Cefazolin and cephalexin kinetics in continuous ambulatory peritoneal dialysis.

We studied single-dose cefazolin (CFZ) and cephalexin (CPX) kinetics in continuous ambulatory peritoneal dialysis (CAPD) patients to establish therapeutic guidelines for two cephalosporins commonly used to treat peritonitis in these patients. CFZ, 10 mg/kg, was given intravenously and intraperitoneally, while CPX, 500 mg, was given orally. CFZ led to serum concentrations of 25 microgram/ml at 24 hr, with a half-life (t 1/2) of 33 hr. CAPD accounted for only 20% of total body clearance. When CFZ was given intraperitoneally, 74% of the dose was absorbed and similar serum concentrations had much the same t 1/2. CPX, on the other hand, had a serum t 1/2 of 8.6 hr and resulted in much lower peritoneal concentrations than CFZ. The kinetic principal of superposition provided a model for the prediction of plasma concentrations after repeated intraperitoneal doses of CFZ. The model predicts that a 10-mg/kg intraperitoneal loading dose, followed by 5-mg/kg doses in each exchange the first day and 2.5-mg/kg doses thereafter, will lead to steady-state plasma concentrations of 50 to 65 microgram/ml. The data suggest that CFZ needs be given only intraperitoneally at doses lower than those in current use. CPX probably adds little to the treatment of peritonitis.

Tobramycin kinetics during continuous ambulatory peritoneal dialysis.

To establish therapeutic guidelines for tobramycin use in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied tobramycin single-dose kinetics in CAPD patients. Tobramycin was studied after a 1.5-mg/kg dose given either intravenously (TOB-IV) or intraperitoneally (TOB-IP). TOB-IV provided a plasma concentration above 3 mg/l at 12 hr with a t 1/2 of 39.5 hr. When tobramycin was given intraperitoneally, 52% of the dose was absorbed; peak plasma concentrations were only 1.8 mg/l, and the t 1/2 was 35 hr. CAPD accounted for only 15% to 20% of total body clearance in both groups. The kinetic principle of superposition was used to predict plasma concentrations after repeated TOB-IP. A model using once-a-day dosing predicted that a loading dose of 4 mg/kg followed by 1.5 mg/kg would achieve steady-state plasma concentrations of 2.8 to 4.2 mg/l. Another model using tobramycin in each exchange predicted that a loading dose of 3 mg/kg followed by 0.3 mg/kg would provide steady-state plasma concentrations of 2.8 to 3.1 mg/l. These data should be useful in treating CAPD patients with tobramycin who have nonperitoneal gram-negative aerobic bacterial infections, as well as those who require the drug for peritonitis.

Vancomycin kinetics during continuous ambulatory peritoneal dialysis.

To establish therapeutic guidelines for vancomycin usage in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied single-dose kinetics of vancomycin in CAPD patients. Vancomycin was studied after a 10-mg/kg dose was given intravenously (VAN-IV) or intraperitoneally (VAN-IP). VAN-IV provided a plasma concentration above 10 mg/l at 12 hr, with a t 1/2 of 81 hr. When VAN-IP was given, 65% was absorbed; peak plasma concentrations were only 6.3 mg/l, and t 1/2 was 66 hr. CAPD accounted for only 15% to 17% of total body clearance in both groups. The kinetic principle of superposition was used to predict plasma concentrations after repeated VAN-IP doses. A model with once-a-day dosing predicted that a loading dose of 30 mg/kg followed by 7 mg/kg would achieve steady-state plasma concentrations of 11 to 14.8 mg/l. Another model with vancomycin in each exchange predicted that a loading dose of 30 mg/kg followed by 1.5 mg/kg would provide plasma concentrations in excess of 10 mg/l at 180 hr. These data should be useful in vancomycin treatment of CAPD patients who have nonperitoneal gram-positive bacterial infections, as well as those who have peritonitis.

Mezlocillin kinetics in hepatic insufficiency.

To establish elimination kinetics of mezlocillin in patients with hepatic insufficiency, we gave eight normal subjects and four patients with hepatic insufficiency and normal renal function a single 3-gm dose of mezlocillin by intravenous infusion. Subjects with hepatic insufficiency all had serum bilirubins levels of above 3 mg/dl, prothrombin times more than 2 sec longer than control, and creatinine clearances above 60 ml/min. Mezlocillin concentrations were determined by microbiologic assay. Kinetic analysis was by model-independent methods. Elimination half-life was 0.96 hr for subjects with normal liver function and 2.62 hr for patients with hepatic insufficiency. Mean total body clearance for normal subjects was 247 ml/min, while in patients with hepatic insufficiency it was 125.4 ml/min. We conclude that hepatic insufficiency prolongs mezlocillin elimination and suggest that therapeutic guidelines be set up.

Use of OKT3 monoclonal antibody in the treatment of acute cardiac allograft rejection.

OKT3 is a murine monoclonal antibody that recognizes the T3 surface antigen present on mature T cells, and it has been used to successfully treat renal allograft rejection. We report our experience with OKT3 in the treatment of cardiac allograft rejection. Eight patients with endomyocardial biopsy evidence of moderate or severe rejection were given fourteen daily intravenous treatments of OKT3. Six of the eight patients had complete recovery following OKT3 therapy; one required additional steroid therapy for recurrence and one patient failed to respond. Five of the six patients with a complete response have experienced no further rejection (mean follow-up 437 days). Adverse reactions to OKT3 were common early in the treatment course, but were well tolerated. We concluded that OKT3 is a safe and effective treatment of cardiac allograft rejection and that a majority of patients experience long-term rejection-free periods.

The safety and tolerability of cyclosporine emulsion versus cyclosporine in a randomized, double-blind comparison in primary renal allograft recipients. The Neoral Study Group.

A 12-week, randomized, double-blind, multicenter pharmacokinetics study was conducted to compare the clinical safety and tolerability of cyclosporine capsules and oral solution for microemulsion and cyclosporine in 101 primary renal transplant recipients Cyclosporine emulsion has more complete absorption and improved bioavailability compared with cyclosporine, and dosing of both cyclosporine formulations was adjusted to achieve comparable whole-blood trough levels. Mean serum creatinine values were higher in the cyclosporine emulsion group at baseline, 8, and 12 weeks (P<0.05). The incidence of acute rejection was similar in both treatment groups although fewer patients required monoclonal antibody therapy in the cyclosporine group (31% vs. 82%, respectively). Despite the increased bioavailability of cyclosporine emulsion, no significant differences in the incidence of adverse events were observed; the safety, tolerability, and efficacy of cyclosporine emulsion and cyclosporine were comparable.

Wegener's granulomatosis complicated by pregnancy. A case report.

A 23-year-old woman who presented in the 17th week of her third intrauterine pregnancy was diagnosed as having active Wegener's granulomatosis. Therapy, consisting of corticosteroids, cyclophosphamide and hemodialysis, was instituted and maintained until delivery. Although Wegener's granulomatosis complicated by pregnancy has been reported previously, this is the first reported patient to be treated successfully with the above agents during the second and third trimesters without apparent harm to her or her infant.

Pharmacokinetics of common antibiotics used in continuous ambulatory peritoneal dialysis.

To establish therapeutic guidelines for the use of antibiotics in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied the single-dose pharmacokinetics of cefazolin, tobramycin, and vancomycin given intravenously (IV) and intraperitoneally (IP) as well as cephalexin given orally. By the IV or oral route, the antibiotics exhibited half-lives similar to those described in nondialysed, functionally anephric patients. CAPD accounted for only a negligible fraction of the total body clearance when the drugs were given by the IV route. However, when given IP, the drugs were promptly absorbed and achieved therapeutic serum concentrations. The kinetic principle of superposition was applied to predict plasma concentrations after repetitive IP dosing. Therapeutic guidelines are provided.

Outcomes of single organism peritonitis in peritoneal dialysis: gram negatives versus gram positives in the Network 9 Peritonitis Study.

The use of the "peritonitis rate" in the management of patients undergoing peritoneal dialysis is assuming importance in comparing the prowess of facilities, care givers and new innovations. For this to be a meaningful outcome measure, the type of infection (causative pathogen) must have less clinical significance than the number of infections during a time interval. The natural history of Staphylococcus aureus, pseudomonas, and fungal peritonitis would not support that the outcome of an episode of peritonitis is independent of the causative pathogen. Could this concern be extended to other more frequently occurring pathogens? To address this, the Network 9 Peritonitis Study identified 530 episodes of single organism peritonitis caused by a gram positive organism and 136 episodes caused by a single non-pseudomonal gram negative (NPGN) pathogen. Coincidental soft tissue infections (exit site or tunnel) occurred equally in both groups. Outcomes of peritonitis were analyzed by organism classification and by presence or absence of a soft tissue infection. NPGN peritonitis was associated with significantly more frequent catheter loss, hospitalization, and technique failure and was less likely to resolve regardless of the presence or absence of a soft tissue infection. Hospitalization and death tended to occur more frequently with enterococcal peritonitis than with other gram positive peritonitis. The outcomes in the NPGN peritonitis group were significantly worse (resolution, catheter loss, hospitalization, technique failure) compared to coagulase negative staphylococcal or S. aureus peritonitis, regardless of the presence or absence of a coincidental soft tissue infection. Furthermore, for the first time, the poor outcomes of gram negative peritonitis are shown to be independent of pseudomonas or polymicrobial involvement or soft tissue infections. The gram negative organism appears to be the important factor. In addition, the outcome of peritonitis caused by S. aureus is worse than that of other staphylococci. Thus, it is clear that all peritonitis episodes cannot be considered equivalent in terms of outcome. The concept of peritonitis rate is only meaningful when specific organisms are considered.

Assessment of function and survival as measures of renal graft outcome following kidney and kidney-pancreas transplantation in type I diabetics.

Reports on renal graft outcome after kidney-alone (KA) and simultaneous pancreas-kidney (SPK) transplants have focused on graft survival instead of function. The aim of this study is to compare renal graft outcome after KA and SPK using graft function and survival as the measures of outcome. The records of 102 transplants performed in type I diabetics from 10/90 to 9/96 were reviewed (SPK 42, KA 60). Serum creatinine (Cr) and calculated glomerular filtration rate (GFR) were used as estimates of graft function. Cr were similar in SPK and KA on day 3 (4.8 +/- 2.9 vs. 4.8 +/- 2.8 mg/dl, P = 0.9) and day 7 (2.5 +/- 1.8 vs. 3.0 +/- 2.5 mg/dl, P = 0.3). GFR was higher KA at 6 months (57 +/- 18 vs. 51 +/- 12 ml/min, P = 0.08), 1 yr (55 +/- 23 vs. 51 +/- 11 ml/min, P = 0.4) and 3 yr (60 +/- 22 vs. 42 +/- 16 ml/min, P = 0.03). Kidney graft survival was similar in KA and SPK at 1 and 5 yr (87% vs. 89% and 44% vs. 47%, P = 0.8). Immunologic failure of the renal graft occurred more frequently in SPK (58% vs. 48%, P = 0.04) whereas death with function was more common in KA (33% vs. 17%, P = 0.04). In KA, risk factors for failure of the renal graft included acute rejection (P = 0.008, relative risk or rr = 3.4) and African American recipient (P = 0.06, rr = 2.8). In SPK, risk factors included donor age > 40 yr (P = 0.05, rr = 5.3) and African American donor (P = 0.03, rr = 4.5). Logistic regression analysis revealed the following risk factors for GFR < 50 ml/min at 1 yr: acute rejection (P = 0.03, rr = 2.2) and Cr > 3 mg/dl on day 7 (P = 0.06, rr = 2.3). In conclusion, although renal graft survival was similar after KA and SPK, better graft function was observed in KA at 3 yr. Assessment of renal graft function allows us to evaluate outcome from a different perspective than graft survival, and these two measures of outcome complement each other.

Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys.

Erythropoietin (EPO)-induced hypertension is a common complication of EPO usage. The hypothesis that erythropoietin is antinatriuretic and that the sodium retention is mediated by intrarenal angiotensin II production was tested. Experiments were performed in Wistar rat kidneys perfused for 60 min in an isolated system. A dose-response curve was performed for EPO at 0, 10, 100, 1,000, and 10,000 mU/mL. EPO administration resulted in a dose-dependent decrease in sodium excretion to a maximum of 50% at the 1,000 mU/mL dose. In a second experiment, kidneys from five groups were perfused: controls, EPO (100 mU/mL), captopril (50 ng/mL), captopril (50 ng/mL) plus EPO (100 mU/mL), and the angiotensin receptor antagonist losartan (1 nM) plus EPO (100 mU/mL). The administration of EPO resulted in an immediate decrease in average sodium excretion (30%) with no change in GFR or other renal function parameters. Pretreatment with captopril or losartan blocked the effect of EPO. Captopril alone had no effect on renal function. A final experiment demonstrated the ability of losartan (10 nM) to block the pressor effects of angiotensin II (0.01, 0.1, and 1 nM). It was concluded that EPO acts within the kidney to cause the production of angiotensin II, which mediates the increased reabsorption of sodium.