Abdominal compartment syndrome secondary to retroperitoneal hematoma as a complication of ERCP after liver transplantation.

Endoscopic retrograde cholangiopancreatography (ERCP) is frequently employed in the management of postoperative biliary complications in the liver transplant patient. Bleeding after ERCP most commonly presents as gastrointestinal bleeding and often can be managed with repeat endoscopy. ERCP can also be complicated by retroperitoneal hematoma, which in rare cases can lead to hemodynamic compromise due to relentless hemorrhage or from secondary abdominal compartment syndrome. We describe the first reported case of post-ERCP retroperitoneal hematoma in a liver transplant recipient that led to abdominal compartment syndrome and shock liver. We will present the case, discuss management, and review the complications of ERCP in the liver transplant recipient. Close post-procedure monitoring, rapid detection, and low threshold for decompressive laparotomy are keys to the successful management of the liver transplant recipient experiencing expanding retroperitoneal hematoma after ERCP.

The effect of terfenadine on the cardiac pharmacodynamics of sparfloxacin.

This double-masked, randomized, placebo-controlled study was conducted to assess the effect of concomitant administration of terfenadine and sparfloxacin on the electrocardiographic (ECG) QT(c) interval in healthy volunteers, before the removal of terfenadine from the market. Eighty-eight men (aged 18 to 49 years, weighing 60.0 to 98.6 kg) with no clinically relevant ECG abnormalities received placebo, sparfloxacin (400 mg on day 1, 200 mg daily on days 2-4), terfenadine (60 mg BID), or the combination of sparfloxacin and terfenadine. After each dose, serial blood samples and ECG measurements were collected to determine sparfloxacin pharmacokinetic and pharmacodynamic variables. The area under the concentration-time curve and maximum concentration for sparfloxacin were approximately 16% less on day 4 compared with day 1, reflecting the higher plasma level after the 400-mg loading dose compared with that after the maintenance dose of 200 mg daily. Concomitant administration of terfenadine had no effect on these pharmacokinetic variables. When compared with the placebo-adjusted increases in QTc interval in the sparfloxacin (19 milliseconds on day 1 and 14 milliseconds on day 4) and terfenadine (2 milliseconds on day 1 and 7 milliseconds on day 4) treatment groups, the placebo-adjusted increases in QTc interval in the volunteers treated with the combination of sparfloxacin and terfenadine (18 milliseconds on day 1 and 22 milliseconds on day 4) were considered to be additive (no statistically significant interaction). Thus there are no apparent pharmacokinetic or dynamic QTc interactions between terfenadine and sparfloxacin. However, sparfloxacin should be administered with caution to patients receiving concomitant medications known to prolong the QTc interval.

The cardiac pharmacodynamics of therapeutic doses of sparfloxacin.

This double-masked, randomized, placebo-controlled study assessed the cardiac safety of sparfloxacin (as measured by the effect on corrected QT [QTc] interval) at the extremes of the expected therapeutic dosage range. Ninety healthy adult male volunteers with no clinically relevant electrocardiographic (ECG) abnormalities received either placebo or 1 of 3 sparfloxacin regimens consisting of a loading dose on day 1 followed by 3 days of daily dosing at half the loading dose (200/100 mg, 400/200 mg, or 800/400 mg). After each dose, serial blood samples and ECG measurements were obtained to determine the pharmacokinetic and pharmacodynamic variables for sparfloxacin. Increases in the area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) for each dosing interval and in the maximum concentration (Cmax) on days 1 and 4 were dose proportional. The steady-state (day-4) values were 6% to 16% lower than the day-1 values. At steady state, the time to C ranged from 2.5 to 3.9 hours across all doses and days studied. The half-life ranged from 18.7 to 20.3 hours. Increases in the placebo-adjusted mean change and mean maximum change in QTc interval were dose related. The placebo-adjusted increases on day 1 were 9, 16, and 28 milliseconds after receipt of the 200/100-mg, 400/200-mg, and 800/400-mg regimens, respectively. The corresponding increases on day 4 were 7, 12, and 26 milliseconds. The placebo-adjusted changes in QTc interval also showed a linear relationship with the AUC0-24 and Cmax of sparfloxacin. In the majority of volunteers (>90%), these increases were within the normal range for the QTc interval (< or = 460 milliseconds).

Pharmacokinetics of sparfloxacin in patients with renal impairment.

Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.

Comparison of sparfloxacin and ciprofloxacin in the treatment of community-acquired acute uncomplicated urinary tract infection in women. Sparfloxacin Multicenter Uncomplicated Urinary Tract Infection Study Group.

Urinary tract infection (UTI) is a common illness, with > or =30% of all women experiencing a UTI during their lifetime. Less than a decade ago, the standard therapy for acute uncomplicated UTIs involved treatment with > or =7 days of an antibacterial agent, but recent studies using a variety of newly introduced antibiotics, including the fluoroquinolones, have demonstrated that a 1- to 5-day treatment regimen can be equally effective. This randomized, double-masked, multicenter study was conducted to compare the efficacy and tolerability of a single dose of sparfloxacin with those of a 3-day regimen of sparfloxacin and a 7-day regimen of ciprofloxacin in the treatment of women with community-acquired acute uncomplicated urinary tract infection. A total of 1175 women were enrolled; 395 received sparfloxacin as a single 400-mg dose on day 1, 394 received sparfloxacin as a 400-mg loading dose on day 1 followed by 200 mg once daily for 2 additional days, and 386 received ciprofloxacin 250 mg twice daily for 7 days. Patients were comparable with respect to demographic characteristics and underlying conditions. A total of 954 patients were clinically assessable; 490 of these were also bacteriologically assessable. All patients treated were included in the tolerability analysis. Escherichia coli (75.4%), Klebsiella pneumoniae (4.9%), Enterococcus faecalis (4.6%), and Staphylococcus saprophyticus (4.1%) were the most commonly isolated organisms. In the all-treated population, clinical success was achieved 5 to 9 days after therapy in 91.8%, 92.2%, and 91.6% of patients in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; bacteriologic success was observed in 91.7%, 92.6%, and 96.6% of those in the 3 groups. Sustained clinical success rates 4 to 6 weeks after therapy were 76.6%, 80.2%, and 79.5% in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; sustained bacteriologic success rates were 80.7%, 90.1%, and 92.6%. The most common adverse events were nausea, headache, vaginal thrush, dizziness, and diarrhea; >92% of adverse events were mild or moderate in severity. The 2 drugs had comparable frequencies of adverse events, except for photosensitivity, which occurred in 3.3% of the 3-day sparfloxacin group, 1.3% of the single-dose sparfloxacin group, and 0.3% of the ciprofloxacin group (P = 0.005). The 3-day sparfloxacin regimen was effective and well tolerated. The initial response to single-dose sparfloxacin treatment was comparable to the response to the other 2 regimens, but the single-dose regimen proved less effective over time, with higher rates of clinical recurrence and bacteriologic relapse. Sparfloxacin provides an alternative to ciprofloxacin for patients with acute uncomplicated urinary tract infection who are not at risk for photosensitivity reactions or adverse events associated with a prolonged corrected QT interval.

Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac repolarization (QTc interval).

This double-masked, randomized, placebo-controlled study was conducted in healthy adult male and female volunteers with no clinically relevant baseline electrocardiographic (ECG) abnormalities to assess the cardiac tolerability margin of sparfloxacin (as measured by the effect on QTc interval) under conditions of potential overdose at up to 4 times the usual therapeutic loading dose. The 23 enrolled volunteers received a sequence of single doses of sparfloxacin (400, 800, 1200, and 1600 mg), 1 dose in each of 4 study periods. Six volunteers received placebo during each period. A 14-day washout separated the periods. Serial blood samples and ECG measurements were collected in each period to determine the pharmacokinetic and pharmacodynamic characteristics of sparfloxacin. The area under the concentration-time curve from time zero to infinity (AUC0-infinity) exhibited dose proportionality. The maximum plasma concentration (Cmax) after the 1200- and 1600-mg doses was lower than would be expected for a linear dose relationship. This was also the case with the mean increase and mean maximum increase in QTc interval. Increases in the QTc interval correlated well with Cmax but not with AUC0-infinity. The time to reach Cmax showed a slight tendency to increase with dose, as did the terminal elimination half-life. Changes in QTc-interval dispersion were similar for both placebo recipients and sparfloxacin-treated volunteers and were of no clinical consequence. At supratherapeutic doses, the extent of sparfloxacin's absorption (AUC0-infinity) was dose independent; however, the rate of absorption was dose dependent, with Cmax increasing substantially less than proportionally to the administered dose. This limited the Cmax of sparfloxacin at supratherapeutic doses and thus the increase in QTc interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QTc-interval prolongation, emphasizing the marked variability in the QTc interval.

Sparfloxacin versus ciprofloxacin for the treatment of community-acquired, complicated skin and skin-structure infections.

Fluoroquinolones have been shown to be effective in the treatment of complicated skin and skin-structure infections, in part because of their broad-spectrum antibacterial activity against causative pathogens that are resistant to older antimicrobial agents. We enrolled 603 adult patients (>58% male, >85% white) in a double-masked, double-dummy, randomized, multicenter trial to compare the efficacy and tolerability of sparfloxacin (400-mg loading dose followed by 200 mg once daily) with those of ciprofloxacin (750 mg twice daily) for 10 days in the treatment of community-acquired, complicated skin and skin-structure infections. The primary efficacy variable was clinical response, based on assessment of signs and symptoms, in the clinically assessable population. Patients in the sparfloxacin and ciprofloxacin groups were comparable with respect to demographic characteristics, underlying diseases, medical history, and laboratory test results. Wound infection was the most common diagnosis, and Staphylococcus aureus was the most frequently isolated pathogen. For the 475 clinically assessable patients, the clinical success rate (percentage of patients cured or improved) was 90.1% (210/233) with sparfloxacin and 87.2% (211/242) with ciprofloxacin. In this analysis (95% confidence interval [CI], -2.8 to 8.6) and the intent-to-treat analyses (95% CI, -4.2 to 6.2), results with sparfloxacin were statistically equivalent to those with ciprofloxacin (95% CI, -1 to 15.3). For bacteriologically assessable patients, eradication rates were 87.0% (141/162) with sparfloxacin and 79.9% (123/154) with ciprofloxacin (95% CI, -1 to 15.3). Eradication rates of S. aureus and coagulase-negative staphylococcal infections were 90.2% (101/112) with sparfloxacin and 77.9% (88/113) with ciprofloxacin. For patients with 2 or more pathogens at baseline (mixed infections), bacteriologic success was 87.6% for sparfloxacin and 77.9% for ciprofloxacin. Pseudomonas aeruginosa infections were eradicated or presumed eradicated in 71.4% (10/14) of sparfloxacin-treated patients and 87.5% (7/8) of ciprofloxacin-treated patients. Overall success rates in the bacteriologically assessable patients for sparfloxacin (84.6% [137/162]) and ciprofloxacin (78.6% [121/154]) were statistically equivalent (95% CI, -2.5 to 14.5). Tolerability was assessed in all patients who received study medication. The overall frequency of treatment-related adverse events was comparable in the 2 treatment groups (26.5% sparfloxacin, 23.3% ciprofloxacin). Drug-related adverse events involving the digestive system occurred in 7.1% of sparfloxacin-treated patients and 19.0% of ciprofloxacin-treated patients; photosensitivity reactions were reported in 11.1% of patients in the sparfloxacin group and 0.7% of patients in the ciprofloxacin group (P < 0.001). The mean change in QTc interval from baseline to the maximum on-treatment value was greater in the sparfloxacin group (9 milliseconds) than in the ciprofloxacin group (3 milliseconds) (P = 0.005; 95% CI, 0.002 to 0.010). The efficacy of sparfloxacin was comparable to that of ciprofloxacin in the treatment of community-acquired, complicated skin and skin-structure infections, including those caused by staphylococci, the most common pathogens. Sparfloxacin's once-daily regimen, high skin-tissue penetration, and improved activity against gram-positive cocci make it a therapeutic alternative to ciprofloxacin for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval.

Safety profile of sparfloxacin, a new fluoroquinolone antibiotic.

The safety profile of sparfloxacin, a newer fluoroquinolone antibiotic, was examined through an integrated analysis of safety data from 6 multicenter phase III trials. These consisted of 5 double-masked, randomized, comparative trials of sparfloxacin (a 400-mg oral loading dose followed by 200 mg/d for 10 days) versus standard therapies (erythromycin, cefaclor, ofloxacin, clarithromycin, and ciprofloxacin) and I open-label trial (noncomparative) in patients with: community-acquired pneumonia (2 trials); acute bacterial exacerbations of chronic bronchitis (1 trial); acute maxillary sinusitis (2 trials, one of which was the noncomparative trial); and complicated skin and skin-structure infections (1 trial). Overall, 401 (25.3%) of 1585 patients treated with sparfloxacin and 374 (28.1%) of 1331 receiving a comparator regimen experienced at least 1 adverse event considered to be related to the study medication. Photosensitivity reactions, usually of mild-to-moderate severity, were seen more frequently with sparfloxacin (7.4%) than with comparator agents (0.5%), whereas gastrointestinal reactions (diarrhea, nausea, dyspepsia, abdominal pain, vomiting, and flatulence), insomnia, and taste perversion were more common in patients taking comparator drugs (22.3% vs 12.1%, 4.3% vs 1.5%, and 2.9% vs 1.2%, respectively). Analysis of electrocardiographic findings showed that the mean change from baseline in QT interval corrected for heart rate (QTc) was significantly greater in sparfloxacin-treated patients (10 msec) than in patients given comparator drugs (3 msec), but no associated ventricular arrhythmias were detected. Adverse events led to discontinuation of study medication in 104 (6.6%) patients receiving sparfloxacin and 118 (8.9%) given com parator drugs. Sparfloxacin may be considered an appropriate choice for the treatment of certain community-acquired infections for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval.

Treatment of community-acquired acute uncomplicated urinary tract infection with sparfloxacin versus ofloxacin. The Sparfloxacin Multi Center UUTI Study Group.

The efficacy and safety of a 3-day regimen of sparfloxacin were compared with those of a 3-day regimen of ofloxacin for the treatment of community-acquired acute uncomplicated urinary tract infections. Four hundred nineteen women were enrolled in a randomized, open-label, observer-blinded, multicenter study; 204 received sparfloxacin as a 400-mg loading dose on the first day and 200 mg once daily thereafter, and 215 received ofloxacin as 200 mg twice daily. A total of 383 patients met the criteria for clinical evaluability, and 174 were also bacteriologically evaluable; all treated patients were included in the safety analysis. Escherichia coli (86%) and Staphylococcus saprophyticus (4.6%) were the organisms most commonly isolated. Positive clinical responses were obtained 5 to 9 days after therapy in more than 92% of the patients in each group; sustained clinical cure rates 4 to 6 weeks after therapy were 78.3 and 76.9% in the sparfloxacin and ofloxacin groups, respectively. A positive bacteriologic response was observed in 98% of the bacteriologically evaluable patients in each treatment group at 5 to 9 days posttherapy and in 88.2 and 92.6% of the patients in the sparfloxacin and ofloxacin groups, respectively, 4 to 6 weeks after therapy. Almost 90% of all adverse events were of mild or moderate severity; the most frequent events at least possibly related to drug treatment were those common to the fluoroquinolones, namely, nausea, diarrhea, headache, insomnia, and photosensitivity. Photosensitivity was more frequent in the sparfloxacin group (6.9% versus 0.5% in the ofloxacin group); insomnia was more frequent in the ofloxacin group (3.7% versus 1.0% in the sparfloxacin group). These data suggest that a once-daily, 3-day regimen of sparfloxacin is effective and generally well tolerated in the treatment of acute uncomplicated urinary tract infections.

Sustained antihypertensive activity of diltiazem SR: double-blind, placebo-controlled study with 24-hour ambulatory blood pressure monitoring.

A new polymeric matrix technology provides a sustained-release formulation of diltiazem hydrochloride (diltiazem SR) suitable for once-daily therapy. The efficacy and safety of diltiazem SR were evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a single-blind, placebo lead-in period, 275 patients with mild to moderate essential hypertension were assigned to receive placebo or diltiazem SR 120, 240, 360, or 480 mg once daily for 4 weeks. The efficacy evaluation was based on office and 24-hour ambulatory blood pressure monitoring. Twenty-four hours after the last dose in the 4-week, double-blind treatment period, the mean reduction from baseline in supine diastolic blood pressure ranged from 5.1 to 10.6 mm Hg in the diltiazem SR 120- to 480-mg groups, resulting in a significant linear trend across all treatments (P less than .001). Reductions in systolic blood pressure were similar. Ambulatory blood pressure monitoring, performed in 138 patients, confirmed the dose-response relationship and showed consistent antihypertensive activity throughout the 24-hour dosing interval. The percentage of patients reporting adverse events was similar in the placebo- and active-treated groups. The results of this study indicate that diltiazem SR is well tolerated, lowers blood pressure in a dose-related manner, and provides sustained activity throughout the 24-hour dosing interval.

Multicenter evaluation of the efficacy and safety of sustained-release diltiazem hydrochloride for the treatment of hypertension.

In a double-blind study, patients with mild-to-moderate hypertension were randomly assigned to receive placebo or increasing daily doses of a new sustained-release formulation of diltiazem: 180 mg, 360 mg, and 540 mg, each once daily for two weeks. The numbers of evaluable patients were 26 in the placebo group and 81 in the diltiazem group at week 2, 24 and 75 at week 4, and 23 and 65 at week 6. Changes from baseline in mean supine trough (before drug administration) systolic/diastolic blood pressures were +1.3/-2.7 mmHg after placebo and -4.7/-6.1 mmHg after diltiazem at week 2; -0.1/-1.7 mmHg after placebo and -7.2/-9.3 mmHg after diltiazem at week 4; and +0.4/-1.7 mmHg after placebo and -6.7/-10.2 mmHg after diltiazem at week 6. The changes were significantly greater after diltiazem than placebo. Increasing the daily dose of diltiazem from 360 mg to 540 mg produced more than proportional increases in mean plasma diltiazem concentrations but only minimal further reductions in blood pressure. Similar rates of adverse experiences were reported by the diltiazem-treated and placebo patients. Treatment was withdrawn in two diltiazem-treated patients because of abnormal electrocardiographic (ECG) changes that were considered to be related to the drug: elevated ST segment in one and first-degree atrioventricular block in the other. No other treatment-related ECG changes were noted. It is concluded that this new once-daily formulation of diltiazem is safe and effective in the treatment of mild-to-moderate hypertension.