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Broad initial antibiotic treatment is crucial for patients experiencing septic shock or severe sepsis. Fourth-generation β-lactam antibiotics, such as cefpirome, are frequently favored in these conditions because of their low toxicity and wide antimicrobial coverage. From recent data, however, there is circumstantial evidence that one reason for the high mortality rate of patients with sepsis might be an impaired penetration of antimicrobial agents from the central compartment to the infectious focus. Thus, the present study aimed at describing penetration properties of cefpirome to the target site of many bacterial infections, which is the extracellular space fluid of soft tissues.Prospective comparative study of two groups.An intensive care unit and research ward in a university hospital.The study population included 12 patients with septic shock or severe sepsis and a control group of six overall age-matched healthy volunteers.To measure cefpirome penetration into the interstitial space fluid of skeletal muscle, we employed microdialysis after single intravenous administration of 2.0 g of cefpirome to patients and healthy volunteers.Maximum concentration and area under the concentration vs. time values in interstitium were significantly lower in patients compared with the control group (p < .004). Cefpirome area under the concentration time values for plasma were 16.0 ± 1.1 mg·min/mL (mean ± sem) and 18.8 ± 1.1 mg·min/mL in patients and healthy volunteers, respectively (p = .075, not significant). In both study groups, mean cefpirome concentrations in interstitium and plasma exceeded 28 μg/mL throughout the observation period of 240 mins and covered completely minimal inhibitory concentration values for a range of clinically relevant pathogens.Cefpirome concentrations reached in tissue interstitium and plasma exceeded minimal inhibitory concentrations of most clinically relevant pathogens in patients with sepsis. Thus, cefpirome exhibits a tissue pharmacokinetic profile, which seems to be particularly valuable for the empirical therapy of patients with sepsis.