selective decontamination of the digestive tract ( sdd ) is an infection - prophylaxis regimen in intensive care unit ( icu ) patients , aiming at eradicating the potentially pathogenic micro - organisms from the mouth and stomach , while preserving the intestinal anaerobic flora to prevent overgrowth with resistant bacteria and yeasts .
most sdd regimens use the combination of topically applied tobramycin , colistin and amphotericin b. these antibiotics are given topically in the mouth and through a  gastric tube in the stomach four times daily .
some regimens combine this local therapy with systemic antibiotic prophylaxis for the first couple of days .
all three of the topical antibiotics mentioned above are regarded as non - absorbable and therefore safe  .
after prolonged use , however , minimal enteral absorption of tobramycin might lead to potentially toxic serum concentrations in patients with impaired renal function  .
renal replacement therapy by continuous venovenous hemofiltration ( cvvh ) leads to only limited drug clearance  .
thus , icu patients with renal failure are at highest risk of developing toxic serum concentrations of tobramycin after enteral administration .
serum concentrations of tobramycin are commonly monitored to minimize the risk of toxicity after systemic administration , aiming at a  trough concentration of less than 2.0  mg / l  .
the aim of this study was to determine whether enteral administration of tobramycin as part of the sdd regimen can lead to detectable and potentially toxic serum concentrations in icu patients with acute renal failure requiring cvvh .
we conducted a  prospective single - center observational study . from june 2006 to october 2006 , all eligible patients were included in the study .
patients with systemic use of tobramycin or another aminoglycoside within the previous 5 days were excluded from the study . because the study involved no interventions , and because measuring serum tobramycin concentrations in patients on cvvh was part of routine patient care , the local medical ethics review board waived the requirement for informed consent .
the sdd regimen consisted of four times daily treatment with approximately 0.5  g of a  paste , applied to the oral cavity , containing 2% colistin , 2% tobramycin , and 2% amphotericin b. patients also received 100  mg colistin sulfate , 80  mg tobramycin , and 500  mg amphotericin b administered through a  gastric tube four times daily .
patients with blind loops ( e.g. , after colostomy ) additionally received suppositories containing 42  mg amphotericin b , 42  mg colistin sulfate , and 64  mg tobramycin ( as sulfate ) .
initiation of cvvh in our department is considered in patients who are oliguric despite adequate fluid resuscitation and/or display a  persistent steep rise in plasma creatinine in addition to persistent shock .
vascular access was obtained by insertion of a  double - lumen catheter ( duo - flow 400xl , 14f    6  in .
( 15  cm ) ; medcomp , harleysville , pa , usa ) into a  large vein ( femoral , subclavian , or internal jugular vein ) .
cvvh was performed using a  diapact hemofiltration machine ( b. braun melsungen , melsungen , germany ) and a  cellulose triacetate hemofilter ( ct-190 g ; baxter healthcare , deerfield , il , usa ) .
blood samples for the measurement of tobramycin concentrations were scheduled for the 3rd day after start of cvvh and every 3 days thereafter .
given the slow absorption and elimination of tobramycin and the frequent ( four times daily ) dosing , tobramycin concentrations were assumed to be steady state , and serum samples were taken randomly ( not as trough or peak concentrations ) .
tobramycin concentrations were determined with a  validated fluorescence polarization immunoassay ( fpia ; axsym , abbott laboratories , il , usa ) .
toxic serum concentrations of tobramycin were defined as more than 2.0  mg / l  .
we conducted a  prospective single - center observational study . from june 2006 to october 2006 , all eligible patients were included in the study .
patients with systemic use of tobramycin or another aminoglycoside within the previous 5 days were excluded from the study . because the study involved no interventions , and because measuring serum tobramycin concentrations in patients on cvvh was part of routine patient care , the local medical ethics review board waived the requirement for informed consent .
the sdd regimen consisted of four times daily treatment with approximately 0.5  g of a  paste , applied to the oral cavity , containing 2% colistin , 2% tobramycin , and 2% amphotericin b. patients also received 100  mg colistin sulfate , 80  mg tobramycin , and 500  mg amphotericin b administered through a  gastric tube four times daily .
patients with blind loops ( e.g. , after colostomy ) additionally received suppositories containing 42  mg amphotericin b , 42  mg colistin sulfate , and 64  mg tobramycin ( as sulfate ) .
initiation of cvvh in our department is considered in patients who are oliguric despite adequate fluid resuscitation and/or display a  persistent steep rise in plasma creatinine in addition to persistent shock .
vascular access was obtained by insertion of a  double - lumen catheter ( duo - flow 400xl , 14f    6  in .
( 15  cm ) ; medcomp , harleysville , pa , usa ) into a  large vein ( femoral , subclavian , or internal jugular vein ) .
cvvh was performed using a  diapact hemofiltration machine ( b. braun melsungen , melsungen , germany ) and a  cellulose triacetate hemofilter ( ct-190 g ; baxter healthcare , deerfield , il , usa ) .
blood samples for the measurement of tobramycin concentrations were scheduled for the 3rd day after start of cvvh and every 3 days thereafter .
given the slow absorption and elimination of tobramycin and the frequent ( four times daily ) dosing , tobramycin concentrations were assumed to be steady state , and serum samples were taken randomly ( not as trough or peak concentrations ) .
tobramycin concentrations were determined with a  validated fluorescence polarization immunoassay ( fpia ; axsym , abbott laboratories , il , usa ) .
toxic serum concentrations of tobramycin were defined as more than 2.0  mg / l  .
patients were treated with cvvh for median 6  days ( interquartile range , iqr , 38 days ) .
serum concentrations of tobramycin and the doses of sdd administered are shown in table  2 .
patients were treated with sdd for median 6  days ( iqr 39 days ) .
table  1patient characteristicspatientage ( years)sex ( male / female)weight ( kg)apache iisofacreat . start cvvhdiuresis ( ml / h)days cvvhdiagnosis 159 m 901812284 29 9cardiac shock with ards 242m1002216287 6 3necrotizing fasciitis and ischemic large bowel 344 m 85
813124 2,5 6abdominal sepsis 468f 563615367 25 3decompensated liver cirrhosis 536f 7523 8318 5 3fluxus postpartum 677 m 7523 9131 17 6cardiac shock after acute myocardial infarct 783 m 753714180 5 6out of hospital cardiac arrest 868 m 902914244 1210septic shock caused by necrotic pancreatitis 951f 702317422 0 6medication induced liver failure1072 m 842712265 31 5complicated cardiac surgery1156 m 992511260 25 8postoperative after thymectomy1266f 7020 7143 67 2cardiac and mesenteric ischemia1361 m 802613327 13 4intra - abdominal arterial bleeding1455f 743115243 3 9abdominal sepsis caused by fecal peritonitis1574f 651813 84 25 3abdominal sepsis caused by ischemia from the small bowel1672 m 732511614 0 3respiratory failure caused by fluid overload1761f 582213162 26 9cardiac shock after massive acute myocardial infarct1854 m 951512157 59 6respiratory failure caused by pneumonia1972 m 802214136108 6cardiac shock caused by mitral valve insufficiency due to acute myocardial infarctapache ii , apache ii score on the day of admission to icu ; sofa , sofa score on day of admission to icu ; diuresis , urine production ( ml / h ) in the last 24  h before starting cvvh ; days cvvh , number of days on cvvh at time first blood sample was drawntable  2treatment with sdd and tobramycin serum concentrationspatientsdd ( orally and via gastric tube)sdd suppositoriesdays on sddtobramycin serum concentrations ( mg / l)1+24 <  0.2+27     0.22+ 3     0.2+ 6     1.1+10     1.73++ 6     0.5++ 9     0.54+ 3     0.25+ 3 <  0.26+19 <  0.27+ 6 <  0.28+ 9     0.79+ 6     0.310+ 6     0.211+ 6 <  0.212+ 3     3.013+ 3     0.214++ 9 <  0.215++ 3     1.116+ 3 <  0.2+ 6     0.317+ 7 <  0.2+ 9 <  0.218+ 6 <  0.2+ 9 <  0.219+ 6     1.0 <  0.2 : below quantification limit patient characteristics apache ii , apache ii score on the day of admission to icu ; sofa , sofa score on day of admission to icu ; diuresis , urine production ( ml / h ) in the last 24  h before starting cvvh ; days cvvh , number of days on cvvh at time first blood sample was drawn treatment with sdd and tobramycin serum concentrations <  0.2 : below quantification limit detectable serum concentrations were found in 12 ( 63% ) of 19 patients and in 15 ( 58% ) of the 26 samples .
we found one patient with a  toxic concentration of 3.0  mg / l . in three other patients
in contrast , no patients with concentrations  <  1  mg / l had intestinal ischemia ( table  1 ) . in six patients more
mg / l after 6  days of cvvh , rising to 1.7  mg / l 4 days later .
we show that in icu patients receiving enteric tobramycin as part of sdd , detectable serum concentrations of tobramycin are found in more than half of patients with acute renal failure treated with cvvh .
these findings are in contrast to the general belief that tobramycin is not absorbed from the gastrointestinal tract and that sdd may be safely used in all patients  . our findings , however , are supported by two previous reports . in 1991
detectable tobramycin concentrations were found in 9 patients and in 50% of the serum samples . in two patients with renal failure ,
toxic serum concentrations  >  2.0  mg / l were found  . in a  more recent investigation ,
camus also reported systemic tobramycin concentrations exceeding 2  mg / l using sdd . in their study comparing two different decontamination regimens , they found toxic tobramycin serum concentrations in 21 of 74 ( 28% ) patients . in all these patients
toxicity of tobramycin includes nephrotoxicity and ototoxicity , which may be seen respectively in 1020% and 10% of the patients with serum trough concentrations  >  2.0  mg / l  .
however , accumulation of tobramycin in renal cortical cells is seen even when trough concentrations do not exceed this limit , potentially resulting in damage to proximal tubuli  .
thus , it can not be excluded that prolonged detectable serum concentrations of tobramycin are toxic even if lower than 2.0 
ml / h in our study )  . in patients with renal failure not treated with renal replacement therapy , the likelihood of accumulation of tobramycin in serum may be even higher . although the risk of toxic serum concentrations will be lower in patients with no major impairment of renal function , prolonged use of sdd may lead to detectable serum tobramycin concentrations in these patients too  [ 2 , 5 , 6 ] .
it may be hypothesized that tobramycin absorption is higher in patients with a  decreased gut barrier function .
indeed , increased absorption of polyethylene glycol has been shown in patients with inflammatory bowel disease  . in normal conditions enteral absorption of tobramycin in humans is very low due to active efflux of the drug by p - glycoprotein in the brush border of the intestinal mucosa  .
if the intestinal mucosa is damaged for any reason , this efflux pump may not function optimally and tobramycin absorption is then increased .
interestingly , in our study the highest tobramycin concentrations were exclusively found in patients with intestinal ischemia . in conclusion ,
administration of sdd can lead to detectable and potentially toxic serum concentrations of tobramycin in patients with renal failure .
we recommend determination of plasma concentrations of tobramycin in all icu patients with severely impaired renal function and on prolonged treatment with sdd .
 objectiveto study whether selective decontamination of the digestive tract ( sdd ) results in detectable serum tobramycin concentrations in intensive care unit ( icu ) patients with acute renal failure treated with continuous venovenous hemofiltration ( cvvh).design and settingprospective , observational , single - center study in a  mixed medical  surgical icu.patientsadult icu patients receiving sdd for at least 3 days and being treated with cvvh because of acute renal failure.measurements and resultstobramycin serum concentrations were measured at the 3rd day after start of cvvh and every 3 days thereafter . 
 detectable serum concentrations of tobramycin were found in 12 ( 63% ) of 19 patients and in 15 ( 58% ) of the 26 samples . with a  toxic tobramycin concentration defined as more than 2.0  
 mg / l , we found one patient with a  toxic concentration of 3.0  mg / l . in three other patients 
 tobramycin concentrations of   1.0  mg / l were found.conclusionsin patients with acute renal failure treated with cvvh , administration of sdd with tobramycin can lead to detectable and potentially toxic serum tobramycin concentrations . 
Introduction
Materials and methods
Study design
Results
Discussion