The effect of pharmacokinetic/pharmacodynamic (PK/PD) parameters of gatifloxacin on its bactericidal activity and resistance selectivity against clinical isolates of Streptococcus pneumoniae

The impact of the pharmacokinetic/pharmacodynamic (PK/PD) parameters (the 24h area under the concentration-time curve [AUC_24h]/minimum inhibitory concentration [MIC] and maximum concentration in serum [C_max]/MIC ratio) after single oral dosing of gatifloxacin on its bactericidal activity and resistance selectivity against quinolone-susceptible clinical isolates of Streptococcus pneumoniae J-69 was investigated using an in vitro PK model. The MICs of gatifloxacin, levofloxacin, and ciprofloxacin were 0.25, 1, and 1µg/ml, respectively. When the range of AUC_24h/MIC ratios was varied from 9.0 to 36 with a constant C_max/MIC ratio of 3.4, the bactericidal activity was correlated with the AUC_24h/MIC ratios. Eradication was observed at an AUC_24h/MIC ratio of 36. On the other hand, the resistance selectivity was associated with the C_max/MIC ratio. Mutant strains were selected at a C_max/MIC ratio of 0.84, but not 1.7 with a constant AUC_24h/MIC ratio of 9.0. These results suggested that an AUC_24h/MIC ratio of 36 and a C_max/MIC ratio of 1.7 might be possible benchmarks to show enough bacterial eradication and prevention of emergence of resistant strains to gatifloxacin, respectively. When the serum concentrations after clinical oral dosing of gatifloxacin (200mg b.i.d.), levofloxacin (100mg t.i.d.), and ciprofloxacin (200mg t.i.d.) were simulated, the bactericidal activity of gatifloxacin was higher than those of levofloxacin and ciprofloxacin. Moreover, no resistant strain was obtained by the exposure to gatifloxacin and levofloxacin, whereas ciprofloxacin selected resistant strains. The clinically relevant oral dosage of gatifloxacin was anticipated to result in a high AUC_24h/MIC₉₀ ratio of 81 and a C_max/MIC₉₀ ratio of 4.4, suggesting that this agent is clinically effective in the treatment of pneumococcal infections.     

Evaluation by Monte Carlo simulation of levofloxacin dosing for complicated urinary tract infections caused by Escherichia coli or Pseudomonas aeruginosa

We evaluated, by Monte Carlo simulation, 500-mg once-daily, 100-mg thrice-daily, 200-mg twice-daily, and 200-mg thrice-daily dose regimens of levofloxacin (LVFX), for the ratio of area under the concentration–time curve for 24 h (AUC_0–24) to minimum inhibitory concentration (MIC) (AUC_0–24/MIC) and the ratio of maximum plasma concentration (C _max) to MIC (C _max/MIC), which predict microbiological outcomes, and the C _max/MIC, which inhibits fluoroquinolone resistance selection, in complicated urinary tract infections (UTIs) with Escherichia coli or Pseudomonas aeruginosa. Monte Carlo simulation was performed for 10000 cases using the pharmacokinetic data of patients with complicated UTIs and the LVFX MIC distributions for E. coli or P. aeruginosa clinical strains. The probabilities of achieving the AUC_0–24/MIC target (66.2–67.9%) and the C _max/MIC target (64.5–67.5%) to eradicate E. coli were similar among the 4 regimens. In eradication of P. aeruginosa, the 200-mg thrice-daily and the once-daily dose regimens produced higher probabilities of achieving the AUC_0–24/MIC target (57.5%) and C _max/MIC target (55.1%), respectively. For the probabilities of achieving the C _max/MIC targets that prevent the emergence of fluoroquinolone resistance, the once-daily dose regimen (66.8%) did not differ from the other multiple-dose regimens (62.3–66.2%) in E. coli, whereas the former regimen (44.2%) was superior to the latter regimens (10.8–31.7%) in P. aeruginosa. The 500-mg once-daily dose regimen of LVFX, which produced the larger AUC_0–24 and higher C _max, could ensure the efficacy of eradication of uropathogens and reduce the risk of fluoroquinolone resistance selection in complicated UTIs.     

Fluoroquinolone susceptibility, resistance, and pharmacodynamics versus clinical isolates of Streptococcus pneumoniae from Indiana

The in vitro activity and pharmacodynamics (AUC_0–24/MIC) of levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin were evaluated against 307 clinical isolates of Streptococcus pneumoniae from Indianapolis, Indiana. Organisms were collected between January 1999 and April 2000, and MICs were determined by broth microdilution. Serum concentration-time profiles were simulated for the following oral regimens administered once daily: levofloxacin 500 mg and 750 mg; gatifloxacin 400 mg; moxifloxacin 400 mg; gemifloxacin 320 mg. Free 24 h area under the serum concentration-time curves (AUC_0–24) were calculated, and the average AUC_0–24/MIC was calculated for each regimen. Differences in AUC_0–24/MIC among agents were determined by analysis of variance (Scheffe post-hoc test, p < 0.05). Overall, gemifloxacin was the most potent agent tested. Five (1.7%), 4 (1.3%), and 2 (0.7%) isolates were resistant to levofloxacin, gatifloxacin, and moxifloxacin, respectively. None of the isolates was resistant to gemifloxacin. Gemifloxacin AUC_0–24/MIC was significantly greater than all other regimens (p < 0.0001), with the exception of moxifloxacin. However, the percent of isolates for which an AUC_0–24/MIC ≥ 30–50 can be achieved is similar for gemifloxacin, moxifloxacin, gatifloxacin, and levofloxacin 750 mg. Large comparative studies are needed to determine if the differences in AUC_0–24/MIC among fluoroquinolones are clinically significant.     

In vitro evaluation of the activity of β-lactams,new quinolones,and other antimicrobial agents againstStreptococcus pneumoniae

The in vitro activities of the β-lactam and quinolone antibiotics panipenem, cefpodoxime, cefdinir, cefditoren, faropenem, tosufloxacin, levofloxacin and grepafloxacin were compared with similar conventional antibiotics against penicillin-resistantStreptococcus pneumoniae (PRSP). Pneumococcal isolates collected from October 1994 to March 1995 (n=1283) consisted of penicillin-susceptibleS. pneumoniae (PSSP; 59.2%), penicillin-intermediately-resistantS. pneumoniae (PISP;11.2%), and PRSP (29.6%). The isolates were highly susceptible to panipenem, faropenem and cefditoren with MIC₉₀ values of 0.125 μg/mL, 0.5 μg/mL and 0.5 μg/mL, respectively. Correlation coefficients for the relationships between the MICs of these β-lactam agents and that of penicillin G ranged from γ=0.7652 to γ=0.8022. These new β-lactam agents produced excellent bactericidal responses at concentrations greater than their MICs for PSSP concomitant with appropriate cellular morphologic changes. However, the bactericidal action of these antibiotics against PRSP was less pronounced and fewer instances of cell lysis were observed. The MIC₉₀ of cefpodoxime was similar to that of cefaclor, whereas that of cefdinir was between those of faropenem and cefpodoxime. The MIC distribution of the new quinolone agents showed 1 peak, but the MIC₉₀ values of tosufloxacin and grepafloxacin were both 0.5 μg/mL and that of levofloxacin was 2.0 μg/mL. Only 1% of all isolates demonstrated cross-resistance to all quinolone agents.     

Evaluation of dosing designs of carbapenems for severe respiratory infection using Monte Carlo simulation

Using the Monte Carlo simulation method, the influence of various doses and dosing frequencies of carbapenems on the antimicrobial activities against Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, which are the main causative organisms of respiratory infections, was studied with the aim of identifying optimized effectiveness. Based on pharmacokinetic (PK) parameters of individual carbapenems in healthy adults, data on changes in the respective blood concentrations in 2000 cases were simulated by applying a lognormal distribution to probability distributions of their volume of distributions and half-life periods. Based on minimum inhibitory concentration (MIC) distribution data of the individual carbapenems against these strains, MICs in the 2000 cases were also simulated. Using these data in blood concentrations and MICs, the probabilities of attaining various percentages of the dosing interval during which drug concentrations remain above MIC (T > MIC) were calculated at several dosing regimens. Considering the probabilities of attaining the bactericidal effect (50% T>MIC) and daily drug costs, imipenem (IPM) at 500 mg i.v. BID, panipenem (PAPM) at 500 mg i.v. BID, and biapenem (BIPM) at 300 mg i.v. BID against Streptococcus pneumoniae; meropenem (MEPM) at 500 mg i.v. BID or TID against Haemophilus influenzae infections; and MEPM at 500 or 1000 mg i.v. TID against Pseudomonas aeruginosa, each over 30 min, were determined as appropriate empirical treatments. Selecting carbapenems with superior antimicrobial activities and optimizing their dose regimens are important to improve the efficacy. Application of Monte Carlo simulation to MIC distributions allows determination of appropriate empiric therapy even if drug susceptibility of a causative organism in individual patients is unknown.     

Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation

In this study we compared the efficacy of a theoretically optimized two-step infusion therapy (OTIT; rapid first-step infusion and slow second-step infusion) to the efficacies of prolonged infusion therapy (PIT) and traditional 0.5 h infusion therapy (TIT) with meropenem against Pseudomonas aeruginosa using an in vitro pharmacodynamic model and a Monte Carlo simulation. In the in vitro pharmacodynamic model, the bactericidal effect against P. aeruginosa was evaluated for 8 h, which is the usual dosing interval of meropenem. It was confirmed that the durability of the bactericidal effect of OTIT (0.25–1 g/0.5 h + 0.25–1 g/4 h t.i.d.) was almost equal to that of PIT and superior to that of TIT (0.5–2 g/0.5–4 h t.i.d.). In addition, the initial bactericidal effects of OTIT were superior to those of the prolonged 4 h infusion. In the Monte Carlo simulation study, the probability of target attainments (PTAs) of all dosing regimens of OTIT at MICs of 2–8 μg/ml were apparently superior to those of TIT and 4- and 6 h-PIT, when the target therapeutic condition for serious life-threatening infections was the achievement of both the percentage of the dosing interval at which the drug concentration exceeds the MIC (%T _>MIC) ≥ 50% and the peak level divided by the MIC (C _max/MIC) ≥ 4. Especially, the PTAs of the dosing regimens of 0.25–1 g/0.5 h + 0.25–1 g/4–6 h were excellent at MICs of 2–8 μg/ml. Against recent clinical isolates of P. aeruginosa in Japan, the dosing regimens of OTIT provided higher PTAs compared with those of TIT and 4- and 6 h-PIT. These results suggested that OTIT with sufficient pharmacokinetic conditions could be useful for enhancing the therapeutic efficacy of meropenem against serious life-threatening infections.     

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy

PurposesTo determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT).MethodsAll necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC_24h/MIC ≥50 for Gram-positive and AUC_24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients.ResultsNo conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2 mg/L. The successful dose (1750 mg on day 1, then 1500 mg q 24 h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg q 24 h was sufficient to attain PTA target of ~90% at the MIC of 2 mg/L for Streptococcus pneumoniae.ConclusionsLevofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.     

In-vitro activity of sitafloxacin (DU-6859a), either singly or in combination with rifampin analogs, against Mycobacterium leprae

 The in-vitro antibacterial activity of sitafloxacin (DU-6859a) against Mycobacterium leprae was evaluated and compared with those of ofloxacin, levofloxacin, and ciprofloxacin. Two biochemical indicators (intracellular ATP and uptake of [³H]-thymidine) were used to measure the in-vitro growth of M. leprae in Dhople-Hanks (DH) medium. Sitafloxacin was found to be more potent than the other three commonly used fluoroquinolones, with the minimum inhibitory concentration (MIC) against M. leprae being 0.1875 μg/ml and the action being bactericidal. The MICs of ofloxacin, levofloxacin, and ciprofloxacin were 1.5, 0.75, and 3.0 μg/ml, respectively. Similar to ofloxacin and levofloxacin, sitafloxacin also exhibited synergistic activity when combined with either rifabutin or KRM-1648, but not with rifampin. Thus, further studies on the incorporation of sitafloxacin in multidrug therapy regimens in treating leprosy patients are suggested. Received: July 30, 2002 / Accepted: October 9, 2002 Acknowledgments The authors wish to thank Daiichi Pharmaceutical Company, Ltd. for supplying sitafloxacin for this study.     

Effects of fluoroquinolones on experimental pneumonia caused by penicillin-resistantStreptococcus pneumoniae in mice

The in vitro and in vivo activities of several fluoroquinolones, ampicillin and cefteram-pivoxil were investigated against penicillin-resistantStreptococcus pneumoniae (PRSP). The MIC₉₀s of sparfloxacin, levofloxacin, tosufloxacin, AM-1155, ampicillin, and cefteram-pivoxil for 13 PRSP strains were 0.78, 3.13, 0.39, 1.56, 3.13, and 3.13 μg/mL, respectively. An experimental fatal pneumonia was induced by intranasal inoculation of PRSP No. 65 in CBA/J mice. The fluoroquinolones were effective against the experimental pneumonia, but ampicillin and cefteram-pivoxil were not sufficiently effective. The oral 50% effective doses (ED₅₀) of sparfloxacin, levofloxacin, tosufloxacin, and AM-1155 on the experimental pneumonia were 6.09, 49.3, 5.07, and 8.59 mg/kg/dose, respectively, when treatment was initiated 3 hours after infection and were 30.0, >50, 17.7, and 45.9 mg/kg/dose, respectively, when treatment was initiated 24 hours after infection. These results suggest that some fluoroquinolones such as sparfloxacin, tosufloxacin and AM-1155 may be effective in the treatment of pneumonia due to PRSP in humans.     

In vitro and in vivo activities of sparfloxacin and reference drugs againstChlamydia pneumoniae

The activities of sparfloxacin and reference drugs againstChlamydia pneumoniae were compared by using in vitro and in vivo methods. The minimum inhibitory concentration (MIC) (μg/ml) ranges of sparfloxacin, levofloxacin, tosufloxacin, grepafloxacin, AM-1155, DU-6859a, clarithromycin, azithromycin, and minocycline for sixC. pneumoniae strains (two standard and four clinical strains) were 0.031 to 0.063, 0.25 to 0.5, 0.063 to 0.125, 0.063 to 0.125, 0.063 to 0.125, 0.031 to 0.063, 0.016 to 0.031, 0.125 to 0.25, and 0.016 to 0.031, respectively. The in vitro potency of sparfloxacin againstC. pneumoniae was similar to that of clarithromycin, minocycline, and DU-6859a, and higher than that of the other fluoroquinolones and azithromycin. Fatal pneumonia was induced in cyclophosphamide-treated leukopenic mice by intranasal inoculation withC. pneumoniae KKpn-2. Infiltration of the lung by neutrophils and lymphocytes was confirmed by histopathologic examination. Oral treatment with the various antichlamydial agents was given for seven days; sparfloxacin and minocycline had the lowest ED₅₀ (effective treatment dose in 50% of the mice; given as mg/kg per dose) (1.11 each), followed by DU-6859a (1.92), tosufloxacin (2.09), grepafloxacin (2.41), clarithromycin and azithromycin (2.48 each), AM-1155 (2.77), and levofloxacin (>10). These results suggest that sparfloxacin may be an effective agent forC. pneumoniae infection in humans.     

Ciprofloxacin therapy for typhoid fever needs reconsideration

Outbreaks of multidrug-resistant Salmonella enterica serotype Typhi in the Indian subcontinent in the late 1980s resulted in the failure of conventional drugs, and ciprofloxacin became the firstline drug to treat enteric fever. However, reduced susceptibility to ciprofloxacin, reported widely since 1994, has posed a therapeutic difficulty. The aim of the present work was to review the situation of drug resistance among S. enterica serotype Typhi in central India from 1988 to 2005. A minimum inhibitory concentration (MIC) study for ciprofloxacin was carried out by the agar dilution method on 314 stock cultures preserved since 1988. The MIC for ciprofloxacin was ≤0.125 mg/l for the 50 isolates isolated during 1989–1994, but during 1998–1999, 60% of the 50 isolates showed MIC > 0.125 mg/l, while in 2002–2003, 82.5 % of the 97 isolates had MIC > 0.125 mg/l and 35% had MIC > 1 mg/l (high-level resistance). In 2004–2005, 88.2% of the 77 isolates had MIC > 0.125 mg/l and 15% had MIC > 1 mg/l (high-level resistance). Sixty-four isolates showing MIC > 1 mg/l with the agar dilution method were also checked by Epsilometer test (E-test, AB Biodisk, Solna, Sweden). Based on the data, it is suggested to withdraw ciprofloxacin as a therapeutic agent for enteric fever. Fortunately, multiple drug resistance, with concurrent resistance to chloramphenicol, cotrimoxazole, and ampicillin, which had reached more than 90% in 1990–1991, started declining over the years and was as low as 5.6% in 2004–2005. According to these observations, older drugs such as chloramphenicol, cotrimoxazole, and ampicillin could be recalled to treat enteric fever.     

Comparison of levofloxacin, alatrofloxacin, and vancomycin for prophylaxis and treatment of experimental foreign-body-associated infection by methicillin-resistant Staphylococcus aureus

The prophylactic and therapeutic activities of two fluoroquinolones, levofloxacin and alatrofloxacin (the L-Ala-L-Ala prodrug of trovafloxacin), were compared to those of vancomycin in two different experimental models of foreign-body-associated infections caused by methicillin-resistant but quinolone-susceptible Staphylococcus aureus (MRSA) isolates. In a guinea pig model of prophylaxis, subcutaneously implanted tissue cages were infected with 10(3) CFU of MRSA, which was a 100% infectious dose in control animals. A single dose of 50 mg of levofloxacin per kg of body weight, administered intraperitoneally 3 h before bacterial challenge, was more efficient than vancomycin for the prevention of infections in tissue cages with MRSA inocula of 10(4) and 10(5) CFU. In a rat model used to evaluate therapy of chronic tissue cage infection caused by MRSA, the efficacies of 7-day high-dose regimens of levofloxacin (100 mg/kg once a day [q.d.] or 50 mg/kg twice a day [b.i.d.]) or alatrofloxacin (50 mg/kg q.d.) were compared to the efficacy of vancomycin (50 mg/kg b.i.d.). Active levels of levofloxacin, trovafloxacin, and vancomycin were continuously present in tissue cage fluid, with the levels exceeding the minimal bactericidal concentrations for MRSA during therapy. The q.d. and b.i.d. regimens of levofloxacin had equivalent activities and were significantly (P < 0.05) more active than alatrofloxacin or vancomycin in decreasing the viable counts of MRSA in tissue cage fluids. No quinolone-resistant mutants emerged during therapy with either fluoroquinolone. The mechanisms explaining the inferior activity of alatrofloxacin compared to the activity of levofloxacin against chronic foreign-body-associated infections by MRSA are unknown.     

A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis

Goals of work Comparing antiemetic efficacy of different 5-HT₃-receptor antagonists (5-HT₃RAs) is difficult due to inter-study variability. Therefore, a meta-analysis was performed to comparatively evaluate dolasetron, granisetron, ondansetron and tropisetron for acute chemotherapy-induced nausea and vomiting (CINV). Patients and methods Comparisons between 5-HT₃RAs were based on 44 randomized studies (including 12,343 patients) identified by MEDLINE, CANCERLIT or EMBASE searches and subcategorized by chemotherapy type (cisplatin- or non-cisplatin-based). Main results When all studies were combined, granisetron was equivalent to ondansetron (n = 27), and showed an advantage vs tropisetron (p = 0.018; n = 12). Ondansetron vs tropisetron (n = 11) and ondansetron vs dolasetron (n = 3) revealed equivalence in each comparison. An advantage for 3 mg granisetron vs 8 mg ondansetron was found in non-cisplatin-based studies (p = 0.015; n = 6). Overall equivalence was seen between ondansetron, 24 or 32 mg, and granisetron, 2 or 3 mg, for all studies (n = 13). There was a possible advantage for higher (24 or 32 mg) vs lower (8 mg) ondansetron dose regimens with cisplatin-based trials (n = 6). No differences were seen between 3 and 1 mg granisetron doses (n = 6). Conclusions Efficacy of 5-HT₃RAs for preventing CINV following cisplatin- and non-cisplatin-based chemotherapy is comparable, with the exception of granisetron vs tropisetron. Some differences were noted in dosing subanalyses. The study has been presented in part at ASCO 5–8 June 2004, New Orleans, USA.     

Randomized,double-blind trial comparing the antiemetic effect of tropisetron plus metopimazine with tropisetron plus placebo in patients receiving multiple cycles of multiple-day cisplatin-based chemotherapy

Purpose To compare the antiemetic efficacy and tolerability of tropisetron plus metopimazine with tropisetron plus placebo during 4 cycles of multiple-day, cisplatin-based chemotherapy. Materials and methods 82 chemotherapy-naive patients with germ cell cancer scheduled to 4 cycles of multiple-day cisplatin-based chemotherapy (20 or 40 mg/m²/day for 5 days) given every 3 weeks were included. A double-blind parallel trial design was used and patients randomized to tropisetron plus metopimazine or tropisetron plus placebo. Tropisetron was administered as a single 5 mg intravenous dose on days 1–5 and a single 5 mg oral dose on day 6, and metopimazine as 30 mg orally t.i.d. on day 1, and q.i.d on days 2–6. Results Patients were evaluable for efficacy during a total of 195 cycles. Small, but certain advantages were obtained with the combination. In cycle 1, complete protection from emetic episodes on day 1, days 1–5, days 6–9 and days 1–9 was achieved in 85.7%, 42.9%, 86.2% and 40.5% with tropisetron plus metopimazine and in 90.0%, 22.5%, 64.3% and 17.5% with tropisetron plus placebo, respectively. This difference achieved statistical significance in the overall period, days 1–9 (P = 0.029). During the entire period (days 1–9), significantly less nausea was seen in patients receiving tropisetron plus metopimazine (P = 0.027), whereas other nausea parameters did not reach statistical significance. The cumulative emetic protection rate after 4 cycles was 0.51 with tropisetron plus metopimazine and 0.25 with tropisetron plus placebo (P = 0.037). Side effects were generally few and mild with both treatments and no significant differences were seen. Conclusion Tropisetron plus metopimazine is superior to tropisetron during 4 cycles of multiple-day cisplatin-based chemotherapy, but both treatments are ineffective in a number of patients. The effect of the combination seems comparable to that of ondansetron plus dexamethasone. Newer drugs such as the neurokinin₁ receptor antagonist, aprepitant, should be investigated to optimize antiemetic therapy in patients receiving multiple-day chemotherapy.     

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (k_el) of 0.11 ± 0.05 h⁻¹ (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (E_max) modeling revealed that the highest E_max was 3.15 ± 1.84 log₁₀ CFU/ml on day 3, and the exposure mediating 50% of E_max (EC₅₀) was a 0- to 24-h area under the concentration time curve (AUC_0–24)-to-MIC ratio of 41.99 ± 31.78 (r² = 0.99). The EC₈₀ was an AUC_0–24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC_0–24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC₈₀ in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin''s efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.     

Effect on carotid atherosclerosis of probucol plus levofloxacin for <Emphasis Type="Italic">Chlamydia pneumoniae</Emphasis> infection

To investigate the effect of levofloxacin on carotid atherosclerosis, patients with hypercholesterolemia whose carotid atherosclerosis was not improved by probucol therapy (500 mg/day) for 24 months were enrolled. All patients were seropositive for anti C. pneumoniae IgA and/or IgG. Carotid atherosclerosis was evaluated by ultrasonic measurement of the maximum intima-media thickness (Max-IMT). All subjects were prescribed three courses of levofloxacin (each course, 400 mg/day for 2 weeks, followed by 14 days off drug treatment). At 12 months after combined therapy with probucol and levofloxacin, Max-IMT was significantly decreased compared with the value before treatment (P < 0.01). These results suggest that the combination therapy was effective for improving carotid atherosclerosis in C. pneumoniae-seropositive patients.     

Pharmacokinetic study of antimicrobial agents in patients undergoing continuous ambulatory peritoneal dialysis

A pharmacokinetic study was done in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) to establish an appropriate treatment for bacterial peritonitis. Twenty-nine CAPD patients were randomized to receive either oral ofloxacin (OFLX) 300 mg, followed by 200 mg once a day; intraperitoneal vancomycin (VCM) 30 mg/kg once a week; or intravenous imipenem/cilastatin (IPM/CS) 1000 mg once a day. Pharmacokinetic simulation models were determined according to changes of doses and duration. The time to reach the maximum plasma concentration (t _max), the maximum plasma concentration (C _max), the plasma elimination half-life (t _1/2), and area under the curve (AUC) were, respectively, 5.2 hours, 4.7 μg/mL, 20.4 hours and 80.5 μg/mL/h (AUC_0–24) for OFLX, 7.0 h, 26.4 μg/mL, 92.0 hours, and 1641 μg/mL/h (AUC_0–120) for VCM, 1.1 hour, 62.3 μg/ml, 3.76 hours, and 229.3 μg/mL/h (AUC₀₋₁) for IPM/CS. Twenty-three of 27 (85%) strains of clinical isolates were gram-positive cocci; 20 strains (74%) consisted of staphylococci or streptococci. The MIC₉₀ of OFLX, VCM, and IPM was 3.13, 1.56, and 0.78 μg/mL, respectively. When the minimum concentration in the dialysate during the initial 5 days was higher than the MIC, all the isolates (7 out of 7) were eradicated, when it was lower, only half of the isolates (3 out of 6) were eradicated. The simulation study suggested a significant drug accumulation in response to shortening the dosing duration.     

Pharmacokinetic–pharmacodynamic study of itraconazole in patients with fungal infections in intensive care units

Severely ill patients in intensive care units (ICU) are frequently at risk of developing fungal infections. Itraconazole (ITCZ), a triazole antifungal agent, is used for the treatment of aspergillosis, candidiasis, and cryptoccosis. The present retrospective pharmacokinetic–pharmacodynamic (PK–PD) analysis was designed to find any factors affecting clinical outcome of ITCZ treatment, and was performed to evaluate the appropriateness of the current dosage regimen in ICU patients. All of the patients admitted to Aichi Medical University Hospital ICU in 2008 who were treated with ITCZ injections for fungal infections were included in the study. After outcomes had been classified as cure or failure, a PK–PD analysis was performed. In addition, the probability of PD target attainment was assessed using a Monte Carlo simulation. Ten patients were enrolled in the study. Satisfactory outcomes were obtained in 4 of the 10 patients. No significant differences in the area under the 24-h curve (AUC_0–24), peak concentrations and trough concentrations were observed between the two groups. However, it was observed that the higher the AUC_0–24, the better the outcome. Moreover, our results showed that additional dosage is needed to attain a sufficiently high AUC_0–24/MIC in about 20% of patients. Our retrospective study is the first to show that it is important to consider the host’s condition when ITCZ is administered, especially in ICU patients. The present findings are also useful for optimizing the individual dosage of ITCZ based on AUC_0–4 for the treatment of patients infected with Candida spp.     

Statistical analysis of the adverse effects of glycopeptide antibiotics, based on pharmacokinetics and toxicokinetics (PK/TK)

The effects of vancomycin hydrochloride (VCM) and teicoplanin complex (TEIC) on hepatic function and renal function were evaluated in rats. VCM was injected via the jugular vein at doses of 40, 100, and 250 mg/kg, and TEIC was injected via the jugular vein at doses of 10, 30, 40, 50, and 60 mg/kg, both after being dissolved in 1 ml of saline solution. Increased doses of VCM significantly increased the integrated plasma concentrations, from 0 to 8 h, for blood urea nitrogen (BUN_0–8) and serum creatinine (SCr_0–8). TEIC gave rise to a slight increase in both BUN_0–8 and SCr_0–8 as its dose was increased. On the other hand, TEIC significantly increased the integrated plasma concentrations, from 0 to 8 h, for aspartate aminotransferase (AST_0–8), and alanine aminotransferase (ALT_0–8), at doses from 40 mg/kg to 60 mg/kg, though VCM did not increase these concentrations. This study suggests the importance of paying attention to hepatic function – in addition to renal function – when TEIC is administered to patients with methicillin-resistant Staphylococcus aureus (MRSA).     

In vitro antifungal activity of luliconazole against clinical isolates from patients with dermatomycoses

The in vitro antifungal activity of luliconazole, a novel topical imidazole, against pathogenic fungi implicated in dermatomycoses was studied. A total of 91 clinical isolates, consisting of 59 Trichophyton rubrum isolates, 26 T. mentagrophytes isolates, 1 Epidermophyton floccosum isolate, and 5 Candida albicans isolates were tested by the broth microdilution method, employing lanoconazole, terbinafine, and bifonazole as reference drugs. The minimum inhibitory concentrations (MICs) of luliconazole against T. rubrum and T. mentagrophytes were in the range of 0.00012–0.004 μg/ml and 0.00024–0.002 μg/ml, respectively. The MIC₉₀ of luliconazole for these two species of dermatophytes was the same, at 0.001 μg/ml, and these values were 4 times, 30 times, and more than 1000 times lower than those of lanoconazole, terbinafine, and bifonazole, respectively. Similarly, the 1 isolate of E. floccosum tested was inhibited by luliconazole with an MIC of 0.001 μg/ml. Luliconazole also proved to be very potent against C. albicans (MIC range, 0.031–0.25 μg/ml), nearly on par, in terms of efficacy, with lanoconazole (0.063–0.25 μg/ml) and more potent than terbinafine (2–>64 μg/ml) and bifonazole (0.5–4 μg/ml). These results showed that luliconazole was very potent in vitro against pathogenic fungi isolated from patients with dermatomycoses, and these findings emphasized the utility of luliconazole for the topical management of this condition.