Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) optimization of antibiotic therapy has been shown to improve outcomes in several antibiotic classes. Despite the frequent use of beta-lactams, clinical data in humans remain limited. OBJECTIVE: This study evaluated the relationship between serum pharmacokinetics, pharmacodynamics, pathogen susceptibility, and clinical outcomes in patients receiving aztreonam or tobramycin monotherapy. METHODS: The case-report forms of hospitalized patients who received either aztreonam or tobramycin for a bacterial infection in 3 clinical trials conducted between 1982 and 1984 were reviewed for the present study. A pathogen was identified for all included patients, and susceptibility testing was performed to determine the minimum inhibitory concentration (MIC) for each agent. Pharmacokinetic parameters for each antibiotic were determined using population modeling, and variables potentially related to outcomes were evaluated using tree-based modeling, logistic regression, and nonlinear regression methods. RESULTS: Data from 91 patients were analyzed, 68 treated with aztreonam monotherapy and 23 treated with tobramycin monotherapy. Of the types of infections treated, 39 were intra-abdominal, 42 involved the lower respiratory tract, and 10 involved the skin and skin structures. The pharmacodynamic ratio of the 24-hour area under the curve (AUC24) to the MIC was associated with clinical outcome for both antibiotics: aztreonam and to-bramycin patients with ratios meeting or exceeding the respective 24-hour inverse serum inhibitory titer breakpoints of 184 and 110 were significantly more likely to achieve a successful outcome than were those with ratios not meeting these values (P < 0.01). The probabilities of clinical success in patients at or above and below the AUC24/MIC breakpoints were a respective 85% and 53% for aztreonam and 80% and 47% for tobramycin (both, P < 0.01). When all patients were considered, the likelihood of achieving cure was 5.1 times greater in patients exceeding the target ratios (P < 0.01). CONCLUSION: PK/PD optimization of both aztreonam and tobramycin is associated with improved patient outcomes.

Synergy of an investigational glycopeptide, LY333328, with once-daily gentamicin against vancomycin-resistant Enterococcus faecium in a multiple-dose, in vitro pharmacodynamic model.

The pharmacodynamics of an investigational glycopeptide, LY333328 (LY), alone and in combination with gentamicin, against one vancomycin-susceptible and two vancomycin-resistant Enterococcus faecium strains were studied with a multiple-dose, in vitro pharmacodynamic model (PDM). Dose-range data for the PDM studies were obtained from static time-kill curve studies. In PDM experiments conducted over 48 h, peak LY concentrations of 0.1x and 1x the MIC every 24 h and peak gentamicin concentrations of 18 micrograms/ml every 24 h (Gq24 h) and 6 micrograms/ml every 8 h (Gq8 h) were studied alone and in the four possible LY-gentamicin combinations. Compared to either antibiotic alone, LY-gentamicin combination regimens produced significantly higher apparent killing rates (KRs) calculated during the initial 2 h postdosing. The mean KRs for LY or gentamicin alone versus those for the LY-gentamicin combination regimens were 0.35 +/- 0.55 log10 CFU/ml/h (95% confidence interval [CI95%], 0 to 0.70) and 1.46 +/- 0.71 log10 CFU/ml/h (CI95%, 1.01 to 1.91), respectively (P < 0.0001). Bacterial killing at 48 h (BK48), which was calculated by subtracting the bacterial counts at 48 h from the initial inoculum, with a negative value indicating net growth, was also significantly greater. The mean BK48S were -0.69 +/- 0.44 log10 CFU/ml (CI95%, -0.41 to -0.97) and 3.72 +/- 2.28 log10 CFU/ml (CI95%, 2.28 to 5.17) for LY or gentamicin alone versus LY-gentamicin combination regimens, respectively (P < 0.0001). None of the 12 regimens with LY or gentamicin alone but 75% (9 of 12) of the LY-gentamicin combination regimens were bactericidal. Eighty-three percent (10 of 12) of the LY-gentamicin combination regimens also demonstrated synergy. No significant differences between the pharmacodynamics of LY-gentamicin combination regimens containing Gq24 h versus those containing Gq8h were detected.

Orthodontic eruption of furca-involved molars.

Guided tissue regeneration techniques, which are used in the treatment of certain advanced Class II and Class II furca-involved teeth, have progressed from promising to predictable. However, furca-modification techniques remain important aspects of treatment. Tooth eruption, combined with standard furca-modification techniques, improves the prognosis for both the treated and the adjacent teeth. Continued eruption of periodontally involved molars improves the crown-to-root ratio and maintains the periodontium of the adjacent dentition. These same concepts can be used to treat restoratively compromised molars, many of which were considered hopeless and subsequently extracted. Passive eruption can be useful in treating cases that need less than 3 mm of tooth eruption; orthodontic-active eruption with fixed appliances is advised if more than 3 mm of eruption is desired. Slower eruption rates (2 mm per month) allow the periodontal ligament to repair and the alveolar bone to remodel between orthodontic adjustments (3 to 4 weeks between adjustments). Periodic periodontal maintenance is accomplished during orthodontic treatment. After a retention period (8 weeks), periodontal++ surgery should be performed to reestablish the tooth's biologic width. After surgical wound healing (6 to 8 weeks), the tooth should be restored.

Pathobiology of cast nephropathy from human Bence Jones proteins.

Renal failure is a common accompaniment of multiple myeloma and is usually due to cast nephropathy, or "myeloma kidney." To understand this lesion, four human Bence Jones proteins (BJP) were purified from the urine of volunteers who had either no evidence of renal dysfunction (BJP1) or renal failure from cast nephropathy (BJP2, BJP3, BJP4). When infused directly into the rat nephron in vivo, BJP2, BJP3, and BJP4 produced intraluminal obstruction by precipitating in the distal nephron; protein casts were never identified before the tip of the loop of Henle. Obstruction was related to the concentration of BJP in the perfusate. Addition of furosemide to the perfusate augmented obstruction in a concentration-dependent fashion. Pretreatment of rats with colchicine completely prevented obstruction and cast formation of perfused nephrons; beta-lumicolchicine did not prevent obstruction. Tamm-Horsfall glycoprotein purified from beta-lumicolchicine-treated and untreated rats coaggregated with BJP3 in vitro. Tamm-Horsfall glycoprotein from colchicine-treated rats did not contain sialic acid and did not aggregate with BJP3 in vitro. Thus, cast-forming human BJP coaggregated with Tamm-Horsfall glycoprotein and obstructed the rat distal nephron. Intranephronal obstruction was aggravated by decreasing extracellular fluid volume or adding furosemide. Finally, by decreasing secretion and altering the carbohydrate moiety of Tamm-Horsfall glycoprotein, colchicine prevented intraluminal cast formation and obstruction of the rat nephron.

Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins.

Proteinaceous cast formation in the distal nephron of the kidney from low molecular weight proteinuria is a significant, but poorly characterized, cause of renal failure. To study this phenomenon, we: (a) microperfused the loop segment (LS) of rats in vivo with artificial tubule fluid (ATF) containing four different low molecular weight proteins, 0.01-50 mg/ml, to detect alterations in LS function, and (b) examined the interaction between several proteins and Tamm-Horsfall glycoprotein (THP) in vitro with turbidity and dynamic light-scattering measurements. Perfusion of the LS for less than 2 min with cast-forming proteins (Bence Jones protein [BJP3] and myoglobin) decreased chloride absorption and elevated early distal tubule fluid (ED) [Cl-], compared with results obtained with control perfusions that used ATF alone. BJP3 decreased chloride absorption in a concentration-dependent fashion. Perfusion with non-cast-forming proteins (albumin and BJP1) enhanced chloride absorption and decreased ED [Cl-]. In vitro, proteins that had isoelectric points (pI) greater than 5.1 aggregated with THP. Aggregation was enhanced with increasing [NaCl] or [CaCl2]. Albumin (pI 4.8) and beta-lactoglobulin (pI 5.1) did not coprecipitate. The molecular size of THP alone increased when [NaCl] greater than 80 mM. Thus, cast-forming proteins aggregated with THP in vitro and caused in vivo LS dysfunction, which elevated ED [Cl-], facilitating aggregation. In contrast, non-cast-forming proteins either did not interact with THP or lowered ED [Cl-], which did not provide an environment for aggregation. Altered LS function and interaction of some proteins with THP were related to different physicochemical properties of the proteins and independently contributed to the formation of proteinaceous casts in the kidney.

Left-handedness and myasthenia gravis.

In two separate studies comparing the handedness of patients suffering from myasthenia gravis with matched controls, no evidence was found to support the Geschwind Behan hypothesis of an association between autoimmune disease and left-handedness. Counter to prediction both studies found marginally lower incidences of left-handedness in myasthenics, and when combined with the similar result of Cosi et al. (Cortex 24, 573-577, 1988) the difference was highly statistically significant. The personality of myasthenics, as assessed by the Eysenck Personality Questionnaire (EPQ), and in particular the psychoticism scale, which has been postulated to be related to androgen levels, was not significantly different from controls. However, assessment of sex-roles using the Bem Sex Role Inventory suggested that female myasthenics were more masculine than controls.

Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo.

To investigate the pathogenetic mechanisms of tubule nephrotoxicity of low molecular weight proteins (LMWP), proximal tubules (PT) of rats were perfused in vivo with artificial tubule fluid (ATF) containing one of five LMWPs: three human Bence Jones proteins (BJP), beta-lactoglobulin (BLG), and rabbit myoglobin (MYG). Volume (JV), chloride (JCl) and glucose (JG) fluxes in these perfused PTs were compared with those determined using ATF alone. In separate experiments, perfused nephrons were examined with electron and immunoelectron microscopy. After exposure to BJP1 or BLG, JV, JCl, and JG were less (P less than 0.05) than corresponding control fluxes. Cell damage of these perfused PTs, along with cellular debris in the distal tubules, was prominent. The PT lysosomes often appeared atypical and contained crystals. In contrast, perfusion with BJP2, BJP3, or MYG did not alter JV, JCl, or JG. These findings were corroborated by the normal ultrastructure of these PTs despite immunohistochemical evidence of endocytosis of the BJPs. Isoelectric point, molecular form, and isotype were not factors associated with PT damage. In addition, proteins with pI less than 7.4 precipitated in the distal nephron, forming acellular casts. Thus, certain nephrotoxic LMWPs damaged the PT, while others precipitated in the distal tubule, obstructing the nephron. These two pathogenetic mechanisms may independently be responsible for tubulointerstitial nephropathy of LMWPs in humans.

Role of the loop segment in the urinary concentrating defect of hypercalcemia.

Hypercalcemia is associated with impaired urinary concentrating ability. To explore the mechanism(s) by which hypercalcemia impairs chloride transport in the loop of Henle, we carried out in vivo microperfusion of the loop segment in Sprague-Dawley rats rendered acutely hypercalcemic (12.1 +/- 0.1 mg/dliter) by calcium gluconate infusion. Control rats were infused with sodium gluconate and had normal plasma calcium (8.0 +/- 0.2 mg/dliter). Compared to control, fractional chloride reabsorption was decreased (61 +/- 4 to 50 +/- 3%; P less than 0.05) and early distal chloride increased 74 +/- 6 to 98 +/- 3 mEq/liter (P less than 0.001) in hypercalcemia. During hypercalcemia, infusion of verapamil failed to increase fractional chloride reabsorption (49 +/- 4%; P less than 0.05) or decrease early distal chloride (95 +/- 2; P less than 0.05) toward control values. Similarly, indomethacin did not improve fractional chloride reabsorption (48 +/- 4%; P less than 0.05) or distal chloride concentration (93 +/- 7; P less than 0.05). In control rats infused with Ringers HCO3, the addition of calcium 8.0 mEq/liter to the perfusate increased early distal calcium (9.22 to 3.11 mEq/liter) but was associated with no change in fractional chloride reabsorption (-6 +/- 6%) and a slight decrease in early distal chloride (-9 +/- 3 mEq/liter; P less than 0.05). These data are consistent with the hypothesis that an elevated plasma, not luminal calcium, concentration impairs chloride reabsorption in the loop segment, primarily the ADH-stimulated component. This may have an important role in the urinary concentrating defect of hypercalcemia.

Effect of ADH on chloride reabsorption in the loop of Henle of the Brattleboro rat.

Both in vivo superficial loop segment microperfusion and in vitro perfusion of isolated medullary thick ascending limb segments were used to assess the effect of vasopressin on loop of Henle chloride absorption in the Brattleboro rat. Superficial loop segments were perfused between the latest proximal and earliest distal tubule in vivo at 19.2 +/- 0.4 nl/min (mean +/- SE) with an artificial tubule fluid. Under control conditions, absolute chloride reabsorption was 1,596 +/- 61 pmol/min and increased to 1,876 +/- 102 after intravenous infusion of vasopressin (P less than 0.005). Distal tubule fluid chloride concentration decreased 4.6 +/- 1.5 meq/liter (P less than 0.05), and fractional chloride reabsorption increased 4.8 +/- 2.0% (P less than 0.05). For in vitro perfusion, medullary thick ascending limb segments were bathed and perfused (9-15 nl/min) with phosphate-buffered solutions at 38 degrees C. Under control conditions, transepithelial voltage was +2.4 +/- 0.3 mV, lumen positive, and the net chloride flux was 147 +/- 24 pmol X min-1 X mm-1 in the absorptive direction. Addition of vasopressin to the bathing solution increased net chloride reabsorption to 342 +/- 56 pmol X min-1 X mm-1 (P less than 0.02) and transepithelial voltage to 3.0 +/- 0.3 mV (P less than 0.002). An additional group of tubules was examined under identical conditions; however, vasopressin was removed from the bathing medium during a subsequent recovery period. In these experiments, net chloride flux and transepithelial voltage significantly increased compared with the control period and returned to control values upon removal of vasopressin from the bath.(ABSTRACT TRUNCATED AT 250 WORDS)

A morphologic study of the mesial root surface of the adolescent maxillary first bicuspid.

Treating periodontitis which involves the mesial concavity of the maxillary first bicuspid can be very challenging. Fifty extracted adolescent maxillary first bicuspids were sectioned in 2-mm thick sections apical to the cementoenamel junction (CEJ). The mesial concavity depth and the cementum and dentin thickness were measured in the sections. The single-rooted bicuspids have a concavity 0.35 mm deep at the CEJ and a concavity 0.59 mm deep 4.7 mm apical to the CEJ. Two-rooted bicuspids furcate at 7.9 mm and have a concavity 0.44 mm deep at the CEJ which increases to 1.08 mm at the 4.7 mm level. Cementum thickness averages from 0.9 mm at the CEJ to 1.1 mm at the 9.4-mm level. Most bicuspids also have a distal concavity which is deepest at the 4.7-mm level. The results imply that any attachment loss around the maxillary first bicuspid involves surfaces which are most likely concave. These concave surfaces make both plaque removal and various periodontal therapeutic procedures difficult.

Effect of potassium depletion on chloride transport in the loop of Henle in the rat.

Microperfusion of the superficial loop segment (latest proximal to earliest distal tubule) was performed in potassium-depleted and control rats. Potassium depletion was confirmed by analysis of muscle content (control 45 +/- 2, potassium depletion 33.5 +/- 0.9 meq/100 g dry solids). During perfusion at 20 nl/min net chloride absorption was decreased (66 +/- 3 vs. 77 +/- 2%, P less than 0.01) and early distal chloride concentration increased (70 +/- 5 vs. 50 +/- 4 meq/liter, P less than 0.01) in the potassium-depleted rats. In separate paired experiments in potassium-depleted rats, indomethacin infusion increased net chloride absorption (P less than 0.05) and lowered early distal chloride concentration (P less than 0.05) toward, but not to, normal. A similar effect of indomethacin to decrease early distal chloride concentration was seen in rats ingesting a normal diet and in control rats. We conclude that in potassium-depleted rats there is impaired net chloride absorption in the loop segment, most likely in the thick ascending limb, and that this effect is not produced by an altered response to prostaglandins. This defect in chloride transport may be responsible, at least in part, for the impaired concentrating capacity seen in potassium-depleted rats.

Effect of volume expansion and plasma chloride on function of the loop segment.

To determine the effect of acute volume expansion and changes in plasma chloride on fluid and chloride uptake in superficial loop segments of rats, this segment was microperfused in vivo at 22 nl/min with a fluid containing Na 145, Cl and 36Cl 130, and HCO3 15 meq/liter during hydropenia and after acute volume expansion with 0.15 M NaCl, 0.15 M NaHCO3, or an isotonic bicarbonate Ringer (Cl 106 meq/liter) solution. Fractional fluid, chloride, and 36Cl reabsorption and early distal chloride concentration did not change during maintained hydropenia (time control) or during volume expansion with NaCl (plasma chloride 120 meq/liter) or bicarbonate Ringer solution (plasma chloride 104 meq/liter). Absolute and fractional reabsorption of chloride and 36Cl increased, without change in fluid reabsorption, and early distal chloride diminished after infusion of NaHCO3 (plasma chloride 90 meq/liter). It is concluded that acute volume expansion, per se, has no effect on either net fluid or net chloride absorption in the superficial loop segment at the load studied. Hypochloremia is associated with increased net reabsorption of chloride and an increased unidirectional efflux of chloride from the loop segment during acute volume expansion, most likely due to a gradient effect on the thick ascending limb of the loop of Henle.

The adrenergic response to surgery involving cardiopulmonary bypass, as measured by plasma and urinary catecholamine concentrations.

Plasma and urinary catecholamine concentrations have been measured in 13 patients undergoing cardiac surgery involving cardiopulmonary bypass. The large and progressive increase in plasma catecholamines during bypass reported in previous studies has not been confirmed, and this may be a result of improvements in surgical, anaesthetic and perfusion techniques. The interpretation of urinary findings was complicated by the finding of a positive correlation between catecholamine excretion and urine flow-rate. The findings suggest the need to modify current concepts of the adrenergic response to cardiac surgery and bypass, and question the validity of measuring the urinary catecholamine concentration as an index of stress in these circumstances.

Isolation and identification of trehalase from Pullularia pullulans.

Trehalase has been isolated from Pullularia pullulans. The enzyme, which is specific for trehalose, was purified approximately 800-fold. The optimal pH was found to be 4.0 and the Michaelis dissociation constant, K(m), was determined to be 3.2 x 10(-3)m.