Intravenous and Intraperitoneal Pharmacokinetics of Dalbavancin in Peritoneal Dialysis Patients.

Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 × 108 ± 1.140 × 109 h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens.

The International Pediatric Peritonitis Registry: starting to walk.

The International Pediatric Peritonitis Registry (IPPR) was created to assess and evaluate the validity of the pediatric peritonitis treatment guidelines issued by the International Society for Peritoneal Dialysis. The study by Schaefer et al., one of the first to emerge from the IPPR, describes regional variability in the frequency of culture-negative peritonitis and of Gram-negative infections. This analysis is a crucial step in the development of evidence-based treatment recommendations whereby to improve outcomes for the youngest peritoneal dialysis patients.

Pulse pressure responses in patients treated with Valsartan and hydrochlorothiazide combination therapy.

In a randomized, double-blind, parallel-group study of middle-aged and elderly patients, we examined the effects of treatment with the angiotensin receptor blocker valsartan (Val) in combination with hydrochlorothiazide (HCTZ) on pulse pressure (PP). After a 2-week washout period, patients entered a 4-week single-blind Val 160 mg once daily run-in period before randomization to one of three treatment groups: Val 160 mg (n = 666), Val 160 mg/HCTZ 12.5 mg (n = 670) or Val 160 mg/HCTZ 25 mg (n = 666), once daily for eight weeks. Sitting PP at baseline was similar in all groups. From baseline to randomization, Val monotherapy reduced PP by 4.7 +/- 10.2 mmHg (mean +/- SD). At the end of the study, overall reductions in PP were 6.7 mmHg for Val 160/HCTZ 12.5 and 7.5 mmHg for Val 160/HCTZ 25. Val monotherapy reduced PP in mild-to-moderate hypertensive patients. Val combined with HCTZ provides an additional dose-related reduction in PP.

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.

Noninfectious causes of cloudy peritoneal dialysate.

The appearance of cloudy dialysate fluid in combination with the clinical manifestations of peritonitis usually heralds infectious peritonitis. Diagnosis is readily established in most cases by routine culture of the turbid dialysate. However, an occasional patient presents with culture-negative, cloudy dialysate. After ruling out atypical infectious etiologies, a diverse set of aseptic causes remains in the differential diagnosis. Herein we review these causes and suggest an organizational scheme, based on identifying the cellular or noncellular constituent producing the dialysate turbidity, to facilitate appropriate diagnostic and therapeutic interventions.

Subcutaneously tunnelled peritoneal dialysis catheters with delayed externalization: long-term follow-up.

We performed a retrospective analysis of our institution's experience with the technique of delayed externalization of subcutaneously tunnelled peritoneal dialysis catheters. From 1993 to 1999, 49 catheters were implanted in 37 patients. Median age of the patients was 43.6 years; 70% were female; 32% had diabetes. Most of the catheters were midline, single-cuff, curled Quinton catheters without a swan neck. One patient underwent transplantation prior to catheter externalization. One catheter leaked prior to externalization and was removed. The remaining catheters were externalized a median of 40 days (range: 18-319 days) post implantation. At externalization, two leaks and one omental obstruction occurred, causing primary catheter failure. Total days of catheter follow-up were 17,895. One-year and two-year catheter survival rates were 70% and 40% respectively. Catheter failure occurred owing to infection in 7 cases and to mechanical complications in 10 cases. The rate of exit-site infection was 1 per 9.9 patient-months, and of peritonitis, 1 per 16.2 patient-months. Including primary failures, mechanical complications were 12 hernias, 6 leaks, and 4 instances of malposition. We conclude that delayed externalization of single-cuff catheters without a swan neck is associated with increased mechanical and infectious complications. These findings may warrant a change to a double-cuff catheter with a swan neck.

A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.

Current phosphate binders used in hemodialysis patients include calcium-based binders that result in frequent hypercalcemia and aluminum-based binders that result in total body aluminum accumulation over time. This investigation describes the use of a calcium- and aluminum-free phosphate-binding polymer in hemodialysis patients and compares it with a standard calcium-based phosphate binder. An open-label, randomized, crossover study was performed to evaluate the safety and effectiveness of sevelamer hydrochloride in controlling hyperphosphatemia in hemodialysis patients. After a 2-week phosphate binder washout period, stable hemodialysis patients were administered either sevelamer or calcium acetate, and the dosages were titrated upward to achieve improved phosphate control over an 8-week period. After a 2-week washout period, patients crossed over to the alternate agent for 8 weeks. Eighty-four patients from eight centers participated in the study. There was a similar decrease in serum phosphate values over the course of the study with both sevelamer (-2.0 +/- 2.3 mg/dL) and calcium acetate (-2.1 +/- 1.9 mg/dL). Twenty-two percent of patients developed a serum calcium greater than 11.0 mg/dL while receiving calcium acetate, versus 5% of patients receiving sevelamer (P < 0.01). The incidence of hypercalcemia for sevelamer was not different from the incidence of hypercalcemia during the washout period. Patients treated with sevelamer also sustained a 24% mean decrease in serum low-density lipoprotein cholesterol levels. Sevelamer was effective in controlling hyperphosphatemia without resulting in an increase in the incidence of hypercalcemia seen with calcium acetate. This agent appears quite effective in the treatment of hyperphosphatemia in hemodialysis patients, and its usage may be advantageous in the treatment of dialysis patients.

"Beer potomania" in non-beer drinkers: effect of low dietary solute intake.

A ovolactovegetarian patient presented with hyponatremia. She had maximally dilute urine and undetectable vasopressin levels. Dietary history revealed very low protein intake but no beer intake. We postulated that the very low intake of solute limited her water excretion and caused the hyponatremia despite only a modest increase in fluid intake. When protein intake was increased in a clinical research center setting, free water excretion increased and serum sodium normalized despite maintaining the water intake at 4 to 5 L daily. We discuss the role of dietary solute in water excretion. Previously described in beer drinkers, the phenomenon can occur in the absence of beer drinking. In this era of weight consciousness, hyponatremia because of low solute intake may be seen with increased frequency.

Mechanisms of defective hydroosmotic response in chronic renal failure.

The kidney's concentrating capacity is impaired in chronic renal failure (CRF) resulting in a relatively large rate of urine formation and nocturia. Normal renal concentrating ability depends on the maintenance of a hypertonic medullary interstitium, a structurally intact countercurrent multiplier system, and normal water permeability of the collecting tubules in response to arginine vasopressin (AVP). Each of these three components may be compromised in the setting of CRF. This review presents current knowledge regarding mechanisms of impaired renal concentrating ability in CRF, from the whole kidney level to the cellular and molecular level.

Vasopressin resistance in chronic renal failure. Evidence for the role of decreased V2 receptor mRNA.

Studies were performed to determine the mechanism underlying deficient arginine vasopressin (AVP)-stimulated adenylyl cyclase activity in chronic renal failure (CRF). As compared to control, principal cells cultured from the inner medullary collecting tubule of rats previously made uremic by 5/6 nephrectomy fail to accumulate cAMP when stimulated with AVP. CRF cells do respond normally to forskolin or cholera toxin and the defect in AVP responsiveness is not prevented by treatment with pertussis toxin, by cyclooxygenase inhibition, or by inhibition or down-regulation of protein kinase C. In contrast to their lack of responsiveness to AVP, CRF cells respond normally to other agonists of adenylyl cyclase such as isoproterenol or prostaglandin E2. Plasma membranes prepared from the inner medullae of CRF rats exhibit a marked decrease in apparent AVP receptor number but no change in the apparent number of beta adrenergic receptors. Reverse transcriptase PCR of total RNA from the inner medullae of CRF animals reveals virtual absence of V2 receptor mRNA; mRNA for alpha s is present in normal abundance. These studies indicate that AVP resistance in CRF is due, at least in part, to selective down-regulation of the V2 receptor as a consequence of decreased V2 receptor mRNA.

Hormonal regulation of MAP kinase in cultured rat inner medullary collecting tubule cells.

Mitogen-activated protein (MAP) kinase is a widely expressed protein serine/threonine kinase that serves as a convergence point for many signaling pathways including receptor tyrosine kinases, G protein-coupled receptors, and protein kinase C (PKC). The hormonal regulation of MAP kinase was studied in cultured established rat inner medullary collecting tubule (RIMCT) cells. Neither vasopressin nor beta-adrenergic agonists stimulated MAP kinase, despite clear stimulation of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. In contrast, carbachol, ATP, and epidermal growth factor (EGF), which are known to antagonize vasopressin action in the RIMCT, stimulated the MAP kinase pathway. This stimulation was mimicked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, which directly activates PKC. The potency with which EGF and carbachol activated MAP kinase was similar to the potency with which they inhibited vasopressin-stimulated cAMP accumulation. To assess the role of Gi proteins in these stimulatory events, RIMCT cells were pretreated with pertussis toxin to inhibit Gi-mediated signaling. Pertussis toxin did not influence ATP- or EGF-stimulated MAP kinase, but completely inhibited carbachol stimulation, suggesting that Gi proteins mediate muscarinic stimulation. Prolonged exposure of RIMCT cells to high phorbol ester concentrations to downregulate PKC ablated carbachol- and ATP-stimulated MAP kinase, but not EGF-stimulated MAP kinase, suggesting that PKC is a component of the network involved in MAP kinase activation by purinergic and muscarinic agonists. Investigation of the sidedness of the hormonal stimulations indicated that EGF-stimulated MAP kinase was highly polarized, occurring exclusively from the basolateral surface, whereas carbachol stimulated MAP kinase similarly from either cell surfaces.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased cytosolic Ca2+ inhibits AVP-stimulated adenylyl cyclase activity in rat IMCT cells by activation of PKC.

In rat inner medullary collecting tubule (RIMCT) cells increasing cytosolic Ca2+ with a calcium ionophore inhibits arginine vasopressin (AVP)-stimulated adenylyl cyclase (AC). Inhibition by Ca2+ is not observed in pertussis toxin (PT)-treated cells, indicating a role for the inhibitory G protein, Gi. The mechanism of activation of Gi remains to be determined. We examined the hypothesis that inhibition of AVP-stimulated AC by increased cytosolic Ca2+ is due to activation of protein kinase C (PKC). Preincubation of RIMCT cells with ionophore results in inhibition of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) formation. To assess whether stimulation of phospholipase C (PLC) and therefore activation of PKC occurs with ionophore and AVP, inositol trisphosphate (IP3) production was measured. Incubation of RIMCT cells with either 10(-7) M AVP or ionophore results in IP3 production that is no different from basal. However, simultaneous exposure to 100 nM AVP with ionophore results in marked enhancement of IP3 production clearly reflecting stimulation of PLC in this setting. Stimulation of PLC is not observed in PT-treated cells. Likewise, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an inhibitor of PKC, mimics the effect of PT to prevent inhibition of AVP-stimulated AC by ionophore, but N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide (H-8), an inhibitor of protein kinase A (PKA), does not. As is the case when PKC is stimulated directly with a phorbol ester, exposure to ionomycin inhibits the response to AVP but does not alter the response to isoproterenol. These studies demonstrate that increased cytosolic Ca2+ does not, as previously postulated, inhibit AC by a direct effect on Gi. Rather, when cytosolic Ca2+ is increased, AVP stimulates PLC; the ensuring activation of PKC inhibits cAMP formation.

Didanosine administration in a human immunodeficiency virus-positive renal transplant patient.

A human immunodeficiency virus-positive renal transplant patient taking no immunosuppressive medication for 40 months was treated with didanosine for the final 13 months of life. Over the latter period there were three acute episodes of creatinine elevation, but none could be attributed to didanosine-induced acute rejection. Based on this case, we cautiously suggest that didanosine may safely be administered in the setting of renal transplantation.

Protein kinase C inhibits arginine vasopressin-stimulated cAMP accumulation via a Gi-dependent mechanism.

Studies were performed to identify the site at which activation of protein kinase C (PKC) inhibits arginine vasopressin (AVP)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured rat inner medullary collecting tubule (RIMCT) cells. Neither endogenous stimulation of PKC by epidermal growth factor (EGF) nor the addition of exogenous 1,2-dioctanoyl-sn-glycerol (DOG) impaired forskolin-stimulated cAMP accumulation. Similarly, neither EGF nor DOG altered cAMP generation in response to cholera toxin. However, pretreatment of RIMCT cells with pertussis toxin resulted in loss of inhibition of AVP-stimulated cAMP accumulation by DOG. Likewise, the ability of the phorbol ester, phorbol 12-myristate 13-acetate (PMA), to inhibit AVP-stimulated cAMP accumulation was eliminated by pretreatment with pertussis toxin. PMA also inhibited AVP-stimulated adenylyl cyclase activity in plasma membranes prepared from rat inner medullas. In contrast to its effects on AVP, activation of PKC did not impair cAMP accumulation in response to isoproterenol or prostaglandin E2. These studies demonstrate that PKC-mediated inhibition of AVP-stimulated cAMP accumulation in cultured RIMCT cells requires the intact inhibitory guanine nucleotide binding protein Gi.

Hormone signaling systems in inner medullary collecting ducts.

The inner medullary collecting duct is a complex tissue that exhibits a variety of hormone signaling systems. These include the following: adenylyl cyclase activity stimulated by vasopressin (AVP), beta-adrenergic agonists, or prostanoids and inhibited by alpha 2-adrenergic agents or adenosine; guanylate cyclase activity in response to atrial natriuretic peptide (ANP); phospholipase C activity stimulated by ANP, AVP, bradykinin, endothelin, epidermal growth factor (EGF), and muscarinic cholinergic agents; and phospholipase A2 activity stimulated by AVP, bradykinin, EGF, and endothelin. The signal transduction mechanisms for each of these hormone signaling systems is succinctly reviewed, and the interactions between different signaling pathways are discussed. Central to this interaction is the mutually inhibitory relationship between activation of adenylyl cyclase and phospholipases. Increasing cellular adenosine 3',5'-cyclic monophosphate content impairs activation of phospholipases A2 and C; conversely, stimulation of phospholipase C impairs AVP-stimulated adenylyl cyclase activity via activation of protein kinase C.