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 patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro.


METHODS
Prospective comparative study of two groups.


METHODS
The intensive care unit and research ward of an university hospital.


METHODS
Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers.


METHODS
To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography.


RESULTS
In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock.


CONCLUSIONS
The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna Medical School, Vienna, Austria.
C
C
Joukhadar
M
M
Frossard
B X
BX
Mayer
M
M
Brunner
N
N
Klein
P
P
Siostrzonek
H G
HG
Eichler
M
M
Müller
D000273:Adipose Tissue / Q000737:chemistry / Q000187:drug effects*; D000368:Aged; D000900:Anti-Bacterial Agents / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems / Q000009:adverse effects* / Q000592:standards; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D017551:Microdialysis; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects*; D010878:Piperacillin / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017410:Practice Guidelines as Topic; D011446:Prospective Studies; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013997:Time Factors; D014018:Tissue Distribution; D017211:Treatment Failure
D000900:Anti-Bacterial Agents; D010878:Piperacillin