In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women). The volunteers received 250 mg of ciprofloxacin, 400 mg of gatifloxacin, 600 mg of grepafloxacin, 500 mg of levofloxacin, 400 mg of moxifloxacin, and 200 mg of trovafloxacin. The concentrations of the six fluoroquinolones in serum and urine were measured by a validated high-performance liquid chromatography method. Blood and urine samples were collected before and at different time points up to 48 h after medication. Levofloxacin had the highest peak concentration (C max , in micrograms per milliliter) (6.21 ؎ 1.34), followed by moxifloxacin (4.34 ؎ 1.61) and gatifloxacin (3.42 ؎ 0.74). Elimination half-lives ranged from 12.12 ؎ 3.93 h (grepafloxacin) to 5.37 ؎ 0.82 h (ciprofloxacin). The total areas under the curve (AUC tot , in microgram-hours per milliliter) for levofloxacin (44.8 ؎ 4.4), moxifloxacin (39.3 ؎ 5.35), and gatifloxacin (30 ؎ 3.8) were significantly higher than that for ciprofloxacin (5.75 ؎ 1.25). Calculated from a normalized dose of 200 mg, the highest C max s (in micrograms per milliliter) were observed for levofloxacin (2.48 ؎ 0.53), followed by moxifloxacin (2.17 ؎ 0.81) and trovafloxacin (2.09 ؎ 0.58). The highest AUC tot (in microgram-hours per milliliter) for a 200-mg dose were observed for moxifloxacin (19.7 ؎ 2.67) and trovafloxacin (19.5 ؎ 3.1); the lowest was observed for ciprofloxacin (4.6 ؎ 1.0). No serious adverse event was observed during the study period. The five recently developed fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin) showed greater bioavailability, longer half-lives, and higher C max s than ciprofloxacin.Fluoroquinolones are widely used alternatives to ␤-lactam agents in the treatment of many bacterial infections. Their antimicrobial activity results from a selective antagonism between host DNA and bacterial DNA without interfering with eucaryotic topoisomerases. The early fluoroquinolones, from the early 1960s, had a limited spectrum of antibacterial activity, mainly against gram-negative pathogens. Further observations of structure-related increases in activity, changes in pharmacokinetic characteristics, and reduced toxicity were followed by numerous chemical modifications of the quinolone molecule. The resulting new fluoroquinolone antimicrobial agents have enhanced activity against gram-positive organisms and anaerobes (1, 2) and improved pharmacokinetic parameters in comparison to previous derivatives. However, only reports on single-drug kinetics have been published so far, and there have been no direct comparisons between the new drugs and the standard drug, ciprofloxacin (1-3).We therefore evaluated and compared the pharmacokinetics of six fluoroquinolones after a single oral dose in the same volunteers.( (mean, 28.4 Ϯ 4.3 years) and with an average weight of 67.4 ...

The 2 x 7 h infusion of ceftazidime 2 g (C2 x 2) was clinically and bacteriologically as effective as the usual 3 x 2 g ceftazidime short-term infusion in the treatment of AECB, and demonstrated advantages in terms of pharmacodynamic parameters compared with the C3 x 2 regimen.

Background Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates. Methods We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia. Results With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever. Conclusions Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011.

Background Timely antimicrobial treatment and source control are strongly recommended by sepsis guidelines, however, their impact on clinical outcomes is uncertain. Methods We performed a planned secondary analysis of a cluster-randomized trial conducted from July 2011 to May 2015 including forty German hospitals. All adult patients with sepsis treated in the participating ICUs were included. Primary exposures were timing of antimicrobial therapy and delay of surgical source control during the first 48 h after sepsis onset. Primary endpoint was 28-day mortality. Mixed models were used to investigate the effects of timing while adjusting for confounders. The linearity of the effect was investigated by fractional polynomials and by categorizing of timing. Results Analyses were based on 4792 patients receiving antimicrobial treatment and 1595 patients undergoing surgical source control. Fractional polynomial analysis identified a linear effect of timing of antimicrobials on 28-day mortality, which increased by 0.42% per hour delay (OR with 95% CI 1.019 [1.01, 1.028], p ≤ 0.001). This effect was significant in patients with and without shock (OR = 1.018 [1.008, 1.029] and 1.026 [1.01, 1.043], respectively). Using a categorized timing variable, there were no significant differences comparing treatment within 1 h versus 1–3 h, or 1 h versus 3–6 h. Delays of more than 6 h significantly increased mortality (OR = 1.41 [1.17, 1.69]). Delay in antimicrobials also increased risk of progression from severe sepsis to septic shock (OR per hour: 1.051 [1.022, 1.081], p ≤ 0.001). Time to surgical source control was significantly associated with decreased odds of successful source control (OR = 0.982 [0.971, 0.994], p = 0.003) and increased odds of death (OR = 1.011 [1.001, 1.021]; p = 0.03) in unadjusted analysis, but not when adjusted for confounders (OR = 0.991 [0.978, 1.005] and OR = 1.008 [0.997, 1.02], respectively). Only, among patients with septic shock delay of source control was significantly related to risk-of death (adjusted OR = 1.013 [1.001, 1.026], p = 0.04). Conclusions Our findings suggest that management of sepsis is time critical both for antimicrobial therapy and source control. Also patients, who are not yet in septic shock, profit from early anti-infective treatment since it can prevent further deterioration. Trial registration ClinicalTrials.gov (NCT01187134). Registered 23 August 2010, NCT01187134

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