared the antibacterial effects and the emergence of resistance to tosufloxacin or levofloxacin for Streptococcus pneumoniae by simulating the serum concentration according to the Japanese clinical regimens using an in vitro pharmacokinetic-pharmacodynamic model. For quinolone-susceptible strain ATCC49619, tosufloxacin showed bactericidal activity, given that both the AUC(0-24h)/MIC ratios at the dosage of 150 mg t.i.d. and 300 mg b.i.d. of tosufloxacin tosilate were 138 and 193, and the C(max)/MIC ranges were 7.93-10.2 and 15.9-17.6, respectively, which were greater than those of levofloxacin (100 mg t.i.d. and 200 mg b.i.d.). The greater area above the killing curves (AAKCs) or shorter time to achieve 99.9% killing (99.9% KT) in both models of tosufloxacin than those of levofloxacin was related to their larger AUC(0-24h)/MIC and C(max)/MIC. Exposure of only 100 mg t.i.d. of levofloxacin led to outgrowth of the parC mutants, which were twofold less susceptible to levofloxacin than the parent strain. Neither of the tosufloxacin tosilate regimens resulted in isolation of resistant mutants of this strain. For the parC mutant strain D-3197, both the AUC(0-24h)/MIC and C(max)/MIC ratios of tosufloxacin were greater than those of levofloxacin, which resulted in comparable or better bactericidal activity as compared to those of levofloxacin. However, both fluoroquinolones and both regimens led to outgrowth of resistant mutants, which possessed a mutation in gyrA in addition to parC. In conclusion, tosufloxacin is superior to levofloxacin in bactericidal activity against S. pneumoniae in the Japanese clinical regimens, especially in the quinolone-susceptible strain, without emergence of resistant subpopulations.

Pharmacokinetic and Pharmacodynamic Aspects of Oral Moxifloxacin 400 mg/day in Elderly Patients with Acute Exacerbation of Chronic Bronchitis

To assess the pharmacokinetic and pharmacodynamic behaviour of moxifloxacin in 15 consecutive elderly patients with acute exacerbation of chronic bronchitis (AECB) treated with the fixed oral moxifloxacin 400 mg/day regimen with the intent of verifying which degree of exposure may be ensured by this standard regimen against AECB pathogens. This was an open-label, observational, pharmacokinetic-pharmacodynamic study. Blood samples were collected at steady state at appropriate intervals. Moxifloxacin plasma concentrations were analysed by means of high-performance liquid chromatography. Standard pharmacokinetic parameters and pharmacodynamic determinants (peak concentration [C(max)]/minimum inhibitory concentration [MIC], area under the plasma concentration-time curve during the 24-hour observational period [AUC(24)]/MIC, pharmacodynamic breakpoints [PDBPs]) were assessed. The mean estimated pharmacokinetic parameters (C(max) 4.40 mg/L at 1.4 hours, AUC(24) 42.67 mg . h/L, elimination half-life 12.55 hours, total body clearance 0.16 L/h/kg) were generally similar to those observed in both young and elderly historic controls (except for higher-dose normalised C(max) and lower volume of distribution of the central compartment). Median C(max)/MIC and AUC(24)/MIC ratios for moxifloxacin in the fully assessable cases were, respectively, 67.5 and 823.9 against Streptococcus pneumoniae, 25 and 310.2 against Moraxella catharralis and 416.5 and 3647.5 against Haemophilus influenzae. Mean estimates of PDBP for achieving C(max)/MIC values of 12.2 and AUC(24)/MIC values of 125 were 0.36 and 0.35 mg/L, respectively. In patients with AECB the pharmacokinetic behaviour of moxifloxacin is not significantly altered by aging processes. This is consistent with moxifloxacin being metabolised mainly by means of phase II hepatic reactions, the activity of which was shown not to decline with age. Both the pharmacokinetic and pharmacodynamic analyses suggest that moxifloxacin 400 mg/day may be a valid therapeutic approach in the treatment of AECB in the elderly. Of note, the unmodified pharmacokinetic behaviour with no need for age-related dosage adjustments combined with the once-daily administration favouring compliance and the low potential for drug-drug pharmacokinetic interactions in case of polytherapy, make moxifloxacin particularly attractive in the treatment of elderly subpopulations at a very high risk of AECB.

In vivo efficacies and pharmacokinetics of DX-619, a novel des-fluoro(6) quinolone, against Streptococcus pneumoniae in a mouse lung infection model.

DX-619 is a novel des-fluoro(6) quinolone with potent activity against gram-positive pathogens. The in vivo activity of DX-619 against Streptococcus pneumoniae was compared with those of fluoro(6) quinolones, sitafloxacin, and ciprofloxacin in a mouse model. Two strains of S. pneumoniae were used: a penicillin-sensitive S. pneumoniae (PSSP) strain and a penicillin-resistant S. pneumoniae (PRSP) strain. Furthermore, these strains showed intermediate susceptibilities to ciprofloxacin. In murine lung infections caused by PSSP, the 50% effective doses (ED50s) of DX-619, sitafloxacin, and ciprofloxacin were 9.15, 11.1, and 127.6 mg/kg of body weight, respectively. Against PRSP-mediated pneumonia in mice, the ED50s of DX-619, sitafloxacin, and ciprofloxacin were 0.69, 4.84, and 38.75 mg/kg, respectively. The mean +/- standard error of the mean viable bacterial counts in murine lungs infected with PSSP and treated with DX-619, sitafloxacin, ciprofloxacin (10 mg/kg twice daily), and saline (twice daily) were 1.75 +/- 0.06, 1.92 +/- 0.23, 6.48 +/- 0.28, and 7.57 +/- 0.13 log10 CFU/ml, respectively. Furthermore, the numbers of viable bacteria in lungs infected with PRSP and treated with the three agents and not treated (control) were 1.73 +/- 0.04, 2.28 +/- 0.17, 4.61 +/- 0.59, and 5.54 +/- 0.72 log10 CFU/ml, respectively. DX-619 and sitafloxacin significantly decreased the numbers of viable bacteria in the lungs compared to the numbers in the lungs of ciprofloxacin-treated and untreated mice. The pharmacokinetic parameter of the area under the concentration-time curve (AUC)/MIC ratio in the lungs for DX-619, sitafloxacin, and ciprofloxacin were 171.0, 21.92, and 1.22, respectively. The AUC/MIC ratio in the lungs was significantly higher for DX-619 than for sitafloxacin and ciprofloxacin. Our results suggest that DX-619 and sitafloxacin are potent against both PSSP and PRSP in our mouse pneumonia model.

Evaluation of PPI-0903M (T91825), a novel cephalosporin: bactericidal activity, effects of modifying in vitro testing parameters and optimization of disc diffusion tests

To evaluate bactericidal activity of PPI-0903M and in vitro testing parameters for this compound. A total of 110 strains were tested to determine MIC and MBC values of PPI-0903M. MIC values were determined by reference broth microdilution whereas MBC was assessed by plating the broth from the MIC well and from those wells above the MIC for each organism onto appropriate drug-free growth media. Seventeen strains were tested by the kill-curve methodology to again evaluate the bactericidal activity of PPI-0903M. Broth microdilution results for 15 strains (in triplicate) were compared with the standard, reference method after modifying several testing parameters. Optimal disc content was assessed by testing seven reference strains with five PPI-0903M disc concentrations (5, 10, 30, 50 and 100 microg). PPI-0903MMBC/MIC ratios were < or = 4 in 90% of strains tested. Kill-curve studies showed >99.9% killing at concentrations < or = 4x MIC within 8 to 24 h against staphylococci and Enterobacteriaceae tested. PPI-0903M MIC results were rarely influenced by the test or medium changes evaluated [high inoculum, low calcium or reduced pH (5.0)]. Human serum had no effect on in vitro antimicrobial activity of PPI-0903M. The 10 microg disc content would be recommended for optimal correlation of MIC breakpoints of < or = 1-4 mg/L. PPI-0903M was generally bactericidal against tested species, and the MIC results were stable across numerous susceptibility test condition changes.

Efficacy and Pharmacodynamics of Flucytosine Monotherapy in a Nonneutropenic Murine Model of Invasive Aspergillosis

The therapeutic efficacy of flucytosine (5FC) monotherapy and the pharmacodynamic index predictive of efficacy were evaluated in a nonneutropenic mouse model of acute invasive aspergillosis. Mice were infected intravenously with an Aspergillus fumigatus isolate (the median MICs of 5FC were 128 mug/ml under the standard condition, 0.5 microg/ml at pH 6.0, and 0.031 microg/ml at pH 5.0) 2 h prior to the start of therapy and were treated for 7 days with different 5FC dosing regimens. The total doses ranged from 50 to 800 mg/kg of body weight/day and were administered at 6-, 12-, and 24-h intervals. The efficacy was assessed by means of survival. The survival rates of the treatment groups ranged from 40 to 90%, while the survival rate of the control group was 20%. The efficacy found depended primarily on the total daily dose. However, the power of our sample size may have been too low to exclude an effect of dose fractionation. The pharmacodynamic index that most strongly correlated with the efficacy was the area under the serum concentration-time curve and MIC ratio (R(2) = 0.86). We conclude that 5FC monotherapy is efficacious in a murine Aspergillus fumigatus infection model.

Pharmacodynamics of moxifloxacin against anaerobes studied in an in vitro pharmacokinetic model.

The antibacterial effects of moxifloxacin against Bacteroides fragilis, Clostridium perfringens, and gram-positive anaerobic cocci (GPAC) were studied in an in vitro pharmacokinetic model. Initially, a dose-ranging study with area under the concentration-time curve (AUC)/MIC ratios of 6.7 to 890 was used to investigate the effect of anaerobic conditions on the AUC/MIC antibacterial effect (ABE) relationship with Escherichia coli. The AUC/MIC ratios for 50% and 90% effects, using a log CFU drop at 24 h as the antibacterial effect measure, were 34 and 59, respectively, aerobic and 54 and 96, respectively, anaerobic. These values are not significantly different. Dose ranging at AUC/MIC ratios of 9 to 216 against the anaerobes indicated a differing AUC/MIC ABE pattern, and the AUC/MICs for 50% and 90% effects were lower: for B. fragilis, they were 10.5 and 25.7, respectively; for C. perfringens, they were 8.6 and 16.2; and for GPAC, they were 7.3 and 17.4. The maximum-effect log drops were as follows: for B. fragilis, -3.2 +/- 0.2 logs; for C. perfringens, -3.7 +/- 0.1 logs; and for GPAC, -2.5 +/- 0.1 logs. Although the anaerobes were not eradicated, there was no emergence of resistance. Comparison of the ABE of moxifloxacin to that of ertapenem against B. fragilis indicated that moxifloxacin was superior at 24 h and 48 h. In contrast, ertapenem was superior to moxifloxacin against GPAC at 24 h and 48 h and against C. perfringens at 48 h. Both drugs performed equivalently against C. perfringens at 24 h. Monte Carlo simulations using human serum AUC data and an AUC/MIC anaerobe target of 7.5 suggests a >90% target achievement at MICs of <2 mg/liter. This divides the B. fragilis wild-type MIC distribution. The pharmacodynamic properties of moxifloxacin against anaerobes are different than those against aerobic species. The clinical implications of these differences need further exploration.

Gemifloxacin for the Treatment of Respiratory Tract Infections: In Vitro Susceptibility, Pharmacokinetics and Pharmacodynamics, Clinical Efficacy, and Safety

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most gram-negative and gram-positive organisms, such as the important community-acquired respiratory pathogens Streptococcus pneumoniae (including multidrug-resistant S. pneumoniae), Haemophilus influenzae , and Moraxella catarrhalis . The agent's mechanism of action involves dual targeting of two essential bacterial enzymes: DNA gyrase and topoisomerase IV. Gemifloxacin was approved by the Food and Drug Administration in April 2003 for treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The drug has an oral bioavailability of approximately 71%. Approximately 20-35% of gemifloxacin is excreted unchanged in the urine after 24 hours. The elimination half-life of gemifloxacin is 6-8 hours in patients with normal renal function, supporting once-daily dosing. The 24-hour free-drug area under the plasma concentration-time curve:minimum inhibitory concentration ratio (fAUC(0-24):MIC) associated with efficacy, based on results from in vitro and animal models of infection, is approximately 30. With a mean fAUC(0-24) of approximately 3 microg*hour/ml (35% of total AUC(0-24) of 8.4) and a median S. pneumoniae MIC for 90% of tested strains of 0.03, a fAUC(0-24):MIC ratio of 100 would be expected after standard dosing (320 mg once/day). In clinical studies involving both hospitalized and outpatient populations, gemifloxacin has been highly effective in the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis. Clinical success rates ranged from 93.9-95.9% in patients with community-acquired pneumonia and 96.1-97.5% in those with acute exacerbation of chronic bronchitis. Gemifloxacin is well tolerated; the frequency of adverse events with this agent is low. Most adverse events are mild-to-moderate in severity, with diarrhea (< 4%), nausea and rash (< 3%), and headache (< 2%) most commonly reported. Drug interactions with gemifloxacin are not common, although absorption is greatly reduced when given with divalent and trivalent cation-containing compounds, such as antacids. Due to its potent activity against many common gram-positive and gram-negative respiratory pathogens, its proven clinical efficacy, and its favorable safety profile, gemifloxacin is a highly effective empiric treatment for community-acquired lower respiratory tract infections.

Pharmacodynamics of tobramycin in patients with cystic fibrosis

Relationships between pharmacodynamic indices (PI), such as the area under the concentration–time curve (AUC)/MIC ratio and time > MIC ( T >MIC), and efficacy have been described for antimicrobial drugs. The use of these quantitative relationships may increase the power to demonstrate significant effects of drugs, obviating the need to include large numbers in comparative trials. Patients with cystic fibrosis (CF) hospitalized for treatment of an infectious exacerbation due to Pseudomonas aeruginosa were eligible for the study. They received tobramycin 3.3 mg/kg tid as initial therapy in combination with ticarcillin 125 mg/kg qid. Blood samples were drawn at t = 0–8 h after infusion. Pharmocokinetic parameters and PI were calculated for every individual and correlated to the relative improvement in forced expiratory volume during the first second (FEV1) and forced vital capacity (FVC) between pretreatment and days 9–11 as a measure of efficacy. The 3 PI fAUC/MIC, f Peak/MIC, and T >MIC of tobramycin showed a significant correlation with effect and was the highest for the fAUC/MIC relationships with FEV1 and FVC as determined both by the Emax model as well as Spearman correlations ( r = 0.77, P = 0.002 and 0.58, P = 0.036 for FEV1 and FVC). Pharmacokinetic parameters AUC and Peak as such showed no significant correlation with effect, nor did the MIC values. There is a significant relationship between PI of aminoglycosides and efficacy parameter (increase in FEV1 and FVC) in patients with CF. This study demonstrates the applicability of pharmacodynamic relationships in determining efficacy of antimicrobial therapy, by demonstrating a strong PI–effect relationship in a group of only 13 patients.

Activity of Gemifloxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model

Gemifloxacin is a novel fluoronaphthyridone quinolone with enhanced in vitro activity against Streptococcus pneumoniae. We investigated the activities of gemifloxacin and trovafloxacin, their abilities to select for resistance in vitro and in vivo, and their efficacies in a mouse model of acute pneumonia. Immunocompetent Swiss mice were infected with 10(5) CFU of a virulent, encapsulated S. pneumoniae strain, P-4241, or its isogenic parC, gyrA, parC gyrA, and efflux mutant derivatives (serotype 3); and leukopenic mice were infected with 10(7) CFU of two poorly virulent clinical strains (serotype 11A) carrying either a parE mutation or a parC, gyrA, and parE triple mutation. The drugs were administered six times every 12 h, starting at either 3 or 18 h postinfection. In vitro, gemifloxacin was the most potent agent against strains with and without acquired resistance to fluoroquinolones. While control mice died within 6 days, gemifloxacin at doses of 25 and 50 mg/kg of body weight was highly effective (survival rates, 90 to 100%) against the wild-type strain and against mutants harboring a single mutation, corresponding to area under the time-versus-serum concentration curve at 24 h (AUC(24))/MIC ratios of 56.5 to 113, and provided a 40% survival rate against a mutant with a double mutation (parC and gyrA). A total AUC(24)/MIC ratio of 28.5 was associated with poor efficacy and the emergence of resistant mutants. Trovafloxacin was as effective as gemifloxacin against mutants with single mutations but did not provide any protection against the mutant with double mutations, despite treatment with a high dose of 200 mg/kg. Gemifloxacin preferentially selected for parC mutants both in vitro and in vivo.