Table of Contents  
RESEARCH PAPER
Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 47-52  

Evaluation of treatment of invasive fungal infections


Department of Clinical Pharmacy, Mediterranean Institute for Transplantation and High Specialization Therapies, Palermo, Italy

Date of Web Publication7-Jan-2014

Correspondence Address:
Ilenia Casucci
Via E. Tricomi 1, 90127 Palermo
Italy
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-500X.124423

Rights and Permissions
   Abstract 

Objective: To identify the risk factors associated with invasive fungal infections (IFI) in immunocompromised patients (IP), and monitor antifungal therapy appropriateness and costs. Materials and Methods: The 1-year observational retrospective study was performed on 101 IP, who received antifungal intravenous therapy with fluconazole (F), liposomal amphotericin-B (A), caspofungin (C), itraconazole (I) for ≥4 days. Patient therapy was divided into three groups: Prophylactic, empirical, and target. Immunosuppressive therapy (IT), total parenteral nutrition (TPN), dialysis, central line, steroid therapy, stent use, neutropenia, and mechanical ventilation were evaluated. Variables were therapy duration, defined daily dose (DDD) consumption, DDD average cost. Results: Main risk factors were central line (65.3%), TPN (56.4%), dialysis (46.5%), IT (42.6%), mechanical ventilation (32.7%), neutropenia (24.8%), steroid therapy (23.8%), and stent use (14.9%). Average duration of prophylaxis was 7 days; F (61%), A (26%), and C (13%) were used. Average duration of empirical therapy was 8 days; F (52.9%), A (26.5%), C (8.8%), I (2.9%), and in association A + C, A + F, C + F (8.9%) were used. Average duration of target therapy was 9 days; F (40.4%), A (23.1%), C (15.4%), I (7.7%), and in association A + C, A + F, C + F (13.4%) were used. DDD consumption and DDD average-cost were: C 50 mg vial: 273 DDD, €381.1; C 70 mg vial: 33.6 DDD, €389.6; F 200 mg vial: 768 DDD, €11.8; F 100 mg vial: 89 DDD, €10.6; I 250 mg vials: 62.5 DDD, €68.8; and A 50 mg vial: 2200 DDD, €93.4; respectively. Conclusions: Data showed an appropriate use of antifungals. Best alternative therapy (cheaper antifungal drug) was prescribed for most patients. The high cost of A and C was justified by IFI resolution.

Keywords: Costs, defined daily dose, invasive fungal infections, prescriptive appropriateness, risk factors


How to cite this article:
Casucci I, Provenzani A, Polidori P. Evaluation of treatment of invasive fungal infections. J Pharmacol Pharmacother 2014;5:47-52

How to cite this URL:
Casucci I, Provenzani A, Polidori P. Evaluation of treatment of invasive fungal infections. J Pharmacol Pharmacother [serial online] 2014 [cited 2019 Nov 14];5:47-52. Available from: http://www.jpharmacol.com/text.asp?2014/5/1/47/124423


   Introduction Top


Invasive fungal infections (IFI) are an important cause of morbidity and mortality in seriously immunosuppressed and immunocompromised patients. [1],[2],[3],[4] Given the limited clinical manifestations and the risk of multiresistant strains developing, there are still many difficulties in preventing, diagnosing, and treating invasive mycoses.

Candida and Aspergillus are the main species responsible for IFI. [5] There are currently few available systemic antimycotic drugs; therefore it is important to enforce a sound therapy limiting resistance as much as possible and at the same time fighting these infections. Developing antifungal drugs with improved tolerance and/or specificity, but with very high costs (liposomal amphotericin B, caspofungin) has improved effective treatment and increased hospitals' pharmaceutical expenditure.

A clinical pharmacist on the unit can be essential to monitor these therapies in terms of appropriateness of prescription, and to rationalize the use of these highly expensive drugs.

This retrospective study done at Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT) in Palermo, has the goal to:

  • Identify major risk factors of IFI development in patients at risk of immunocompromisation from major surgery, immunosuppressive therapy for replacement surgery or severe disease, or undergoing systemic antifungal therapy; over a period of 12 months [6],[7],[8]
  • Monitor the appropriateness of prescription of empirical, prophylactic, and target therapies in compliance with the Infectious Diseases Society of America (IDSA) [9],[10] and European Organization for Research and Treatment of Cancer (EORTC) guidelines
  • Assess adherence to microbiology outcomes in case of target therapy
  • Monitor consumption to rationalize costs of more expensive antimycotic drugs.



   Materials and Methods Top


The 1-year observational retrospective study was performed at ISMETT, a 78-bed transplant center in Palermo, Italy, reviewing the electronic medical records and antimycograms of all patients undergoing systemic antifungal therapy.

Analysis criteria were based on the clinical profile of the patients indicated below, monitoring consumption of fluconazole (F), liposomal amphotericin B (A), caspofungin (C), and itraconazole (I) in prophylactic, empirical, and target therapy; and also on compliance with microbiology results in cases of ascertained infections.

The study included solid organ transplant recipients (liver, kidneys, heart, and lung), patients who underwent cardiac and abdominal surgery, and patients with serious internist diseases (carcinoma, cirrhosis, short bowel syndrome, cardiac decompensation, and respiratory failure) admitted in the intensive care unit (ICU) and inpatient units. Inclusion criteria were the presence of at least one risk factor and an empirical, prophylactic, and target therapy lasting 4 days or more.

Individuals reporting at least one of the following factors according to IDSA classification were considered at risk of developing IFI: Patients with a central line in place, on total parenteral nutrition (TPN), on dialysis, with a stent or other prosthesis device, on immunosuppressive and steroids therapy, or mechanical ventilation.

We also performed a cost analysis (%) and a review of DDD antimycotic drug consumption for prophylactic, empirical, and target therapies.

For each antimycotic drug and for every therapeutic regimen enforced in the period under consideration, we reviewed:

  • Number of patients undergoing (prophylactic, empirical, target) therapy to assess IFI incidence in the population at risk
  • Average length of therapy (days)
  • Total expenditure (in Euro) and average cost (in DDD) for each antimycotic drug utilized (all drug costs were considered without value added tax (VAT)
  • Average cost per patient based on average number of days of therapy (in Euro).



   Results Top


The sample included 101 patients on systemic antifungal therapy of which 17 were children (average age: 7-year-old (yo)], 52 men (average age: 53 yo), and 32 women (average age: 57 yo).

Of the 101 patients, 43 underwent a solid organ transplant (six heart, seven lung, four kidney, 24 liver, and two liver and kidney combined); eight suffered respiratory failure, five cardiac decompensation, one chronic ischemic cardiomiopathy, six underwent cardiac surgery (one mitral valve repair, one mitral prosthesis implant, four aortic valve replacement); 13 were affected by neoplasia (two stomach adenocarcinoma, six cholangiocarcinoma, two hepatocarcinoma, two pancreas neoplasia, and one nephroblastoma); four were affected by short bowel syndrome, seven liver cirrhosis, three liver failure, two renal failure, two liver resections, four bowel resection; while four had undergone various abdominal surgery interventions.

Risk factors

The average number of risk factors in the sample is three.

Risk factors encountered were: 42.6% immunosuppressive therapy, 56.4% TPN, 46.5% dialysis, 65.3% central line, 23.8% steroid therapy, 14.9% valves-stent-medical devices, 24.8% neutropenia, and 32.7% mechanical ventilation.

Therapies

13.9% of patients (n = 14) only received prophylactic therapy with an average duration of 7 days; 33.7% (n = 34) received only empirical therapy with an average duration of 8 days, and 33.7% (n = 34) received only target therapy with an average length of 9 days.

For 3% (n = 3) of patients it was deemed appropriate to perform a prophylactic therapy followed by an empirical therapy, for 9.9% (n = 10) empirical therapy followed by target therapy, for 5% (n = 5) prophylactic followed by target therapy, and for 1% (n = 1) prophylactic therapy followed by empirical and then by target therapy.

Prophylactic therapy

The first choice of drug for prophylactic therapy was F 61% (n = 14), followed by A 26% (n = 6), and C 13% (n = 3).

Empirical therapy

The first choice of antifungal was F 52.9% (n = 18), followed by A 26.5% (n = 9), C 8.8% (n = 3), and I 2.9% (n = 1). Only in 2.9% of cases we performed a combined therapy with two active principles (A + C, A + F, C + F).

Target therapy

In the 50 target antimycotic drug prescriptions, the most commonly-used medication was F 40.4% (n = 21), followed by A 23.1% (n = 12), C 15.4% (n = 8), and I 7.7% (n = 2). In the other cases, it was necessary to resort to a combined regimen of antifungals (A + C, A + F, C + F, A + I).

Four deaths occurred during target treatment: Two patients showed infections from Candida glabrata and C. albicans in several microbiology cultures, one from Geotricum capitatum encountered in the blood culture and one from Aspergillus fumigatus seen in the bronchial culture.

An additional three patients died a few days after the end of the target treatment. Microbiology results showed C. glabrata colonies present after the therapy. Of the seven deceased patients, four of them were under treatment with A, two with C, and one with F. As shown by microbiology results, the antimycotic drug regimen established in these patients failed to eradicate the infection thus possibly contributing to their death.

The isolated fungal species were: Candida 90.1%, Aspergillus 6.7%, Cryptococcal 1.7%, Geotrichum 1.7%. The antifungal target prescription rate [Figure 1] for each isolated fungal species was: C. albicans F 22 patients, A seven patients, C five patients; C. glabrata F two patients, A seven patients, C seven patients, I three patients; C. krusei F one patient; A. niger A one patient; A. terreus A two patients; A. pneumonia A one patient; Cryptococcal neoformas A one patient; Geotrichum F one patient.
Figure 1: Antifungal prescription rate for each isolated fungal species

Click here to view


During the study period IFI's incidence in the population with major risks (reviewed sample: 101 patients) was 49.5 and 3.8% in the overall hospital population (2,632 patients), respectively.

The average durations of the three therapeutic regimes for each antimycotic drug reviewed were.

A: Prophylactic and empirical therapy 7 days and target therapy 10 days; C: Prophylactic therapy 7 days, empirical therapy 8.5 days, and target therapy 8 days; F: Prophylactic therapy 6 days, empirical therapy 8 days, and target therapy 9 days; I: Empirical therapy 4 days and target therapy 8 days.

Cost analysis

A [Table 1]: Costs were calculated based on daily doses (mg/kg body weight) prescribed per patient. For prophylactic therapy costs were approximately €670 for one 250 mg/day dose (median), corresponding to 3.6 mg/kg/day (median) for average body weight of 58 kg; average cost per patient for 7 days of treatment was €6961.7.
Table 1: Ambisome® cost analysis


Click here to view


For empirical and target therapies, costs were approximately €540 for one 200 mg/day dose (median), corresponding to 3.3 mg/kg/day (median) for average body weight of 54 kg for empirical therapy and 56 kg for target therapy. Average cost per patient for 7 days of empirical therapy was €3870.1, while for 10 days of target therapy it was €5471.5.

C [Table 2]: Costs per patient were calculated considering a 70 mg/day loading dose and a 50 mg/day maintenance dose. For prophylaxis therapy the cost was €2815 for 7 days, for empirical therapy it was €4083.2 for 8.5 days, and for target therapy €5420.7 for 8 days.

F [Table 3]: This was the most commonly prescribed antifungal drug for all treatments. The average cost per patient in prophylaxis for 6 days of therapy was €120.3, for empirical therapy €150.7 for 8 days, and for target therapy €169.3 for 9 days.
Table 2: Caspofungin cost analysis


Click here to view
Table 3: Fluconazole cost analysis


Click here to view


[Table 4]: Only one patient received a 4-day empirical treatment with an average cost of €345; three patients received target therapy against C. glabrata for 8 days with an average cost per patient of €1318.6. No patient enrolled in the study received prophylaxis with I.

The total expenditure for the period under consideration for all utilized antimycotic drugs was: A 61% for 40 patients, C 34.8% for 26 patients, F 3% for 66 patients, and I 1.3% for four patients.
Table 4: Itraconazole cost analysis


Click here to view


The total expenditure over 1 year for each antifungal with reference to a " n" number of patients who received prophylactic treatment was: A €41,770 for 6 patients, C € 11,260 for four patients, F €1,684 for 14 patients; empiric treatment was: A €54,181 for 14 patients, C €42,547 for ten patients, F €3,917 for 26 patients, I €345 for one patient; and target treatment was: A €109,429 for 20 patients, C €63,333 for 12 patients, F €4,403 for 26 patients and I €3,956 for three patients [Figure 2].
Figure 2: Expenditure (€) over 1 year for each antifungal with reference to a "n" number of patients who received prophylactic, empirical, and target treatment

Click here to view


Intravenous (I.V.) antifungal consumption reviewed in terms of DDD in the period under consideration [Table 5] was: C 50 mg vial 273 DDD, C 70 mg vial 33.6 DDD, F 200 mg vial 768 DDD, F 100 mg vial 89 DDD, I 250 mg vial 62.5 DDD, and A 50 mg vial 2,200 DDD.
Table 5: DDD and average cost of DDD of intravenous antifungals reviewed in study period


Click here to view


The DDD average cost shows the total expenditure divided for the total doses consumed and, on average, the cost of one day of therapy: C 50 mg vial €381.1, C 70 mg vial €389.6, F 200 mg vial €11.8, F 100 mg vial €10.6, I 250 mg vial € 68.8, and A 50 mg vial €93.4.


   Discussion Top


Today a timely and reliable diagnosis of IFI is still hard to perform as IFI tends to manifest itself as an undifferentiated clinical syndrome. IFI have a different incidence according to the patient and graft: [11],[12] Candida, for example, often infects the liver and kidneys of patients who received these grafts and the cardiac valves, while Aspergillus is mostly responsible for lung infections. [4],[13],[14]

Prophylaxis should be started before the symptoms. [15] It is essential to treat transplant recipients and patients more at risk and customize therapy based on their clinical conditions.

If a patient reports clinical signs of infection (e.g., antibiotic-resistant fever, failure to identify the pathogenic agent, and no radiology evidence), the plan of therapy should involve starting an empirical antimycotic therapy followed by a target therapy with antifungals to which the pathogenic microorganism, according to the antimycogram, is sensible to, and if there are compatible radiology evidences. [15],[16],[17] The most commonly-isolated species in this study were Candida and Aspergillus.

As can be detected from the results of the reviewed population, immunosuppressive therapy is one of the major risk factors, immediately after the central lines and TPN. The TPN lipid component does favor microbial development and proliferation. Although encountered in a lower percentage, other risk factors included mechanical ventilation, neutropenia, steroid therapy, and placement of stents and other devices.

Prescriptions that are based on microbiology outcomes, involved switching empirical therapy to target therapy and were considered appropriate. Of the ten patients who received empirical therapy followed by target therapy, five received the same antimycotic drug for both therapeutic regimes, three were administered a different antimycotic (changing the medication from empirical to target therapy was justified by the antifungal's specific action against isolated species), two received a combination of two antimycotic drugs (A + F) in their target therapy due to persisting infection of multiple fungal species. Assessing patients who underwent a prophylactic treatment followed by a target therapy showed two patients under prophylaxis with F had to undergo one target treatment with I against C. glabrata and one with A against A. niger. Failure to succeed of the prophylaxis with F in these two patients was due to resistance to F of these two fungal species.

The assessment of the target therapies showed the physicians' approach, following the IDSA guidelines, when treating C. albicans infections initially resolved to using F; and then as a second choice, A. In the case of isolation of C. glabrata, a fungal species that has developed resistance to F, the drugs of choice were A and C. Target treatment against A. niger was performed with A only.

IFI are difficult to treat and often require long-term therapies. With soaring costs of antimycotic treatments and hospital stay, [18] The need was therefore stressed to assess the appropriateness of prescriptions, identifying any use not compliant with international guidelines and/or therapeutic indications, and monitor consumption of particularly expensive antifungals expressing them in terms of DDD. The world Health Organization's (WHO's) definition of DDD is "the assumed average maintenance dose per day of a drug used for its main indication in adults". [19] The DDD should therefore be considered only as a technical tool, an indicator of consumption, to measure drug prescriptions.

In the scope of every A and C therapeutic regimen, being the most expensive, two antifungals showed a DDD average cost higher than the one for treatment with F, despite the number of patients treated with this azole was almost 50% more compared to A and C.

F was always the first choice drug in all three therapeutic regimens. Treating C. albicans infections we encountered an overall good outcome rate using any of the four antimycotics reviewed indifferently. This caused physicians to pick the less expensive alternative preferring F to the more expensive antifungals.

The use of I, given its higher cost and wider spectrum compared to F, was limited to cases of F-resistance. The pharmacology treatment using A, C, and F in seven out of 50 patients undergoing target therapy was unable to eradicate the mycotic infection, resulting as ineffective. The persistence of such infections in these patients, already heavily compromised, may have contributed to their death.

An analysis of the medical records and antimycograms showed the antimycotic drugs reviewed were used appropriately in the ascertained IFI, in compliance with the IDSA guidelines.

Prescriptions that upon an initial analysis of the microbiology reports appeared inappropriate and not supported by evidence in literature, were subsequently supported by an infectivologist for the heavily compromised patients.

Examples of prescriptions not entirely compliant with the guidelines included:

  • Choice of drug not tested in antibiogram, but assumed to be effective based on scientific data (7%)
  • Association of two drugs despite antimycogram showed resistance to one of the two (e.g., A + C in invasive aspergillosis or candidiasis, A + F); 4% of target therapies.


The resolution of fungal infections in several patients as per the negative outcomes of microbiology results (no mycotic growth) for posttransplant cultures supported the high costs of A and C.

It should be noted, we did encounter a certain degree of attention among the medical staff, supported by clinical pharmacists, while prescribing, whenever possible, the less expensive antifungals, seeking the best alternative treatment for the highest number of patients.


   Conclusions Top


Foreseeing the success of IFI treatment is often difficult given the fact that several issues are involved, either related to fungal strain, or to the drug of choice, or to the host.

Monitoring and assessing the appropriateness of the prescription is an essential tool to rationalize the use of antimicrobials, to control and prevent hospital-acquired fungal infections, and to limit the onset of microbial resistance. In this scope, the support of a clinical pharmacist performing a clinical, therapeutic, and pharmacoeconomic analysis becomes essential. With a similar approach and guaranteeing compliance with the standard guidelines, it will be possible to provide a better quality and customized therapy, while at the same rationalizing resources for these highly expensive antifungal treatments.

 
   References Top

1.Maertens J. Antifungal therapy, a challenge in the management of immunocompromised patients. Eur J Hosp Pharm Prac 2007;13:16.  Back to cited text no. 1
    
2.Fortún J, Ruiz I, Martín-Dávila P, Cuenca-Estrella M. Fungal infection in solid organ recipients. Enferm Infecc Microbiol Clin 2012;30 Suppl 2:49-56.  Back to cited text no. 2
    
3.Paloušová D, Lengerová M, Volfová P, Bejdák P, Kocmanová I, Mayer J, et al. Invasive fungal infections in immunocompromised patients with focus on aspergillosis and its causative agents. Klin Mikrobiol Infekc Lek 2012;18:96-101.  Back to cited text no. 3
    
4.Shoham S, Marr KA. Invasive fungal infections in solid organ transplant recipients. Future Microbiol 2012;7:639-55.  Back to cited text no. 4
[PUBMED]    
5.Quindós G. Candidiasis, aspergillosis and other invasive mycoses in recipients of solid organ transplants. Rev Iberoam Micol 2011;28:110-9.  Back to cited text no. 5
    
6.Nucci M, Spector N, Bueno AP, Solza C, Perecmanis T, Bacha PC, et al. Risk factors and attributable mortality associated with superinfections in neutropenic patients with cancer. Clin Infect Dis 1997;24:575-9.  Back to cited text no. 6
[PUBMED]    
7.Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: Changes in epidemiology and risk factors. Blood 2002;100:4358-66.  Back to cited text no. 7
    
8.De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, et al. Revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group consensus group. Clin Infect Dis 2008;46:1813-21.  Back to cited text no. 8
    
9.Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 Update by the infectious diseases society of America. Clin Infect Dis 2009;48:503-35.  Back to cited text no. 9
    
10.Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Infectious Diseases Society of America. Treatment of aspergillosis: Clinical practice guidelines of infectious diseases society of America. Clin Infect Dis 2008;46:327-60.  Back to cited text no. 10
[PUBMED]    
11.Parize P, Rammaert B, Lortholary O. Emerging invasive fungal diseases in transplantation. Curr Infect Dis Rep 2012;14:668-75.  Back to cited text no. 11
[PUBMED]    
12.Pacholczyk M, Lagiewska B, Lisik W, Wasiak D, Chmura A. Invasive fungal infections following liver transplantation-risk factors, incidence and outcome. Ann Transplant 2011;16:14-6.  Back to cited text no. 12
[PUBMED]    
13.Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003;37:1172-7.  Back to cited text no. 13
[PUBMED]    
14.Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: A propensity analysis. Clin Infect Dis 2005;41:1232-9.  Back to cited text no. 14
[PUBMED]    
15.Hadley S, Huckabee C, Pappas PG, Daly J, Rabkin J, Kauffman CA, et al. Outcomes of anifungal prophylaxisin high-risk liver transplant recients. Transpl Infect Dis 2009;11:40-8.  Back to cited text no. 15
[PUBMED]    
16.Segal BH, Almyroudis NG, Battiwalla M, Herbrecht R, Perfect JR, Walsh TJ, et al. Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis 2007;44:402-9.  Back to cited text no. 16
[PUBMED]    
17.Rieger CT, Ostermann H. Empiric vs. preemptive antifungal treatment: An appraisal of treatment strategies in haematological patients. Mycoses 2008;51 Suppl 1:31-4.  Back to cited text no. 17
[PUBMED]    
18.de Pauw B. Is there a need for new antifungal agents? Clin Microbiol Infect 2000;6:23-8.  Back to cited text no. 18
[PUBMED]    
19.Guidelines for DDD. WHO Collaborating Centre for Drug Statistics and Methodology: Oslo. Uppsala; 2002.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


This article has been cited by
1 Potentially inappropriate drug prescribing in elderly hospitalized patients: an analysis and comparison of explicit criteria
Concetta Di Giorgio,Alessio Provenzani,Piera Polidori
International Journal of Clinical Pharmacy. 2016;
[Pubmed] | [DOI]
2 Economic Comparison of an Empirical Versus Diagnostic-Driven Strategy for Treating Invasive Fungal Disease in Immunocompromised Patients
Rosemary Barnes,Stephanie Earnshaw,Raoul Herbrecht,Orla Morrissey,Monica Slavin,Eric Bow,Cheryl McDade,Claudie Charbonneau,David Weinstein,Michal Kantecki,Haran Schlamm,Johan Maertens
Clinical Therapeutics. 2015; 37(6): 1317
[Pubmed] | [DOI]



 

Top
  
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Materials and Me...
   Results
   Discussion
   Conclusions
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed2007    
    Printed75    
    Emailed0    
    PDF Downloaded510    
    Comments [Add]    
    Cited by others 2    

Recommend this journal