Prospective, randomized, multicentric, open, comparative study on the efficacy of a prophylactic single dose of 500 mg levofloxacin versus 1920 mg trimethoprim/sulfamethoxazole versus a control group in patients undergoing TUR of the prostate

OBJECTIVES: Transurethral resection of the prostate (TUR-P) is one of the most frequent urological procedures. The efficacy of a prophylactic single dose of levofloxacin vs. trimethoprim/sulfamethoxazole (TMP/SMZ) vs. a control group, receiving no antibiotic prophylaxis, in patients undergoing TUR-P was investigated in a multicentre study. The aims were to assess the rate of bacteriuria (cfu> or =10(4)/ml) 5 to 7 days, and 3 to 5 weeks after TUR-P, as well as postoperative complications. METHODS: The study was prospective, randomized, multicentric, open and comparative. Patients without bacteriuria (cfu<10(4)/ml) scheduled for TUR-P and not having received antibiotics prior within four days were enclosed. Patients received an oral single dose prophylaxis with either 500 mg levofloxacin, or 320/1600 mg TMP/SMZ, or no prophylaxis according to a 2:2:1 randomization. Clinical examination of the patients and urine culture were performed prior to, 5 to 7 days and 3 to 5 weeks after TUR-P. RESULTS: 14 urological centres throughout Germany recruited 400 patients. 376 patients were evaluable until day 5 to 7, 339 until week 3 to 5. Overall bacteriuria rate at day 5 to 7 was 22% (levofloxacin 21%; TMP/SMZ 20%; control group 30%). Bacteriuria rate at week 3 to 5 was 28% (levofloxacin 26%; TMP/SMZ 26%; control group 36%). Complication rate at week 3 to 5 was 10% (levofloxacin 8%; TMP/SMZ 10%; control group 16%). The rates of postoperative bacteriuria ranged widely between centers (0%-75%). Statistically significant (p<0.05) risk factors for bacteriuria (range) were qualification of surgeon (19%-37%), presence of a suprapubic catheter (22%-34%), disconnection of the closed drainage system (25%-52%), operating time (12%-31%) and operative centre (0%-75%). Total antibiotic consumption (for prophylaxis and treatment) in the control group was higher and more expensive than in groups with antibiotic prophylaxis (6.9 vs. 5.0 doses/patient; 24.9 vs. 19.7 /patient) (p<0.0001). Postoperative complications in patients with bacteriuria (cfu> or =10(4)/ml) were more frequent than in non bacteriuric (cfu<10(4)/ml) patients (17% vs. 8%) (p<0.01). CONCLUSIONS: It is debatable whether postoperative bacteriuria is the key parameter to define efficacy of antimicrobial prophylaxis in patients undergoing TUR-P. The rate of bacteriuria, however, correlated well with the overall rate of postoperative complications. Therefore, it seems reasonable to lower the rate of bacteriuria by prophylaxis. Since patients without antibiotic prophylaxis received at the end even more antibiotic doses than patients with prophylaxis, the overall selection pressure by antibiotic usage can obviously not be lowered by resigning prophylaxis. Therefore we conclude that at least patients at risk should receive antibiotic prophylaxis prior to TUR-P.     

Oral trimethoprim-sulphamethoxazole levels in stable HIV-infected children.

BACKGROUND: Effective treatment of Pneumocystis jiroveci pneumonia (PCP) requires therapeutic serum concentrations of 5-10 microg/ml trimethoprim (TMP); consequently intravenous trimethoprim-sulphamethoxazole (TMP-SMZ) is recommended therapy. However, oral therapy is desirable as the intravenous route is costly, time-consuming, more difficult to administer and carries a risk of needlestick injury. OBJECTIVE: To investigate whether therapeutic TMP levels for treatment of PCP can be attained with oral therapy in HIV-infected children. METHODS: A prospective dose-escalation study was undertaken of serum TMP levels attained following oral doses of TMP of 5 mg/kg, 10 mg/kg or 20 mg/kg in stable HIV-infected children. Children who received a 20 mg/kg dose were randomised to get a second dose (5 or 10 mg/kg TMP) at 6 hours. TMP levels were measured at baseline, peak (3 hours), and trough (6 hours) using liquid chromatography. An additional TMP level was taken at 9 hours in those who received a second TMP dose. RESULTS: Median (25th-75th percentile) peak serum TMP levels following a 5 mg/kg, 10 mg/kg or 20 mg/kg oral loading dose were 0.93 (0.5-1.5) microg/ml, 1.94 (1.4-2.2) microg/ml and 7.68 (6.1-7.8) microg/ml respectively. Peak TMP levels at 9 hours after a second TMP dose of 5 or 10 mg/kg were 6.98 (3.4-8.8) microg/ml and 9.25 (8.2-10.3) microg/ml respectively. CONCLUSION: Therapeutic concentrations of TMP for treatment of P. jiroveci can be attained with an oral loading dose of 20 mg/kg and sustained with a second dose at 6 hours of either 5 mg or 10 mg/kg in stable HIV-infected children.     

Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole during hemodialysis

The pharmacokinetics of intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) were studied in patients receiving hemodialysis. 16 stable end-stage renal disease patients received a single ampul of TMP-SMZ (160 mg TMP, 800 mg SMZ) with 250 ml 5% dextrose and water over 45 min just prior to beginning hemodialysis. All patients were dialyzed for 4 h with a 1.0 m2 cuprophane hollow-fiber dialyzer at a blood flow of 200 ml/min. Mean arterial TMP concentration peaked at 1.93 micrograms/ml following infusion and fell to 1.03 micrograms/ml by the end of dialysis (p less than 0.001). Mean arterial SMZ concentration peaked at 41.8 micrograms/ml at the end of the infusion and fell to 16.4 micrograms/ml by the end of dialysis (p less than 0.005). The extraction ratio averaged 19% for TMP and 21% for SMZ. The elimination half-life during dialysis for TMP was 6.0 h and for SMZ was 3.1 h. Dialysis clearance averaged 38 ml/min for TMP and 42 ml/min for SMZ. 44% of the administered TMP and 57% of the administered SMZ were removed during dialysis. Therefore, 50% of the maintenance dose of TMP-SMZ should be supplemented after each dialysis session.     

Lower risk of urinary tract infection with low‐dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid‐withdrawal immunosuppression regimen

Giullian JA, Cavanaugh K, Schaefer H. Lower risk of urinary tract infection with low‐dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid‐withdrawal immunosuppression regimen.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01129.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Urinary tract infections (UTI) are common in renal transplant recipients. Trimethoprim/sulfamethoxazole (TMP/SMZ) in moderate to high daily doses prevents Pneumocystis jiroveci (PCP) and reduces the risk of UTI in renal transplant patients. Low‐dose TMP/SMZ also reduces the risk of PCP, although its ability to reduce the risk of UTI is uncertain. Design: Retrospective review of 158 patients who received a renal transplant without corticosteroids for maintenance immunosuppression. Results: Forty percent of patients initially prescribed TMP/SMZ ultimately stopped this medication early because of an adverse reaction. Urinary infection occurred in 16% without a significant difference in the risk of UTI between those treated with dapsone vs. those treated with TMP/SMZ (HR [95%CI]: 1.7 [0.75, 3.9], p = 0.2). In the subset of patients who were older than age 47 yr (mean age for this cohort, SD ± 6.2 yr), those treated with dapsone originally or who switched from TMP/SMZ to dapsone had a greater risk of UTI compared to patients who remained on TMP/SMZ (HR [95%CI]: 4.3 [1.2, 15.5], p = 0.024). Conclusions: For renal transplant recipients over the age of 47 yr, treated without long‐term glucocorticoids, our retrospective data suggest that low‐dose TMP/SMZ is associated with a lower risk of UTI compared to dapsone prophylaxis.     

Trimethoprim-sulfamethoxazole pharmacokinetics during continuous ambulatory peritoneal dialysis

Eight adult patients without peritonitis maintained on chronic ambulatory peritoneal dialysis (CAPD) were administered a single oral dose of 320 mg trimethoprim (TMP) and 1600 mg sulfamethoxazole (SMX) to characterize the pharmacokinetics of TMP and SMX. Ten blood samples were drawn following the dose. TMP and SMX-active (SMXA) concentrations were quantified in serum and dialysate. The half-life of TMP and SMXA determined by model independent methods were 33.7 +/- 10.5 h (mean +/- SD) and 13.8 +/- 2.2 h respectively. Total body clearance of TMP was 32.8 +/- 10.1 ml/min and SMXA was 21.9 +/- 6.4 ml/min. CAPD clearance of TMP was 2.27 +/- 0.81 ml/min and SMXA was 1.72 +/- 0.93 ml/min. The average peritoneal dialysate concentrations over the 72-hour collection period of TMP and SMXA were 0.9 +/- 0.1 mg/l and 5.3 +/- 0.8 mg/l respectively. A dose of 320 mg TMP and 1600 mg SMX every 48 hours is recommended for CAPD patients with mild to moderate systemic infections.     

Combination of caspofungin and low‐dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients

Pneumocystis jirovecii pneumonia (PJP) is a severe and life‐threatening complication in immunocompromised patients. Trimethoprim/sulfamethoxazole (TMP‐SMZ) is well known for its effectiveness as prophylaxis of PJP. However, the use of TMP‐SMZ is associated with various adverse effects that may not be tolerated by critically ill patients. Caspofungin is recommended for invasive fungal infections, but the treatment of PJP after solid organ transplantation (SOT) is an off‐label use of this drug. In this study, three cases of severe PJP in renal transplant recipients treated with a combination of caspofungin and low‐dose TMP‐SMZ were presented. Initial findings indicated that the combined treatment may be beneficial for the treatment of PJP and decrease the incidence of TMP‐SMZ‐related adverse effects.     

Serum and dialysate concentrations of cephalexin following repeated dosing in CAPD patients

Oral cephalexin, 1 to 2 g daily for 3 days, was given to six stable, noninfected patients receiving maintenance continuous ambulatory peritoneal dialysis (CAPD). The peak serum concentration after a 2 g initial dose was between 73 and 123 mg/L. On the second and third day in five patients who received a 2 g daily oral dose, the serum concentrations were between 35 and 118 mg/L in serum obtained 1 to 1.5 hours after the dosing. Similar serum concentrations were seen in one patient who only received a 1 g oral dose on the second and third day. Cephalexin concentrations in the peritoneal dialysate reached a peak on the first day between 4 to 14 hours after the dose and were between 31 to 78 mg/L. During the second and third day, the highest cephalexin concentration was 118 mg/L and the lowest was 12 mg/L. The data are consistent with the feasibility of oral cephalexin for treatment of CAPD-associated peritonitis with microorganisms that are sensitive to these levels of cephalexin.     

A single dose tinidazole and doxycycline prophylaxis in elective surgery of colon and rectum. A prospective controlled clinical multicenter study.

Antimicrobial prophylaxis with agents active against aerobic and anaerobic micro-organisms leads to a significant reduction of infectious complications following colorectal surgery. A single dose (1600 mg) of tinidazole (a nitroimidazole derivate) and doxycycline (400 mg) will provide serum and tissue values well above minimum inhibitory concentration (MIC) values for more than 24 hours. To reduce the unwanted side effects and cost of prolonged antimicrobial prophylaxis, a prospective controlled clinical multicenter study comparing the effect of a single dose before operation of tinidazole and doxycycline to five days of prophylaxis before operation in 234 patients undergoing elective colorectal surgery was undertaken. Six patients given a single dose of prophylaxis before operation (n = 118) developed infectious complication (5.1%). Prolongation of prophylaxis before operation for four days after operation (n = 116) did not lead to any further reduction of infectious complications. A single dose of tinidazole and doxycycline before operation is a simple and effective prophylaxis against infectious complications following elective colorectal surgery.     

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients

BACKGROUND: Many regimens using different doses of folic acid (FA) alone or with supplementation of B-complex vitamins (BCV) have been tested for the reduction of total homocysteine (tHcy) levels in hemodialysis (HD) patients. BCV are usually administered orally and for a short period. In the present study, we assessed the effect of long-term intravenous (IV) BCV on serum tHCy levels in HD patients, and the effect produced by moderate oral supplementation with FA. METHODS: In a cohort of 37 patients under chronic HD treatment for a mean of 50.2 +/- 46.7 months, serum concentrations of tHcy, folate and vitamin B12 were determined at the end of four sequential periods: (A) three months without any FA supplementation, (B) three months with oral supplementation of 5 mg of FA three times weekly, (C) six months without FA supplementation, and (D) three months without BVC or FA supplementation. From the start of HD treatment and throughout the study until the beginning of period D, patients received a standard IV dose of BCV (B1 250 mg + B6 250 mg + B12 1.5 mg) three times per week, post-dialysis. RESULTS: At the end of period B, mean serum tHcy levels were significantly lower than in periods A and C (13.7 +/- 3.6 micromol/L vs 19.6 +/- 10.8 micromol/L and 21.3 +/- 9.4 micromol/L, respectively, p < 0.001) and mean serum folate levels were significantly higher (20.7 +/- 7.4 ng/mL vs 5.0 +/- 2.8 ng/mL and 4.5 +/- 1.4 ng/mL, respectively, p < 0.01). At the end of period D, mean serum tHcy levels were significantly higher than in all the previons periods (29.3 +/- 13.5 micromol/L, p < 0.001). Twenty-six of the 37 patients (70.2%) had normal (< 15 micromol/L) serum tHcy levels at the end of period B and only one (2.7%) had normal tHcy at the end of period D. Mean serum vitamin B12 levels at the end of periods A, B and C were 100 times the usual normal values. At the end of period D, although significantly lowered (p < 0.001), they remained above the normal range. CONCLUSIONS: Long-term high-dose BCV IV three times a week post-dialysis reduced serum tHcy levels only when combined with oral FA supplementation.     

Antibiotic prophylaxis for ureteral stent removal after kidney transplantation

There are no guidelines for antibiotic prophylaxis for ureteral stent removal after kidney transplantation. We reviewed the charts of 277 adult kidney transplant recipients with ureteral stents transplanted at our center between September 2014 and December 2015 and investigated whether antibiotic prophylaxis for stent removal was associated with reduced incidence of urinary tract infections (UTI). We defined UTI as a urine culture ≥10⁴ CFU/mL of bacterial isolates irrespective of symptoms. Primary outcome was the incidence of UTI within four weeks of stent removal. Among the 277 recipients, 199 (72%) were on sulfamethoxazole/trimethoprim (SMZ/TMP) as Pneumocystis jirovecii prophylaxis. At the time of ureteral stent removal, 56 recipients (20%) received additional antibiotic prophylaxis (ABX+) and 221 (80%) did not (ABX‐). The difference in the incidence of UTI in the ABX(+) group (16%) and ABX(?) group (19%) was not statistically significant (P = 0.85). Variables independently associated with the development of UTI were recipient age (odds ratio [OR] 1.04, [95% confidence interval 1.01‐1.07]) and UTI while stents were in situ (OR 3.9 [2.00‐7.62]). Use of SMZ/TMP was protective (OR 0.35 [0.18‐0.7]). Our study does not show a statistically significant benefit for additional antibiotic prophylaxis for ureteral stent removal. Antibiotic prophylaxis may be beneficial for recipients not on SMZ/TMP at the time of stent removal.     

High-dose aprotinin with gentamicin-vancomycin antibiotic prophylaxis increases blood concentrations of creatinine and cystatin C in patients undergoing coronary artery bypass grafting

Both aprotinin and gentamicin-vancomycin antibiotic prophylaxis have been used widely in cardiac surgery to prevent bleeding and infections, respectively. As the drugs are excreted almost entirely by glomerular filtration, we investigated their action on renal function when administered either separately or together. To increase consistency, we measured serum concentrations of creatinine and cystatin C, a new marker of glomerular filtration rate, that many recent studies have shown to be more sensitive than serum creatinine. One hundred patients undergoing coronary artery bypass surgery were allocated randomly to one of four groups: group A received antibiotic prophylaxis with cefamandole and no aprotinin; group B received cefamandole and high- dose aprotinin; group C received antibiotic prophylaxis with gentamicin and vancomycin, but no aprotinin; and group D received both high-dose aprotinin and gentamicin-vancomycin antibiotic prophylaxis. Data from 84 patients, for whom data collection was complete, were analysed. In the first week after operation, mean serum concentrations of cystatin C and creatinine either remained constant or decreased slowly in all groups, except for group D. In group D, both markers increased gradually from postoperative day 2 onwards. The increase in cystatin C was significant on postoperative day 5 (from mean 1.02 (SD 0.11) mg litre-1 before operation to 1.35 (0.32) mg litre-1; P < 0.05), reaching a peak on postoperative day 7 (1.45 (0.35) mg litre-1; P < 0.05), while the increase in creatinine concentration was significant on postoperative day 6 (from 1.05 (0.16) mg dl-1 before operation to 1.29 (0.34) mg dl-1; P < 0.05). We conclude that simultaneous administration of high-dose aprotinin and prophylactic use of gentamicin with vancomycin increased serum concentrations of cystatin C and creatinine in the first postoperative week in patients undergoing cardiac surgery.      

Influence of oral vitamin E therapy on micro-inflammation and cardiovascular disease markers in chronic hemodialysis patients

BACKGROUND: The aim of this study was to evaluate the influence of oral vitamin E therapy on serum concentrations of several markers of micro-inflammation and cardiovascular disease in chronic hemodialysis (HD) patients. METHODS: 29 HD patients were randomized into two groups: 15 patients were treated orally with 400 mg of vitamin E daily for a period of five weeks, and 14 patients received no antioxidant supplementation. Before and after vitamin E therapy, serum concentrations of vitamin E (high-performance liquid chromatography), pregnancy-associated plasma protein-A (immunochemical--TRACE assay), C-reactive protein (nephelometry), intercellular adhesion molecule-1 (ELISA), and E-selectin (ELISA) were measured. HD patients were compared with 16 healthy controls. RESULTS: Baseline serum concentrations of PAPP-A and CRP were significantly higher in HD patients than in healthy controls (PAPP-A: 26.23+/-11.94 vs. 11.41+/-1.94 mIU/L, p<0.001; CRP: 5.20+/-3.50 vs. 3.40+/-3.80 mg/L, p<0.05). After five weeks of oral vitamin E intake, serum PAPP-A, CRP, ICAM-1, and E-selectin concentrations remained unchanged in both groups of HD patients. CONCLUSION: Chronic micro-inflammation in HD patients is documented by the elevation of CRP and PAPP-A. A daily oral dose of 400 mg of vitamin E does not seem to be able to reduce enhanced oxidative stress and micro-inflammation in chronic HD patients.     

三甘氨酰基赖氨酸加压素对肝移植术病人围术期肾功能的影响

Objective To evaluate the effects of teriipressin on perioperative renal function in patients undergoing liver transplantation. Methods Forty ASA Ⅲ or Ⅳ patients (31 males and 9 females) aged 35-55 yr and weighing 46-81 kg were randomly divided into 2 groups (n=20 each): terlipressin group and control group. The patients were premedicated with intramuscular midazolam 2- 3 mg and atropine 0.5 mg. Swan-ganz catheter was placed via the right internal jugular vein and the radial artery was cannulated. Electrocardiography (ECG), blood pressure (BP), heart rate (HR), central venous pressure (CVP) and pulmonary artery pressure (PAP) were monitored during general anesthesia. General anesthesia was induced with midazolam (0.1-0.2 mg/kg), fentanyl (5-10 μg/kg), propofol(1-2 mg/kg) and vecuronium (0.1 mg/kg) and maintained with 0.5%-1.5% isoflurane, propofol infusion at 2-5 mg·kg-1·h-1 and intermittent i.v. boluses of fentanyl and vecuronium. The patients were mechanically ventilated after tracheal intubation. In the terlipressin group, 2 mg of terlipressin was added to 50 ml of normal saline (NS) and was continuously infused at 10 ml/L from beginning of operation until the end of anhepatic phase, while in the control group, NS was infused only. Blood and urine samples were taken before operation(T0), at the end of anhepatic phase (T1), at the end of operation (T2), and on the 1st and 2nd day after operation (T3, T4)for determination of plasma angiotensin Ⅱ (AT- Ⅱ ), serum β2-microglobulin (MG), blood urea nitrogen (BUN) and creatinine (Cr) concentrations and N-acetyl-βd-glucosaminidase (NAG) concentrations in the urine. Urine output was measured during pre-anhepatic, anhepatic and neo-hepatic phase and on the 1 st and 2nd day after operation. Results The urinary NAG and serum β2-MG concentrations were significantly increased at T1 as compared with the baseline at T0 in both groups. The urinary NAG, plasma AT-Ⅱ, serum β2-MG, BUN and Cr concentrations were significantly lower and the urinary output was significantly higher during T2-4 in the terlipressin group than in the control group. Conclusion Terlipressin has protective effects on renal function in patients undergoing orthotopic liver transplantation.     

The effect of two different doses comprising the simultaneous administration of intravenous B-complex vitamins and oral folic acid on serum homocysteine levels in hemodialysis patients

Background: Several regimens using different doses of folic acid (FA) alone or supplemented with B-complex vitamins (BCVs) have been tested for their ability to reduce total homocysteine (tHcy) serum levels in hemodialysis (HD) patients. In the present study, we assessed the effect of two different doses comprising the simultaneous administration of intravenous (IV) BCVs and an oral FA supplementation on serum tHCy levels in HD patients. Patients–methods: In a cohort of 49 patients (31 male, 18 female) undergoing chronic HD treatment for a mean of 40.0±40.7 months, serum concentrations of tHcy, folate and vitamin-B12 (vB12) were determined at the end of three sequential periods as follows: 20 weeks without any BCV and/or FA supplementation (period A), 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA once a week (period B), and 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA thrice a week (period C). An IV dose of BCVs consisting of a 5 mL solution containing vitamin B₁ (250 mg), vitamin B₆ (250 mg) and vitamin B₁₂ (1.5 mg) was administered at the end of hemodialysis. Results: Mean serum tHcy levels were significantly higher at the end of period A relative to levels at the end of periods B and C (35.8±23 μmol/L vs. 22.0±17.6 and 15.0±4.5 μmol/L, respectively; p < 0.000001). Mean serum folate levels and mean serum vB12 levels were significantly lower at the end of period A relative to levels at the end of periods B and C (p < 0.000001). Mean serum tHcy levels were lowest at the end of period C (p < 0.000001 in comparison to periods A and B), and 26 of the 49 HD patients (67.3%) possessed tHcy levels below 16 μmol/L. Conclusions: In HD patients, high doses consisting of the simultaneous administration of IV BCVs and an oral FA supplementation resulted in the efficient reduction of serum tHcy levels.     

Cyclosporine and long-term kidney graft survival

BACKGROUND: Previous analysis of kidney transplant data from the Collaborative Transplant Study database showed that patients receiving cyclosporine 3-6 mg/kg/day 1 year posttransplantation had the best graft survival rate 7 years posttransplantation. Longer-term and additional analyses have now been performed. METHODS: Data from cadaver kidney transplants performed between 1985 and 1998 were analyzed retrospectively. Patients were included if they had a functioning graft 1 year posttransplantation, and the daily cyclosporine dose administered 1 year posttransplantation was reported. Data on cyclosporine dose, serum creatinine concentration, and systolic blood pressure were recorded 1 and 5 years after transplantation; information on graft survival was documented at yearly intervals. RESULTS: Patients receiving cyclosporine 3-6 mg/kg/day 1 year posttransplantation had the best graft survival rate 10 years posttransplantation. Cyclosporine <2 mg/kg/day was least beneficial overall and in subanalyses based on age, risk level, and 1-year serum creatinine concentration. The microemulsion cyclosporine formulation (Neoral) was associated with a significantly higher 4-year graft survival rate than the conventional formulation (Sandimmune; P=0.0001). Median systolic blood pressure 5 years posttransplantation was similar in each 1-year cyclosporine dose category (range of medians 139.0-140.0 mmHg). The percentages of patients with serum creatinine concentrations of <130, 130-260, 260-400, or >400 micromol/L 1 and 5 years posttransplantation were similar across 1-year cyclosporine dose categories, with the exception of >6 mg/kg/day, where there was a shift toward a less favorable serum creatinine concentration over time. CONCLUSIONS: The 1-year cyclosporine dose was significantly associated with long-term graft survival, with evidence of underimmunosuppression at doses <3 mg/kg/day and overimmunosuppression at doses >6 mg/kg/day, but had little influence on systolic blood pressure or serum creatinine concentration at doses up to 6 mg/kg/day.     

Serum and urinary inorganic fluoride concentrations after prolonged inhalation of sevoflurane in humans.

Serum and urinary concentrations of inorganic fluoride were measured before and after sevoflurane anesthesia in 10 patients without renal disease, who were scheduled for surgery lasting 13.4 +/- 0.9 h (mean +/- SE). The mean concentration of serum inorganic fluoride reached a maximal value of 42.5 +/- 4.5 mumol/L at the end of anesthesia. However, 5 of 10 patients had serum inorganic fluoride concentrations that exceeded 50 mumol/L (i.e., the nephrotoxic dose). A positive correlation was found between serum inorganic fluoride concentration and anesthetic dose. The largest urinary excretion of inorganic fluoride was 1804 +/- 378 mumol/day in the first postoperative day and rapidly decreased thereafter. We concluded that lengthy sevoflurane anesthesia created serum inorganic fluoride concentrations that could influence renal function, although nephrotoxicity was not demonstrated in our biochemical study.     

Pharmacokinetics of intermittent intravenous cefazolin and tobramycin in patients treated with automated peritoneal dialysis

There is increasing use of intermittent dosing of antibiotics to treat peritoneal dialysis (PD)-related peritonitis. The disposition of intravenous cefazolin and tobramycin was studied in automated PD (APD) patients. Ten patients were recruited and received a single intravenous dose of cefazolin (15 mg/kg) and tobramycin (0.6 mg/kg). Blood and dialysate samples were collected at the beginning, middle, and end of dwells 1 to 3 (on cycler), and at the end of dwells 4 to 5 (off cycler) for a 24-h period. Baseline and 24-h urine samples were collected. Pharmacokinetic parameters were calculated using a monoexponential model. Cefazolin and tobramycin half-lives were markedly different on cycler than off cycler (cefazolin on cycler : 10.67 +/- 4.66 h; cefazolin off cycler : 23.09 +/- 5.6 h; P = 0.001; tobramycin on cycler : 14.27 +/- 4.53 h; tobramycin off cycler : 68. 5 +/- 26.47 h; P < 0.001). Mean serum and dialysate concentrations were above minimum inhibitory concentrations of susceptible organisms throughout the 24-h period for both drugs with intravenous administration. A model was developed to examine serum and dialysate concentrations after intermittent intraperitoneal administration of 15 mg/kg cefazolin and 0.6 mg/kg tobramycin. Model-predicted intraperitoneal cefazolin provides adequate serum and dialysate concentrations for 24 h. Intermittent intraperitoneal tobramycin doses must be 1.5 mg/kg for one exchange during the first day and then given as 0.5 mg/kg thereafter. It is concluded that the current empiric dosing recommendations for PD-related peritonitis may be adequate for cefazolin (15 to 20 mg/kg); however, tobramycin doses must be changed to 1.5 mg/kg intraperitoneally on day 1, then to 0.5 mg/kg intraperitoneally thereafter in APD patients.     

Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation,given alone or in combination with cyclosporine or RAD

BACKGROUND: FTY720 is a novel immunomodulator with a unique mechanism of action, i.e. chemokine-dependent lymphocyte homing into secondary lymphoid organs associated with profound lymphocyte depletion in blood. We investigated its efficacy, either FTY720 alone or together with cyclosporine or the rapamycin derivative rapamycin derivative (RAD), in cynomolgus monkey kidney allotransplantation. METHODS: Life-supporting allotransplantation was performed in bilaterally nephrectomized hosts. Compounds were given once daily by oral gavage. Monitoring was done by serum creatinine and urea, and rejection was concluded when values exceeded 500 micromol/L and 50 mmol/L, respectively (5-6 times the upper limit of reference values). Rejection was confirmed by graft histology. The termination point was set to 100 days after transplantation. In addition, animals were monitored for 24 hr drug concentrations and thorough inspection of potential adverse side effects. RESULTS: FTY720 given alone at 3.0 mg/kg per day prolonged rejection-free survival (33-85 days, mean 24 hr concentration between 54 and 66 ng/mL [n=3]), but it was not efficacious at a 0.3 mg/kg per day dose. For cyclosporine alone, 30 mg/kg per day during maintenance was efficacious (average concentration above 100 ng/mL, historical data from our group), and for RAD alone 0.75 mg/kg per day (concentration above 10 ng/mL). Efficacious FTY720-cyclosporine-A (CsA) or FTY720-RAD combinations were established using 0.1-0.3 mg/kg per day FTY720, 10-30 mg/kg per day cyclosporine, and/or 0.25-0.50 mg/kg per day RAD. Compared with single-compound treatment, FTY720 effective doses and 24 hr trough concentrations were at least tenfold lower in combination treatment and those of cyclosporine and RAD about twofold lower, indicative of effective synergy between the compounds. Already at the lowest FTY720 dose tested (0.03 mg/kg per day), there was a profound lymphocyte depletion down to about 30% of pretransplant values, which further increased at the highest dose (3.0 mg/kg per day, to about 14% of pretransplant values). Lymphocyte depletion was reflected by a decrease in T and B subpopulations. CONCLUSION: FTY720 is an effective immunosuppressant in prevention of acute kidney allograft rejection in cynomolgus monkeys and synergizes with cyclosporine and/or RAD in yielding rejection-free allograft survival.     

Prophylaxis with oral cefadroxil versus intravenous cefuroxime in trochanteric fracture surgery

A prospective, randomized study was performed in 559 patients to compare two doses of oral cefadroxil with three doses of intravenous cefuorxime as antibiotic prophylaxis in intra- and subtrochanteric hip fracture surgery. Antibiotic concentrations in the wound fluid were determined at the start and at the end of the operation. The first dose of cefadroxil was given about 2 h before surgery and cefuroxime about 30 min before operation. In 226/242 (93%) patients randomized to oral cefadroxil, the concentration in the wound during surgery was on average 15 /gmg/ml, i.e., well above the minimum inhibitory concentration (MIC-90) for Staphylococcus aureus. In the cefuroxime group, antibiotic levels in the wound exceeded the MIC-90 for S. aureus in 204/210 (97%) of the patients at the start and/or at the end of surgery. All patients were followed up for 4 months. One deep and five superficial infections occurred in the cefuroxime group and no deep but one superficial infection in the cefadroxil group (P = 0.07). S. aureus was cultured in three of the infected cases while cultures were negative in four patients. Four of the seven infected patients had adequate levels of antibiotic in the wound during surgery, and in three patients no antibiotic assay was performed. The infected patients did not differ in age, sex, operation time, bleeding or any other basic variable compared with patients who healed without complications. Two doses of cefadroxil seems to be practical and as effective as intravenously administered cefuroxime as antibiotic prophylaxis in trochanteric hip fracture surgery.     

Teicoplanin pharmacokinetics during albumin dialysis

Teicoplanin (TP) pharmacokinetics was assessed in a critically ill patient during albumin dialysis (AD), which was performed with the molecular adsorbent recirculating system. After a 1200-mg loading dose (24 mg/kg), doses of 1200 and 1000 mg (20 mg/kg) on day 2 and 3, respectively, were administered during two cycles of AD. The mean TP peak and trough concentrations amounted to 99.3 and 21.4 μg/mL, respectively, during AD. A mean half-life of 5.5 h, an apparent volume of distribution of 0.302 L/kg, and a mean total TP clearance of 39 mL/h/kg were calculated. Ninety minutes after the start of AD, the extracorporeal clearance was 3560 mL/h. Within 8 h of AD therapy, the serum concentrations decreased by about 75%. Despite a considerable elimination of TP by AD, therapeutic serum levels could be maintained during the entire treatment by administration of high doses and close monitoring of TP serum concentrations.