In Europe, most reported human cases of babesiosis have been attributed, without strong molecular evidence, to infection with the bovine parasite Babesia divergens. We investigated the first known human cases of babesiosis in Italy and Austria, which occurred in two asplenic men. The complete 18S ribosomal RNA (18S rRNA) gene was amplified from specimens of their whole blood by polymerase chain reaction (PCR). With phylogenetic analysis, we compared the DNA sequences of the PCR products with those for other Babesia spp. The DNA sequences were identical for the organism from the two patients. In phylogenetic analysis, the organism clusters with B. odocoilei, a parasite of white-tailed deer; these two organisms form a sister group with B. divergens. This evidence indicates the patients were not infected with B. divergens but with an organism with previously unreported molecular characteristics for the 18S rRNA gene.

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Background-Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation. Methods and Results-In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F 1ϩ2 (PϽ0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; PϽ0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F 1ϩ2 and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (PϽ0.01). Concomitantly, factor VIIa levels dropped by Ͼ50% at 50 minutes after initiation of either heparin infusion (PϽ0.01). Conclusions-This

This prospective crossover study compared the pharmacokinetics of meropenem by continuous infusion and by intermittent administration in critically ill patients. Fifteen patients were randomized to receive meropenem either as a 2 g iv loading dose, followed by a 3 g continuous infusion (CI) over 24 h, or by intermittent administration (IA) of 2 g iv every 8 h (q8h). Each regimen was followed for a period of 2 days, succeeded by crossover to the alternative regimen for the same period. Pharmacokinetic parameters (mean +/- SD) of CI included the following: concentration at steady state (Css) was 11.9+/-5.0 mg/L; area under the curve (AUC) was 117.5+/-12.9 mg/L x h. The maximum and minimum serum concentrations of meropenem (Cmax, Cmin) and total meropenem clearance (CItot) for IA were 110.1+/-6.9 mg/L, 8.5+/-1.0 mg/L and 9.4+/-1.2 L/h, respectively. The AUC during the IA regimen was larger than the AUC during CI (P < 0.001). In both treatment groups, meropenem serum concentrations remained above the MICs for the most common bacterial pathogens. We conclude that CI of meropenem is equivalent to the IA regimen and is therefore suitable for treating critically ill patients. Further studies are necessary to compare the clinical effects of CI and IA in this patient group.

OBJECTIVE: To investigate whether weight adjusted cipro¯oxacin dosing results in comparable target site concentrations in obese and lean subjects. DESIGN: Comparative study in two populations. SUBJECTS: Twelve obese subjects (mean weight 122 AE 22.6 kg, 28 ± 52 y, maleXfemale ratio 4X8) and 12 age-and sex-matched lean controls (mean weight 59 AE 8.6 kg). METHODS: Sampling of interstitial space¯uid by means of calibrated in vivo microdialysis after a weight-adjusted intravenous bolus dose of 2.85 mgakg cipro¯oxacin. Analysis of drug concentration by high pressure liquid chromatography. RESULTS: We found signi®cantly higher peak and trough levels of cipro¯oxacin in plasma for obese subjects (9.97 AE 5.64 and 0.44 AE 0.10 mgaml vs 2.59 AE 1.06 and 0.19 AE 0.09 mgaml in lean subjects, P`0.05), while concentration ± time curves of interstitial¯uid of muscle and subcutaneous fat did not differ between the groups. Tissue penetration, expressed as AUC tissue aAUC plasma ratio was signi®cantly lower in obese subjects (0.45 AE 0.27 vs 0.82 AE 0.36, P`0.01). CONCLUSION: We conclude that the penetration process into the interstitial space¯uid is impaired in obese subjects. Therefore antibiotic doses need not be adjusted for an increase in fatawater ratio. Weight-adjusted dosing based on actual body weight will yield adequate tissue levels for cipro¯oxacin.

To characterize the potential of ciprofloxacin penetration into human soft tissues following intravenous (i.v.) and oral (p.o.) administration, we measured the free ciprofloxacin concentrations in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue by microdialysis. In addition, ciprofloxacin concentrations were measured in cantharis-induced skin blisters, saliva, and capillary plasma and were compared to the total concentrations in venous plasma. The concentrations in saliva and capillary blood were similar to the corresponding total levels in plasma. In vitro both in vivo ciprofloxacin concentration-time profiles were equally effective against select bacterial strains. In conclusion, single-dose administration of two bioequivalent dosage forms of ciprofloxacin might lead to differences in target site pharmacokinetics. These differences, however, are not related to a difference in target site pharmacodynamics.

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Abstract-During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) induces tissue factor (TF) expression.TF expression is mediated by nuclear factor B and amplified by activated platelets. TF forms a highly procoagulant complex with activated coagulation factor VII (FVIIa). Hence, we hypothesized that aspirin, which inhibits LPS-induced, nuclear factor B-dependent TF expression in vitro and platelet activation in vivo, may suppress LPS-induced coagulation in humans. Therefore, we studied the effects of aspirin on systemic coagulation activation in the established and controlled setting of the human LPS model. Thirty healthy volunteers were challenged with LPS (4 ng/kg IV) after intake of either placebo or aspirin (1000 mg). Acetaminophen (1000 mg) was given to a third group to control for potential effects of antipyresis. Neither aspirin nor acetaminophen inhibited LPS-induced coagulation. However, LPS increased the percentage of circulating TF ϩ monocytes by 2-fold. This increase was associated with a decrease in FVIIa levels, which reached a minimum of 50% 24 hours after LPS infusion. Furthermore, LPS-induced thrombin generation increased plasma levels of circulating polymerized, but not cross-linked, fibrin (ie, thrombus precursor protein), whereas levels of soluble fibrin were unaffected. In summary, a single 1000-mg dose of aspirin did not decrease LPS-induced coagulation. However, our study showed, for the first time, that LPS increases TF ϩ monocytes, substantially decreases FVIIa levels, and enhances plasma levels of thrombus precursor protein, which may be a useful marker of fibrin formation in humans. ). 1,2 DIC is defined by enhanced activity of coagulation factors, exhaustion of endogenous coagulation inhibitors, and activation and depletion of platelets by formation of thrombi in the vasculature. 3 Results of several studies suggest that initiation of coagulation in sepsis is driven primarily by the tissue factor (TF)-dependent pathway of coagulation. 4,5 Inhibition of the TF-dependent activation of coagulation using antibodies against TF or activated factor VII (FVIIa) completely prevents LPS-induced activation of coagulation in animals. 6 -8 Thus, inhibition of TF expression on monocytes during endotoxemia may present a promising therapeutic option for dampening the coagulation cascade. A recent in vitro study showed that acetylsalicylic acid (ASA) reduces LPS-induced TF expression on isolated monocytes. 9 Conversely, whole-blood experiments showed that ASA enhanced TF activity on monocytes. 10,11 Furthermore, TF expression on human monocytes is enhanced by the presence of granulocytes and activated platelets, suggesting an even more complex regulation of TF in vivo. [12][13][14][15][16] In addition, results of animal studies suggest that inhibition of thromboxane A 2 -mediated platelet activation may improve DIC induced by LPS. 3 Besides in vitro studies and experiments in animals, infusion of small doses of LPS into humans has emerged as a valuable tool to explore the pathogenesis ...