Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients.

The pharmacokinetics of cefepime were studied in 12 adult patients in intensive care units during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) with a Multiflow60 AN69HF 0.60-m(2) polyacrylonitrile hollow-fiber membrane (Hospal Industrie, Meyzieu, France). Patients (mean age, 52.0 +/- 13.0 years [standard deviation]; mean weight, 96.7 +/- 18.4 kg) received 1 or 2 g of cefepime every 12 or 24 h (total daily doses of 1 to 4 g/day) by intravenous infusion over 15 to 30 min. Pre- and postmembrane blood (serum) samples and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, 8, and 12 or 24 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t(1/2)) of cefepime were 35.9 +/- 6.0 ml/min and 12.9 +/- 2.6 h during CVVH versus 46.8 +/- 12.4 ml/min and 8.6 +/- 1.4 h during CVVHDF, respectively. Cefepime clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 40 and 59% of CL(S), respectively. The results of this study confirm that continuous renal replacement therapy contributes substantially to total CL(S) of cefepime and that CVVHDF appears to remove cefepime more efficiently than CVVH. Cefepime doses of 2 g/day (either 2 g once daily or 1 g twice daily) appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC

Pharmacokinetics of levofloxacin and ciprofloxacin during continuous renal replacement therapy in critically ill patients.

The pharmacokinetics of intravenously administered levofloxacin and ciprofloxacin were studied in intensive care unit patients during continuous venovenous hemofiltration (CVVH; four patients received levofloxacin, and five received ciprofloxacin) or hemodiafiltration (CVVHDF; six patients received levofloxacin, and five received ciprofloxacin). Levofloxacin clearance was substantially increased during both CVVH and CVVHDF, while ciprofloxacin clearance was affected less. The results of this study suggest that doses of levofloxacin of 250 mg/day and ciprofloxacin of 400 mg/day are sufficient to maintain effective drug concentrations in the plasma of patients undergoing CVVH or CVVHDF.

The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and clofazimine.

STUDY OBJECTIVES: Determine hemodialysis clearances of the second-line antitubercular drugs cycloserine (CS), ethionamide (ETA), para-aminosalicylate (PAS), and clofazimine (CFZ). DESIGN: Open-label, pharmacokinetic study SETTING: Outpatient long-term hemodialysis unit PARTICIPANTS: Eight long-term hemodialysis patients Interventions: Single oral doses of CS, 500 mg, ETA, 500 mg, PAS, 4,000 mg, and CFZ, 200 mg, were given 2 h (4 h for PAS) prior to hemodialysis (median blood flow rate, 400 mL/min; median dialysate flow rate, 600 mL/min; median hemodialysis time, 3.5 h). MEASUREMENTS AND RESULTS: Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate fluid was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using validated high-performance liquid chromatography (for ETA and PAS), capillary electrophoresis (for CS), and colorimetry (for CFZ). Dialysate samples were analyzed for acetyl-PAS. Median recoveries of drug in dialysate were 56% (CS), 2.1% (ETA), 6.3% (PAS parent compound), and 0% (CFZ) of the doses administered. Acetyl-PAS was dialyzed to a greater extent than its parent compound. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during dialysis were 189 (CS), 58 (ETA), 206 (PAS), and 0 (CFZ) mL/min. CONCLUSIONS: ETA, CFZ, and PAS were not significantly dialyzed. CS is significantly removed by hemodialysis and should be dosed after hemodialysis.

The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol.

This study examines hemodialysis clearances of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Seven chronic hemodialysis patients were studied. Six were given single oral doses (INH 300 mg, RIF 600 mg, PZA 1000 mg, and EMB 25 mg/kg) 2 h before hemodialysis (Cobe Centrysystem 3 hemodialysis machine; Fresenius F80B dialyzer; median blood flow rate 400 ml/min; dialysate flow rate 600 ml/min; median hemodialysis time 3.5 h). The seventh subject, being treated for tuberculosis (TB), was studied with his usual regimen. Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using high-performance liquid chromatography (HPLC) (INH, RIF) and gas chromatography/mass spectrometry (GC/MS) (PZA, EMB) methods. Median recoveries of drug in dialysate were 9% (INH), 4% (RIF), 45% (PZA), and 2% (EMB) of the doses administered. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during hemodialysis were 124 (INH), 40 (RIF), 270 (PZA), and 46 (EMB) ml/min. INH, RIF, and EMB were not significantly removed by hemodialysis. PZA is significantly dialyzed and should be dosed after hemodialysis.

Influence of renal failure in rats on the disposition of salicyl acyl glucuronide and covalent binding of salicylate to plasma proteins.

Many acyl glucuronides are labile, reactive and form covalent adducts with proteins. In the present experiment, the stability of salicyl acyl glucuronide (SAG), its reactivity with serum albumin in vitro and the influence of renal failure in rats on the disposition of SAG and covalent binding of salicylate (SA) to rat plasma proteins were investigated. In vitro studies showed that SAG was hydrolyzed to SA or undergoes isomerization to positional isomers. The half-life of SAG was 1.3 hr in 0.15 M phosphate buffer at pH 7.4 and 37 degrees C, but the stability of its isomers was much greater with an apparent half-life of 19 hr. Incubation of SAG in solutions of human serum albumin revealed the formation of covalent adducts with the protein, with maximal binding of 2.8% of total SA equivalents added to the solution. For in vivo studies, one group of rats was administered 5 mg/kg of uranyl nitrate i.p. to induce renal failure. After administration of 100 mg/kg of SA i.v., the AUC 0-26 hr of SAG in rats with renal failure was 9 times higher than that observed in control rats. The apparent clearance of SA decreased from 64 +/- 21 ml/hr in control rats 28 +/- 8.7 ml/hr in rats with renal failure. The level of SA covalent adducts with plasma proteins reached about 0.5 ng/mg of protein in control rats, whereas in rats with renal failure the binding was increased significantly and achieved an average peak concentration of 18 ng/mg of protein when measured 26 hr after dosing. The data indicate that reactive SAG can accumulate in renal failure which then increases covalent addition of SA to proteins. Such binding may have a role in enhancing the potential for toxicity of acidic drugs such as SA in renal disease.

Diagnostic value of clinical examination and various imaging techniques for breast implant rupture as determined in 81 patients having implant removal.

To determine sensitivity and specificity of magnetic resonance imaging (MRI) and ultrasonography (US) in the detection of breast implant rupture, and also to determine the relative merits of clinical examination and mammography, we studied 81 patients (160 implants). All patients had implants removed, thus allowing confirmation of the presence or absence of rupture. Clinical examination positively identified only one patient with implant rupture, and mammography detected only two implant ruptures (both extracapsular). The sensitivity for US was 70% and specificity was 90%, while for MRI it was 75.6% and 94%, respectively. These differences between MRI and US were not statistically significant. Combining the results of US and MRI did not seem to add to the diagnostic discrimination. The most cost-effective method of diagnosing implant rupture was US in our study.

Torsion, necrosis, and inflammation of an epiploic appendix of the large bowel: a diagnostic and therapeutic dilemma.

We present the case of a young patient with abdominal pain of 3 weeks' duration and a preoperative presumptive diagnosis of acute appendicitis, diverticulitis, colon perforation, or possibly neoplasm. Even after resection of a large mass involving the right colon, the diagnosis was not confirmed until surgical pathology identified torsion, partial necrosis, and inflammation of an epiploic appendix of the right colon.

Utility of magnetic resonance imaging and ultrasonography in diagnosing breast implant rupture.

We prospectively evaluated 81 patients (with 160 implants) who subsequently had implants removed to determine sensitivity and specificity of both magnetic resonance imaging and ultrasonography. Positive and negative predictive values were also calculated to determine whether a statistically beneficial interaction existed when ultrasonography and magnetic resonance imaging were used in combination to examine an implant. Finally, the misdiagnoses were retrospectively evaluated to identify the pitfalls of the investigations. Positive diagnostic criteria were described. The sensitivity and specificity of ultrasonography were 47% and 83%, respectively, and of MRI, 46% and 88%, respectively. On retrospective review by the radiologist, the sensitivity and specificity of ultrasonography were 70% and 90%, respectively, and of magnetic resonance imaging, 75.6% and 94%, respectively. Although definite conclusions could not be obtained, there did not seem to be an additive benefit from using both ultrasonography and magnetic resonance imaging.

Hypokalemia complicating emergency fluid resuscitation in children.

Our clinical observations suggested that vigorous fluid therapy in children often resulted in hypokalemia. A retrospective review was conducted of four years of admissions to a pediatric intensive care unit. A total of 29 patients were identified who received at least 20 ml/kg of intravenous fluid in their first hour of care and had a pretreatment and posthydration serum K obtained. The potassium levels dropped from a mean pretreatment value of 4.6 +/- 1.0 mEq/L to a mean of 3.3 +/- 0.8 mEq/L (P less than 0.005). Coincidental arterial pH measurements were available in 16 cases. A separate analysis of potassium change in this group revealed that pH change alone could not account for the drop in serum K. Significant hypokalemia may occur after aggressive rehydration of critically ill pediatric patients.

Sonography of ovarian fibromas/thecomas.

The sonographic findings in 14 patients with ovarian fibromas/thecomas are described. A broad spectrum of sonographic features are presented and include hypoechoic mass with posterior shadowing (two cases); anechoic mass with good through transmission (with septations, two cases; without septations, four cases), echogenic mass with well-defined posterior wall (three cases); calcified mass (two cases); mixed echogenicity mass (one case). The pattern of a hypoechoic adnexal mass with acoustic shadowing should still suggest a fibroma/thecoma, but in most cases the appearance is nonspecific.