Background: Data are limited on aminoglycoside pharmacokinetic differences between acute renal failure (ARF) and chronic kidney disease (CKD) or infection survival when maintaining peak and pre-hemodialysis serum concentrations between 7 and 10 and 3.5 and 5 mg/L, respectively. Objective: To report aminoglycoside pharmacokinetic observations in a consecutive series of patients receiving intermittent hemodialysis (IHD), including treatment impact of patient-specific dosing regimens. Methods: In this prospective study, all calculated pharmacokinetic parameters used concentrations drawn more than 12 hours after the initial dose and peak concentrations at least 2 hours after the dose. Analysis included pharmacokinetic parameters in stage 5 CKD, ARF, impact of the dialysis prescription, and treatment results of individualized dosing regimens lasting more than 4 days. Results: Consecutive patients with IHD (N = 167) receiving 216 courses of aminoglycosides were evaluated. The mean ± SD volume of distribution was 0.39 ± 0.15 L/kg ideal body weight, and elimination half-life during dialysis was 4.2 ± 2.3 hours. The elimination half-life off IHD was 30% shorter in ARF (31.9 ± 20.8 h) versus 45.7 ± 24.2 hours in CKD (p < 0.001). Mean extrapolated peak concentrations and pre-IHD levels were 7.7 ± 1.6 and 3.9 ± 1.2 mg/L, respectively. A 91% treatment success rate was observed in 117 individualized treatment courses in 100 patients receiving greater than or equal to 5 days of aminoglycoside therapy. Conclusions: A large variability in aminoglycoside pharmacokinetic parameters in IHD exists, with aminoglycoside elimination off IHD significantly faster in ARF. Individualized regimens using serum concentrations drawn in patients requiring treatment (non-synergistic) targeting peak concentrations of 7–10 mg/L and pre-hemodialysis serum concentrations of 3.5–5 mg/L appears successful for eradicating infections.

BACKGROUND The low-molecular-weight heparins (LMWHs) have been shown to be effective in the outpatient treatment of deep vein thrombosis (DVT). Data regarding outpatient use of any LMWH in pulmonary embolism (PE) or tinzaparin in DVT while transitioning therapy to a vitamin K antagonist are limited. OBJECTIVE To determine the safety and efficacy of tinzaparin in patients with either DVT or PE being transitioned to warfarin during LMWH therapy in the outpatient setting. METHODS All patients who were treated with at least one outpatient dose of tinzaparin for venous thromboembolism (VTE) were identified. Charts of all patients followed within the University of California Davis healthcare system were reviewed. The incidence of bleeding and recurrent thromboembolism over a minimum of the first 4 weeks to a maximum of 12 weeks after initiating anticoagulation was assessed. RESULTS A total of 178 patients with acute VTE were treated with tinzaparin, and outcomes could be determined in 140 cases. Forty-seven percent of these patients had objectively documented PE. Only one (0.7%) case of recurrent VTE was observed. Major bleeding was documented in 5 (3.6%) and minor bleeding in 8 (5.8%) patients. Two bleeding events, both major, occurred during tinzaparin therapy. CONCLUSIONS Outpatient use of tinzaparin during transition to warfarin therapy in the treatment of VTE, including PE, appears to be feasible in patients who are judged candidates for home therapy.

CONTEXT:Direct thrombin inhibitors (DTIs) and fondaparinux represent a new class of anticoagulants. The effects of DTIs on activated partial thromboplastin time and prothrombin time measurements have been reported previously, but there are limited data on the impact of these anticoagulants on other coagulation tests.OBJECTIVE:To determine the effects of fondaparinux and 3 DTIs (argatroban, bivalirudin, and lepirudin) on miscellaneous coagulation tests.DESIGN:Bivalirudin, lepirudin, argatroban, and fondaparinux were added to pooled normal plasma and tested for fibrinogen, antithrombin (thrombin and Xa substrate methods), plasminogen, protein C (clot and chromogenic methods), protein S, von Willebrand factor, D-dimer, lupus anticoagulant testing (dilute Russell viper venom test [DRVVT] with ratio), and factors II, IX, and X activities.RESULTS:We found no drug interference on antithrombin, plasminogen, chromogenic protein C, von Willebrand factor, or D-dimer results. All DTIs falsely decreased fibrinogen values, while falsely increasing protein C and protein S levels. All DTIs prolonged the DRVVT, and only argatroban yielded DRVVT ratios less than 1.2. Lepirudin demonstrated no effect on factor II activity, and only argatroban demonstrated decreased factor X activity. All DTI samples demonstrated a linear, dose-dependent, false decrease of factor IX activity.CONCLUSIONS:Using in vitro methods, we demonstrated DTI effects on numerous clot-based assays, but we found no interference with latex agglutination, chromogenic, or platelet aggregation methods. Fondaparinux only affected measurement of protein S activity. Caution must be used when interpreting coagulation test results on patients receiving these drugs.

BACKGROUND: Previous studies have indicated the variability of anti-Xa activity in different sources of heparin and the variability of different methods used for measuring anti-Xa activity. Manufacturers of low-molecular-Weight heparins (LMWHs) determine each lot's anti-Xa activity against the World Health Organization standard, but little information is known about anti-Xa activity variation between lots of LMWH and the impact on reported anti-Xa activity in patient samples.OBJECTIVE: To determine the variation of plasma anti-Xa activity in patients receiving enoxaparin when different lots of enoxaparin are used for test calibration.METHODS: We obtained 7 lots of enoxaparin containing approximately 10 000 IU/mL and one lot containing approximately 15 000 IU/mL of anti-Xa activity. For each lot, a 2.0 anti-Xa IU/mL dilution was prepared and a calibration curve performed using a chromogenic method. To test the variation in reported results between the different calibration lots, 20 patient samples were tested. Nineteen patients receiving enoxaparin and one patient not receiving enoxaparin (negative control) were tested in a blinded fashion, and the changes in light absorbance recorded. Anti-Xa activity results from tested plasmas were then extrapolated from each enoxaparin lot calibration curve.RESULTS: Using Student's paired t-test, there were statistically significant differences between the plasma anti-Xa activities generated from the various enoxaparin lots. In the range of 0.5-1.0 IU/mL of anti-Xa activity, 3 (4.2%) samples had a >0.2 IU/mL difference (maximum difference 0.33 IU/mL) in anti-Xa activity between 2 lots of enoxaparin. For samples that had supratherapeutic anti-Xa activities (1.0-1.5 IU/mL anti-Xa activity), there was a wider variation (>0.2 IU/mL) in anti-Xa activity, which may have resulted in a dosing change.CONCLUSIONS: The statistical differences in plasma anti-Xa activities noted between enoxaparin lots are not clinically significant. However, anti-Xa activities in the upper therapeutic and supratherapeutic ranges (>1.0 IU/mL of anti-Xa activity) resulted in a deviation of >0.3 IU/mL in reported anti-Xa activity, which may result in dosing changes.

BACKGROUND:The use of enoxaparin in low-weight pediatric patients is becoming common practice. Anti-Xa stability of unit-dose syringes prepared after dilution beyond one day is presently unknown.OBJECTIVE:To evaluate the anti-Xa stability of diluted enoxaparin stored in glass vials and tuberculin syringes.METHODS:Four separate batches of enoxaparin were diluted with sterile water to a final concentration of 20 mg/mL (2000 IU/mL) and aliquoted into plastic 1-mL syringes containing 6 mg (0.3 mL) or maintained in the glass vial. Syringes were stored at room temperature or under refrigeration. The glass vial used for diluting was stored at room temperature. The anti-Xa activity was measured on the date of preparation to 4 weeks. Statistical comparisons determined whether differences in anti-Xa activity in diluted enoxaparin are affected by the storage medium or temperature. A paired t-test was used to determine any significant differences between the anti-Xa activity on date of preparation (baseline) and subsequent time periods, with p < 0.05 considered statistically significant.RESULTS:The mean baseline anti-Xa activity was 2607 IU/mL (95% CI 2300 to 2914). No measurable decrease occurred in diluted enoxaparin anti-Xa activity in the glass vial maintained over the 4-week period. Compared with the glass vial, room temperature and refrigerated syringe samples had trending decreases of anti-Xa activity at weeks 3 and 4, but did not reach statistical significance.CONCLUSIONS:A nonsignificant decrease in anti-Xa activity occurred starting at day 22 for the diluted enoxaparin in tuberculin syringes, regardless of storage temperature. Storage up to 4 weeks of diluted enoxaparin in glass or prefilled syringes does not result in a statistically significant loss of anticoagulant potential, as measured by anti-Xa activity.

BACKGROUND: Patients with heparin-induced thrombocytopenia and thrombosis may be acutely anticoagulated with direct thrombin inhibitors (DTIs). The anticoagulation is typically monitored using the activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). OBJECTIVE: To compare 14 methods for measuring aPTT, as well as ECT and thrombin inhibitor management test (TIM), in samples containing DTIs. METHODS: DTIs were added to pooled normal plasma to achieve low (0.1–1.2 μg/mL) and high (1.5–8.0 μg/mL) drug concentrations. Each low-concentration DTI sample was tested using all aPTT reagents, while each low- and high-concentration DTI was tested using the ECT and TIM. RESULTS: All aPTT reagents had a significant dose-dependent correlation with drug concentration. Only Actin FSL and APTT-S demonstrated equivalent aPTT ratios obtained from any DTI. The TAS-aPTT was the most sensitive aPTT reagent to argatroban, with the aPTT ranging from 52.7 to 121.2 seconds corresponding to 0.1 to 1.2 μg/mL of drug concentration. The TAS-aPTT and Pathromtin were the most sensitive aPTT reagents to bivalirudin, with aPTTs of 87.4 seconds and 101.5 seconds, respectively, at 1.2 μg/mL of drug. Pathromtin was the most sensitive aPTT reagent to lepirudin, with a maximum aPTT of 108.9 seconds at 1.2 μg/mL of drug. There was no statistically significant difference between the TIM and ECT clotting times for each DTI. Lepirudin and bivalirudin ECT and TIM clotting times were equivalent. CONCLUSIONS: There are unique differences between reagent manufacturers in the monitoring of DTIs. Acceptable alternatives to aPTT monitoring of DTI anticoagulation include the ECT and TIM.

Direct thrombin inhibitors (DTIs) represent a new class of promising anticoagulation agents. The DTIs frequently are used to provide initial anticoagulation, with long-term therapy requiring eventual transition to coumarins. Unfortunately, DTIs not only prolong the activated partial thromboplastin time but also can affect international normalized ratio (INR) values. We approximated the DTI effect on INRs by each drug to pooled plasma at concentrations between 0.1 and 1.2 microg/mL. We then concurrently tested these samples using 14 prothrombin time (PT) reagents. By using repeated measures analysis of variance, we found significant differences (P < .05) between the median INRs for lepirudin and argatroban for all PT reagents, between lepirudin and bivalirudin for all reagents except PT-Fibrinogen HS Plus (P = .07), and between bivalirudin and argatroban for all reagents except Thromborel S (P = .05). The DTI effect on INRs was dependent on drug, drug concentration, and reagent. Argatroban had the most effect on INRs, while lepirudin had the least effect. Reagents with a lower international sensitivity index were less affected by DTI; ThromboMax HS was the least sensitive PT reagent to any DTI.

Gram-negative pathogens are increasingly resistant to extended-spectrum cephalosporins (ESCs). Using a prospective, case-controlled observational study, we examined the prevalence and the risk factors for development of resistance to ESCs in group I beta-lactamase-producing organisms. Of the 386 isolates of Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, and Serratia marsescens from 340 consecutive patients, 70 (18.1%) were resistant to ESCs; the highest rates of resistance were found among Citrobacter freundii (40.9%), Enterobacter cloacae (31.1%), and Enterobacter aerogenes isolates (18.9%). Patients' prior antibiotic use and the mean number of antibiotics used were significantly greater in association with resistant vs. susceptible isolates. Resistance was associated with prior use of ceftizoxime or cefotaxime (P = .008), ceftazidime (P = .004), and piperacillin (P = .001). Other antibiotics were not associated with resistance. Resistance was less frequent in patients receiving ESCs and an aminoglycoside. We conclude that prior use of ESCs is associated with the isolation of resistant group I beta-lactamase-producing organisms. Concomitant use of an aminoglycoside may decrease this risk.

Ceftibuten is a new, third-generation oral cephalosporin currently being reviewed for approval by the FDA. The drug, which will likely be available in both suspension and tablet formulations, has proven clinical efficacy in treating adults and children with respiratory or urogenital infections. Ceftibuten has increased stability to beta lactamase hydrolysis, which enhances its antimicrobial activity to gram-negative community-acquired pathogens. Its oral bioavailability is superior to other currently available expanded-spectrum oral cephalosporins. Ceftibuten's absorption characteristics and relatively low incidence of adverse effects in clinical trials make it a useful alternative to other drugs used to treat a variety of community-acquired infections.

OBJECTIVE:To report a case of Pseudomonas aeruginosa endocarditis that was successfully treated with high-dose imipenem/cilastatin and to discuss dosage modification based on individual pharmacokinetic parameters.DATA SOURCES:Clinical studies, review articles, and relevant laboratory and pharmacokinetic information.CASE SUMMARY:A 27-year-old man with right-sided P. aeruginosa endocarditis was successfully treated with long-term imipenem/cilastatin and tobramycin. The imipenem dose required to achieve therapeutic serum concentrations and cidal activity was 6 g/d. The manufacturer's recommended maximum dose is 4.0 g/d or 50 mg/kg/d. Because of the patient's large apparent volume of distribution, low serum imipenem concentrations, and lack of serum cidal activity, the clinical decision was made to increase the dose to 6 g/d or 54 mg/kg/d. Treatment was tolerated for seven weeks without any adverse effects. The patient remains free of symptoms 24 months after the diagnosis.CONCLUSIONS:Careful and discriminate use of larger-than-recommended doses of imipenem may be indicated in certain clinical situations. Dosage may need to be adjusted to body size in order to obtain optimal serum concentrations and activity.