Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock

Objective: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic pat ients, however, the interstitial space of soft tissues in addition to the c entral compartment represents the target site of infection. We thus hypothe sized that one explanation for therapeutic failure during antibiotic treatm ent might be the inability to achieve effective antimicrobial concentration s in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered p-lactam antibiotic, often fails to be effective despite documented susceptibility of the causat ive pathogen in vitro Design: Prospective comparative study of two groups. Setting: The intensive care unit and research ward of an university hospita l. Subjects: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. Interventions: To measure piperacillin penetration into the interstitial sp ace fluid of skeletal muscle and subcutaneous adipose tissue, we employed m icrodialysis after a single intravenous administration of 4.0 g of piperaci llin to patients and healthy volunteers. Piperacillin concentrations were a ssayed by using reversed-phase high-pressure liquid chromatography, Measurements and Main Results: In septic shock patients, interstitial piper acillin concentrations in skeletal muscle and subcutaneous adipose tissue w ere five- to ten-fold lower than corresponding free plasma concentrations ( p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue ne ver exceeded 11 <mu>g/mL, which is below the minimal inhibitory concentrati on for a range of relevant pathogens in patients with septic shock, Conclusion: The results of the present study demonstrate that in septic sho ck patients, piperacillin concentrations in the interstitial space may be s ubinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might b e attributable to inadequate target site penetration of antibiotics.