Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Double-blind randomized trial of nicotinamide on early-onset diabetes.

OBJECTIVE--To determine the efficacy of nicotinamide in inducing remission in early-onset insulin-dependent diabetes mellitus. RESEARCH DESIGN AND METHODS--This study was a double-blind, randomized clinical trial. CONCLUSIONS--Nicotinamide failed to induce remission or differences on beta-cell secretion between the two groups.     

Recent advances in solid organ transplantation

Advances in organ transplantation have come rapidly and consistently in recent years as the result of improved surgical techniques and immunosuppressive drug therapies. Experience gained in renal transplantation over the past 30 years has made this a standard therapeutic approach for treating chronic renal failure. This knowledge has been successfully applied to the transplantation of other organs to produce steadily increasing survival rates and improved quality of life. This article reviews the advances that have been made in solid organ transplantation and immunosuppressive drug therapy.     

The effects of delayed function on recipients of cadaver renal allografts. A study of 158 patients randomized to cyclosporine or ALG-azathioprine

We randomized 158 recipients of cadaver renal allografts to cyclosporine-prednisone (83) or antilymphocyte globulin-azathioprine-prednisone (75) to evaluate: the effects of immunosuppression and pretransplant risk factors on the incidence of delayed graft function, the effects of immunosuppression on the resolution of delayed graft function, and the effects of delayed graft function and pretransplanted risk factors on patient and graft survival. Cyclosporine did not increase the incidence of delayed graft function, compared with ALG-azathioprine-treated patients (33% versus 27%, P = 0.550) but doubled the mean (+/- SD) duration of oliguria (11.8 +/- 11.0 versus 5.9 +/- 3.2 days, P = 0.002) and the number of required dialyses (6.6 +/- 7.6 versus 3.2 +/- 1.3, P = 0.031). Retransplanted patients had a higher incidence of delayed graft function that recipients of primary grafts in both the cyclosporine (82% versus 25%, P = 0.001) and ALG-azathioprine (55% versus 22%, P = 0.025) treatment groups. The presence of delayed function reduced one-year graft survival from 89% in all patients without delayed function to 72% (P = 0.011) in all patients with delayed function. Cyclosporine-treated patients had a slightly, but not significantly better one-year graft survival rate than ALG-azathioprine treated patients both with (73% versus 68%, P = 0.750) and without (92% versus 82%, P = 0.069) delayed graft function. A preservation time longer than 24 hr did not increase the incidence of delayed graft function in cyclosporine-treated patients (34% versus 32%, P = 0.811) or ALG-azathioprine-treated patients (27% versus 27%, P = 0.902). Cyclosporine-treated patients given kidneys with greater than 24 hr of preservation time had reduced graft survival only when delayed graft function occurred (67% versus 92%, P = 0.009). In conclusion, (1) cyclosporine did not increase the incidence of delayed graft function over ALG-azathioprine treatment; (2) cyclosporine did significantly slow recovery of kidneys with delayed function; (3) delayed graft function correlated with poorer graft survival rate in both treatment groups; but (4) prolonged preservation time did not increase the incidence of delayed graft function or reduce graft survival.     

Interaction between cyclosporine and fluconazole in renal allograft recipients

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.     

Effect of Streptococcus pneumoniae and Influenza A Virus on Middle Ear Antimicrobial Pharmacokinetics in Experimental Otitis Media

Antimicrobial treatment failures in children with acute otitis media and concomitant viral respiratory tract infection prompted us to study the effects of influenza A virus infection on middle ear antimicrobial drug penetration. Using a chinchilla model of Streptococcus pneumoniae we compared middle ear elimination rates in 4 groups of chinchillas: (1) control, (2) influenza A virus inoculation alone intranasally, (3) both influenza A and S. pneumoniae inoculation directly into the middle ear, and (4) S. pneumoniae inoculation alone into the middle ear. After infection was established, a solution containing amoxicillin, sulfamethoxazole, and trimethoprim was instilled into the middle ear and removed 4 hours later. The rate constant of elimination and half-life were calculated from measured drug concentrations initially and at 4 hours. S. pneumoniae infection alone significantly shortened the middle ear elimination half-life compared with the control group: amoxicillin, 2.65 ± 0.73 vs. 6.63 ± 2.55 hr; sulfamethoxazole, 1.75 ± 0.28 vs. 2.74 ± 0.6 hr; and trimethoprim, 1.06 ± 0.14 vs. 1.56 ± 0.34 hr (n = 16 ears, p values all <0.01). The combined influenza virus and S. pneumoniae infection significantly lengthened the half-life compared with the S. pneumoniae infection alone: amoxicillin, 5.65 ± 6.44 vs. 2.65 ± 0.73 hr; sulfamethoxazole, 2.5 ± 0.85 vs. 1.75 ± 0.28 hr; and trimethoprim, 1.26 ± 0.42 vs. 1.06 ± 0.14 hr (n = 16 ears, p values all <0.01). Influenza virus produced the longest half-lives for all 3 antimicrobials: amoxicillin 25.52 ± 14.96 hr; sulfamethoxazole, 5.46 ± 0.87 hr; and trimethoprim, 2.57 ± 0.75 hr. These effects demonstrate that influenza and S. pneumoniae infections alone and together affect middle ear antimicrobial penetration. The decreased penetration of antimicrobials that occurred with the combined viral and bacterial infection vs. the bacteria alone supports the clinical observation that patients with infections caused by both organisms may have decreased middle ear antimicrobial concentrations, producing treatment failures.     

Mizoribine pharmacokinetics and pharmacodynamics in a canine renal allograft model of local immunosuppression.

We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (MZB) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (i.a.) versus intravenous (i.v.) MZB delivery, with and without a background of oral cyclosporine. Five autotransplanted mongrel dogs with programmable, implantable pump/catheter systems were given MZB by both i.v. bolus (5 mg/kg) and i.a. infusion (5.0 mg/kg/day). Mean +/- SD elimination half-life was 3.02 +/- 0.81 hr, and the transplanted kidney removed as much as 47-59% (mean 56%) of locally infused MZB. With increasing local and systemic MZB delivery in a single autografted dog undergoing both i.a. and i.v. pump/catheter placement, renal extraction decreased from at least 47% (5.0 mg/kg/day) to 33% (7.5 mg/kg/day), finally to 18% (10.0 mg/kg/day). A dose of 3.0 mg/kg/day MZB did not significantly prolong survival of renal allograft recipients over that of untreated controls (median survival time [MST] = 8 days) when administered either locally (MST = 9 days) or systemically (MST = 12 days). All dogs receiving 4.0 mg/kg/day MZB i.a. died from rejection, and a survival advantage was still not realized (MST = 7 days). In contrast, 4.0 mg/kg/day i.v. prolonged survival over controls (MST = 14 days; P = 0.03) but not when directly compared with the i.a. group (P = 0.30), and produced death from severe debility in five of seven animals with significantly higher mean systemic MZB levels (P = 0.02). Four of six dogs receiving 5.0 mg/kg/day MZB i.a. (MST = 14 days) and two of four dogs receiving 5.0 mg/kg/day i.v. (MST = 14 days) died from severe debility, though survival in both groups was prolonged over control values (P = 0.01 and P = 0.05, respectively). Coadministration of a subtherapeutic dose of oral CsA (5 mg/kg/day) significantly prolonged the overall survival of dogs receiving MZB 4.0 mg/kg/day i.a. (MST = 23; P = 0.01) but not i.v. (MST = 11; P = 1.00), so that a significant difference in overall survival between the combined MZB i.a. + CSA and MZB i.v. + CSA groups was now realized in favor of the former (P = 0.04). We conclude that at local doses required to achieve immunosuppression, the transplanted kidney was not able to extract enough MZB to prevent death from systemic toxicity, presumably as a result of saturation of renal elimination mechanisms, so that an overall survival benefit was not realized.(ABSTRACT TRUNCATED AT 400 WORDS)     

The pharmacokinetic advantage of local 6-mercaptopurine infusion in a canine renal transplant model

In light of recent technologic advances, we developed a canine renal allograft model utilizing implantable, programmable infusion pumps and biocompatible catheters to reexplore the concept of local immunosuppression. Thirteen mongrel dogs underwent bilateral nephrectomy and autotransplantation of 1 kidney via end-to-end renal-iliac artery and end-to-side renal-iliac vein anastomoses. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein just proximal to the venous anastomosis. During a period of i.a. infusion of heparinized saline ranging from 19 to 63 days, serum creatinine remained normal in all but 1 animal, which developed pyelonephritis and catheter-tip perforation of the iliac artery. No cases of arterial thrombosis or catheter migration were observed at necropsy. In 7 additional autotransplanted dogs, simultaneous iliac vein and systemic (jugular vein) concentrations of 6-mercaptopurine (6-MP), the major immunosuppressive metabolite of azathioprine, were determined during a continuous 24-hr i.a. infusion (10 mg/kg/24 hr). Following termination of the infusion, 10 mg/kg 6-MP was administered to the same 7 dogs as an i.v. bolus, and systemic drug concentrations were determined over a 4-hr period. Mean +/- SE total-body clearance and elimination half-life were 887 +/- 159 ml/min and 1.4 +/- 0.2 hr, respectively, in the i.v. bolus study, indicating that 6-MP is rapidly cleared from the systemic circulation. Unexpectedly, the kidney removed as much as 60-95% of locally infused 6-MP, reducing the amount of active drug entering the systemic circulation to 5-40% of that which would be present during an i.v. infusion of the same dose. According to the principles governing the advantages of i.a. infusions, these data demonstrate that 6-MP can be infused intrarenally to produce both a 4-fold increase in drug concentration within the kidney and an 80% decrease in systemic drug delivery when compared to same-dose i.v. administration. The overall result is the presence of a 30-fold gradient between local and systemic drug concentrations during intrarenal 6-MP infusion. We conclude that i.a. infusion of an immunosuppressive agent is technically feasible with preservation of renal function, and that 6-MP can be delivered locally in a canine model with great pharmacokinetic and potential therapeutic advantage.