It has been identified as the causative agent in many food poisoning outbreaks and is probably responsible for even more cases in individuals and family groups than the records show. Foods are examined for the presence of S. Conclusions regarding the significance of S. The presence of a large number of S. The isolated S. Conversely, small staphylococcal populations at the time of testing may be remnants of large populations that produced enterotoxins in sufficient quantity to cause food poisoning.
Therefore, the analyst should consider all possibilities when analyzing a food for S. Methods used to detect and enumerate S. Processed foods may contain relatively small numbers of debilitated viable cells, whose presence must be demonstrated by appropriate means. Analysis of food for S. The methods of analysis for S. There has been considerable controversy about the significance and correct method of reading the coagulase test.
Those strains suspected of being S. Studies of colonial morphology on Baird-Parker agar, lysostaphin sensitivity, coagulase and thermonuclease production, and glucose and mannitol fermentation were conducted on enterotoxigenic and 51 nonenterotoxigenic strains of S. This research indicates that none of these tests can be relied upon to differentiate toxic and nontoxic staphylococci. This method is suitable for the analysis of foods in which more than S.
It conforms to the method in ref. Media and reagents. Transfer suspect S. Inoculate agar slant of suitable maintenance medium, e. Retain slant cultures at room temperature for ancillary or repeat tests in case coagulase test results are questionable. Add 0. Only firm and complete clot that stays in place when tube is tilted or inverted is considered positive for S.
Test known positive and negative cultures simultaneously with suspect cultures of unknown coagulase activity. Stain all suspect cultures with Gram reagent and observe microscopically. We suggest that health systems develop and implement guidelines on anticoagulant reversal and HIT evaluation and management. Dosing is generally based on total body weight and renal function, evaluated using the Cockcroft-Gault method, further influences dosing requirement [ 59 ]. Use of enoxaparin 1.
This dosing option is based on a single randomized, clinical trial comparing unfractionated heparin UFH to enoxaparin 1. Patients with symptomatic PE, obesity and malignancy all had higher rates of recurrent VTE when treated with 1. Limiting dalteparin to the treatment of cancer-associated VTE is not necessary. Therapy should be initiated as soon as possible, as long as it is determined that fibrinolytics are not going to be administered for acute VTE. Finally, an elevated pre-treatment PT or aPTT may detect the presence of an underlying coagulation defect.
We suggest that when enoxaparin is used for the treatment of VTE, only the twice daily dosing strategy be used, except in patients with severe renal insufficiency see below. Further, we suggest that once daily dalteparin can be used for the treatment of both cancer - and non - cancer - associated VTE. What weight should be used to calculate dosing, and should obese and low body weight patients be treated differently? In clinical trials evaluating the effectiveness and safety of LMWH for the treatment of VTE, total body weight has been used to calculate dosing.
Due to concerns that dosing based on total body weight may lead to over-anticoagulation in obesity, dose capping has been suggested and is recommended in the product information for dalteparin. In addition, limiting the dose of LMWH by using dose capping may result in inadequate anticoagulation and an increased risk of recurrent VTE [ 65 ].
A multivariate analysis concluded that obesity was not associated with an increased risk of bleeding. The average dose of enoxaparin was clinically similar between the groups 0. The incidence of new thromboembolic events was statistically similar 3. This difference may reflect the benefits of a higher total daily dose with the twice daily regimen.
There are limited data on dosing LMWH in patients with low body weight. However, an open label prospective trial in patients showed that mean peak anti-Xa levels were similar between obese and healthy weight individuals receiving enoxaparin 1. We suggest that in all patients, including underweight and obese, LMWH dosing should be based on total body weight. Dose capping should be avoided.
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Routine monitoring of peak anti - Xa levels is not suggested in patients on LMWH, whether obese or non - obese. LMWHs are cleared renally. There is an inverse relationship between CrCl and anti-Xa levels, with accumulation of anti-Xa activity at the end of the dosing interval as renal function declines [ 12 , 71 , 72 ].
Enoxaparin appears to be more dependent on renal function for elimination than is dalteparin [ 73 ]. Compared to patients with normal renal function, the risk of major bleeding increases in patients with renal insufficiency exposed to LMWH.
Fifteen of the 18 studies evaluated enoxaparin and seven of those involved the use of therapeutic dosing rather than dosing for VTE prophylaxis. When data were analyzed based on LMWH preparation, major bleeding was increased with standard dose enoxaparin 8. There were no data on bleeding associated with the use of dalteparin. An increased risk of bleeding has also been observed in patients with moderate renal impairment. The incidence of major bleeding was 5. More data on dose adjustment in renal impairment are needed. LMWH is routinely avoided in patients on renal replacement therapy RRT because of the numerous variables that can affect clearance filter type, interruption, regimen change.
When LMWH is used for acute treatment of VTE in patients with renal impairment, we suggest that vigilant attention to potential bleeding risk and monitoring for signs and symptoms of bleeding be employed. Renal function should be estimated using the Cockcroft - Gault method for calculating CrCl. LMWHs have predictable pharmacodynamic profiles and wide therapeutic windows that do not require routine coagulation monitoring in clinically stable and uncomplicated patients.
There are currently no commercial assays available for LMWH. Anti-Xa activity is a surrogate marker that measures the anticoagulant effect of LMWH and is assumed to correlate with hemorrhagic and thromboembolic events. While LMWH anti-Xa concentrations may be helpful in evaluating dosing in special patient populations, routine LMWH anti-Xa monitoring is unnecessary and potentially harmful if misinterpreted [ 12 , 59 , 78 ]. LMWHs are excreted by the kidney and accumulation may occur in renal impairment.
Occasional monitoring of renal function using serum creatinine, and calculation of CrCl using the Cockcroft-Gault method may be useful to assess changes in renal function that may indicate the need for a dosing adjustment. We suggest all patients receiving LMWH be monitored for signs and symptoms of bleeding and be observed for changes in renal function that may require a dose adjustment. The clinical trials evaluating LMWH did not use anti-Xa levels to guide dosing and anti-Xa levels have not been evaluated in large studies.
Although anti-Xa levels have been used as a marker of LMWH activity they are not routinely evaluated in clinically stable or uncomplicated patients.
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Trough anti-Xa levels may be used to evaluate accumulation of anticoagulant effect at the end of dosing interval. The value of peak anti-Xa levels is less clear. In a retrospective review, the majority of anti-Xa levels were drawn inappropriately, limiting their utility for interpretation [ 68 ]. Data supporting a relationship between elevated LMWH anti-Xa levels and bleeding are quite limited and include a study in which dalteparin was administered by continuous infusion and bleeding was increased in those with mean levels above 0.
In the uncommon situations in which anti-Xa activity is monitored, it should be determined using a chromogenic method and a calibration curve based on the LMWH used. Target anti-Xa levels are not clinically validated, and there is no standardized method for adjusting doses based on anti-Xa level [ 59 ]. Peak anti-Xa levels observed in patients treated with enoxaparin range from 0.
Importantly, there are no data to suggest that making dosing adjustments based on peak levels is correlated with improved safety or efficacy. Elevated troughs reflect lack of LMWH clearance and may suggest both an increased risk of bleeding and the need for a prolonged dosing interval. Trough anti-Xa concentrations may be helpful to evaluate the safety of LMWH dosing in special patient populations including patients with severe renal impairment although usefulness undetermined in patients on RRT and extremely low body weight [ 12 , 59 ].
The role of peak anti-Xa concentrations for evaluating efficacy in special populations including pregnancy and extremes of body weight is not defined. We suggest that in limited populations, including patients with severe renal failure, trough anti - Xa levels may have a role in evaluating LMWH accumulation and the need to prolong the dosing interval.
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We suggest that peak anti - Xa levels not be utilized to evaluate dosing regimens in clinical practice. What is the appropriate duration of therapy when transitioning to oral anticoagulant therapy? LMWH alone is an option for patients in whom INR is difficult to control or in whom oral anticoagulation is not an option, and is more effective than VKA therapy in patients with cancer [ 69 ]. Among trials with the highest methodological quality, a recent meta-analysis showed a non-significant reduction in the odds of recurrent VTE OR 0.
Nevertheless, oral anticoagulation remains a more common approach due to the expense of LMWH and the need for drug delivery by injection. A Cochrane review of 6 randomized controlled trials including patients with DVT showed that outpatient therapy was associated with a lower rate of recurrent VTE, reduced mortality and no difference in minor bleeding [ 86 ]. While PE has historically been treated on an inpatient basis, a systematic review and meta-analysis of 11 studies, including patients, showed that low risk patients with PE can safety be treated as outpatients [ 87 ].
Studies included in the meta-analysis utilized either a risk stratification method or clinical judgment to determine low risk patients. The incidence of VTE recurrence and major bleeding was low in the studies and the event rates between the studies that used a risk stratification model versus clinical judgment were similar. Approximately one-third to one-half of acute PE patients may be classified as low-risk [ 88 ].
In addition, DVT patients who may require hospitalization include those with venous gangrene or extensive iliofemoral involvement, severe acute obstruction phlegmasia cerula dolens , poor social circumstances, active bleeding or a high risk of bleeding, severe pain, renal impairment, significant communication deficits or mobility problems [ 11 , 92 ]. Home circumstances for adequate outpatient treatment include well-maintained living conditions, strong support from family or friends, phone access and ability to quickly return to hospital if there is clinical deterioration [ 11 ].
We suggest patients with VTE be evaluated to determine treatment setting. How should LMWH-induced over-anticoagulation, thrombocytopenia and bleeding be managed? When significant bleeding or over-anticoagulation occurs, LMWH should be discontinued immediately. Observation without intervention is appropriate if bleeding is not present as demonstrated in a case series of intentional LMWH overdose [ 94 ].
Appraising case files: practical and preservation issues
While it fully reverses the anti-IIa fraction of LMWH, it only partially reverses the anti-Xa component of LMWH due to the reduced sulfate charge in the ultra-low molecular weight heparin fragments present. Enoxaparin appears to be less susceptible to protamine sulfate reversal than dalteparin because its structure has less sulfonation [ 95 ]. There are limited clinical data on the use of protamine sulfate to reverse LMWH [ 93 , 96 ]. A retrospective, single center study that evaluated the use of protamine sulfate to emergently reverse LMWH found that 4 of 14 patients with active bleeding continued to bleed or rebled after protamine administration [ 93 ].
No correlation was evident between anti-Xa levels and bleeding cessation. In patients with impaired renal function the anticoagulant effect of LMWH may persist and the treatment window for protamine sulfate may be extended. A second dose of 0. A lower initial dose of protamine sulfate 0. Nevertheless, if thrombocytopenia or thrombosis develops during LMWH treatment, the patient should be evaluated for HIT as outlined previously for UFH, and treated according to current guidelines [ 55 ]. We suggest that protamine sulfate be used to reverse LWMH if major bleeding occurs.
The timing of the last dose of LMWH should be assessed when determining if protamine sulfate should be administered and the appropriate dose to be administered.
A repeat dose of protamine may be administered if bleeding continues or if the aPTT is prolonged 2—4 h after the initial dose. Fondaparinux was dosed based on weight terciles. Major bleeding was also not different between fondaparinux and enoxaparin 1. Major bleeding was also similar between the groups 1. In both studies, mortality did not differ between the groups. Therapy should be initiated as soon as possible and it is determined that fibrinolytics are not going to be administered.
A baseline weight is required to determine the correct dose of fondaparinux. A baseline CBC should also be evaluated. The rate of recurrent VTE was non-inferior with fondaparinux compared with heparin in both non-obese 3. As with body weight, the efficacy of fondaparinux appeared to be similar regardless of BMI. Major bleeding rates were also not different between patients receiving fondaparinux and a heparin in non-obese 1.
Data on low body weight patients are more limited. There were only a total of 2. The rate of recurrent VTE in the fondaparinux and heparin groups were similar It should also be noted that the numbers are quite small 6 events for fondaparinux vs. Major bleeding rates were consistently low for both the fondaparinux and heparin group 1. We suggest patients be dosed based on total body weight. Fondaparinux is eliminated almost completely through the kidney as unchanged drug.
Patients with a Scr greater than 2. There were 51 2. In these patients, there were 4 major bleeding events 7. Therefore, there could be some drug accumulation in these patients with longer than usual courses of therapy. We also suggest that patients with moderate renal insufficiency be monitored closely for bleeding during longer durations of therapy due to potential accumulation.
Due to the predictable pharmacokinetic and pharmacodynamic profile of fondaparinux, routine coagulation monitoring is not necessary. As with any anticoagulant, the most common adverse effect is bleeding. Therefore, monitoring for signs and symptoms of bleeding is paramount. The need for platelet count monitoring is uncertain. The mean increase in the PT at therapeutic levels of fondaparinux 0. The mean increase in the aPTT was only 4. Therefore, these assays are not appropriate for measuring fondaparinux therapy.
We suggest that most patients receiving fondaparinux do not require therapeutic drug monitoring. If the clinical setting suggests the need to assess accumulation of fondaparinux, we suggest using an anti - Xa assay calibrated for fondaparinux, and we suggest against the use of a PT, aPTT, or activated clotting time ACT. Most patients receiving fondaparinux should not receive anti-Xa monitoring.
While fondaparinux provides a predictable anticoagulant response, there may be special situations in which measuring plasma concentrations may be helpful. While evidence to support measuring plasma concentrations is lacking, concentrations may be helpful to guide therapy in patients on long-term therapy, or with sudden changes in renal function, extremes in body weight, or pregnancy. However, there are no data to suggest that dosing adjustments in response to known plasma concentrations have any influence on patient outcomes. A chromogenic anti Xa assay calibrated with fondaparinux produces reliable and reproducible results [ — ].
Fondaparinux needs to be used to form the standard curves to measure fondaparinux levels [ 12 ]. Results obtained using a LMWH standard curve are less accurate and standard curves using UFH are completely inaccurate and should not be used [ , ]. Target anti-Xa levels for fondaparinux are not established; however peak anti-Xa levels in patients receiving treatment doses of fondaparinux range from 0. Observed trough levels in patients receiving fondaparinux are in the range of 0.
If the clinical setting suggests a benefit of measuring trough fondaparinux levels, we suggest a chromogenic anti - Xa with the standardization curve calibrated with fondaparinux. If fondaparinux is administered to a patient who will be transitioned to a TSOAC, the oral agent should be initiated at the time that the next fondaparinux dose would have been given.
The timing of the first dose of a TSOAC is based on when the next scheduled dose of fondaparinux would be due. These numbers were similar to the enoxaparin patients treated as outpatients 8. In patients receiving some outpatient therapy, the rate of recurrent VTE was similar between the fondaparinux and enoxaparin groups 2. Major bleeding was also similar between groups 1. The rate of recurrent VTE was 3. These values are similar to those in the overall study. Outpatient treatment with fondaparinux has demonstrated similar efficacy and safety to inpatient treatment of VTE.
Therefore, patients who would be considered outpatient candidates for LMWH therapy should also be considered outpatient candidates for fondaparinux.
We suggest patients with VTE be evaluated to determine the treatment setting. Due to the smaller size of the molecule and low affinity for platelet factor 4, fondaparinux does not cross react with HIT antibodies [ ]. While there have been a small number of case reports of fondaparinux-associated HIT with the use of fondaparinux for VTE prevention [ — ], no cases of HIT have been reported in any of the major clinical trials evaluating the efficacy and safety of fondaparinux in the prevention of VTE, the treatment of VTE, or in treatment of patients with acute coronary syndrome.
More data exist for the ability of fondaparinux to be used in the treatment of HIT or as a safe alternative in those with a history of HIT [ ]. A number of case reports and case series support the potential role of using fondaparinux in the treatment of HIT [ — ]. Fondaparinux doses varied from 2. In the only prospective study in the literature, 7 patients with acute HIT were treated with fondaparinux and compared to 10 similar historical control HIT patients from the same hospital [ ].
Patients presenting with thrombosis 6 of the 7 received treatment doses of fondaparinux based on weight as in the MATISSE trials, while the patient presenting without thrombosis received 2. Eight of the 10 historical control patients presented with thrombosis. All fondaparinux patients experienced platelet count recovery compared to 8 of the 10 historical controls. There were no new thromboses, major bleeding events, or death in the fondaparinux treated patients. There were 2 deaths in the historical control patient group. PTT confounding can be caused by disseminated intravascular coagulation, hepatic failure, VKA use and lupus anticoagulant.
Progressive thrombosis then ensues while the aPTT remains elevated. Although fondaparinux may offer a benefit, its long elimination half-life, dependence on renal function for elimination and non-reversibility must be considered. In the most recent guidelines from ACCP, fondaparinux is mentioned as an option for the treatment of patients with HIT without thrombosis, as well as for use in patients with a history of HIT who require anticoagulation [ 63 ]. While the guidelines mention the limitations of the data, it should be remembered that there are no high quality data available for any agent in the treatment of HIT.
When fondaparinux is used in patients with acute HIT, we suggest that treatment doses be used. While protamine sulfate is effective at reversing the anticoagulant effect of UFH and to some extent LMWH, it is not effective in reversing fondaparinux [ ]. Since protamine does not bind to the low molecular weight molecule due to the reduced sulfate charge of fondaparinux, there is no reversal of the anticoagulant effect. Case reports and case series also support a role for rFVIIa in stopping fondaparinux-induced bleeding [ — ].
The ability of concentrated clotting factors to reverse the impact of fondaparinux on thrombin generation test has been evaluated in one in vitro study [ ].
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More data and experience with these agents are needed, particularly considering the risk of thrombosis associated with their use. We suggest the use of rFVIIa in the setting of life threatening bleeding induced by fondaparinux, and that potential benefits must be weighed against thrombotic risk. Despite advances in the development of oral anticoagulants, the parenteral heparins continue to be a component of the treatment of VTE. Their appropriate use, particularly in special populations, remains a challenge for clinicians. We wish to acknowledge the support provided by Myelin and Associates with the preparation of this manuscript for submission.
The work contained in this manuscript was partially funded by support from the following companies: Boehringer Ingelheim, Daiichi Sankyo and Janssen Pharmaceuticals. National Center for Biotechnology Information , U. Journal of Thrombosis and Thrombolysis. J Thromb Thrombolysis. Published online Jan Maureen A. Smythe , Jennifer Priziola , Paul P. Paul P. Ann K. Author information Copyright and License information Disclaimer.
Wittkowsky, Email: ude. Corresponding author. This article has been cited by other articles in PMC. Abstract Venous thromboembolism VTE is a serious and often fatal medical condition with an increasing incidence. Introduction Heparin has been a component of the initial treatment of venous thromboembolism VTE for decades.
Open in a separate window. Guidance Heparin for the treatment of acute VTE How should heparin be initiated, including baseline laboratory tests and dosing? The full text of this article hosted at iucr.
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Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. It is important to determine the severity of atopic dermatitis AD for evaluation of disease improvement after and during therapy. Scoring of the severity of AD is demanded in clinical trials. The extent can be graded 0— Each item can be graded on a scale 0—3. The subjective items include daily pruritus and sleeplessness.
The maximum subjective score is In this formula A is defined as the extent 0— , B is defined as the intensity 0—18 and C is defined as the subjective symptoms 0— Bonus points are given for severe disfiguring eczema on face and hands. The TIS score corresponds well with the more detailed objective SCORAD and can be used as a prescreening system or as a quick system in studies and is excellent for epidemiological studies.
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