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The effect of multifactorial, multidisciplinary educational interventions on appropriate use of teicoplanin
International Journal of Antimicrobial Agents 27 (2006) 344–350
The effect of multifactorial, multidisciplinary educational interventions on appropriate use of teicoplanin Federico Pea a,∗ , Pierluigi Viale b , Federica Pavan a , Marcello Tavio b , Donatella Poz a , Anna Beltrame b , Mario Furlanut a a
b
Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, P.le S. Maria della Misericordia 3, 33100 Udine, Italy Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine, Udine, Italy Received 29 September 2005; accepted 21 November 2005
Abstract The aim of this study was to determine the effect of multifactorial, multidisciplinary educational interventions over a 3-year period on the appropriate use of teicoplanin. Teicoplanin was considered a valid surrogate marker of good antibiotic use in clinical practice owing to its peculiar pharmacokinetics (i.e. necessity for an initial loading dose regardless of the patient’s renal function for early achievement of optimal exposure, namely Cmin ≥ 10 mg/L) and to the opportunity of comparing current routine therapeutic drug monitoring (TDM) results with those of a historical retrospective study. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study, both when considered as a whole (66.6% versus 38.6%, respectively; P < 0.001) or when stratified according to the degree of estimated renal function (78.4% versus 60.4% for creatinine clearance (CLCr ) >50 mL/min; 59.8% versus 26.8% for CLCr 20–50 mL/min; and 27.7% versus 5.5% for CLCr <20 mL/min). The highest adherence was observed in haematological wards (97.7%). The percentages of patients with teicoplanin Cmin ≥ 10 mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. Our findings suggest that continuous application of a multifactorial educational programme including active TDM may be efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin. © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Teicoplanin; Therapeutic drug monitoring; Loading dose; Antibiotic policy; Education
1. Introduction Infections due to multidrug-resistant pathogens frequently represent a major threat for severely ill hospitalised patients [1]. In recent years, several authors documented that the probability of survival in critically ill patients with infections may be significantly decreased in cases of inadequate empirical therapy [2,3]. Considering that Gram-positive cocci, particularly Staphylococcus spp. and Enterococcus spp., are among the most frequent hospital-acquired infection isolates in Intensive Care Unit (ICU) patients [4–6], often with a high incidence of multiresistance [7], antimicrobial regi∗
Corresponding author. Tel.: +39 0432 559 833; fax: +39 0432 559 833. E-mail address: [email protected] (F. Pea).
mens comprising adequate coverage against Gram-positive pathogens should be frequently considered. Glycopeptides, either vancomycin or teicoplanin, are still considered effective weapons for the treatment of documented or suspected hospital-acquired life-threatening multiresistant Gram-positive bacterial infections [8,9]. Interestingly, it has recently been demonstrated that in the setting of appropriate antibiotic choice, the role of prompt initial administration of antibiotics may be crucial for survival [10]. To ensure rapid therapeutically effective concentrations of teicoplanin, appropriate loading doses at the commencement of therapy, regardless of the patient’s renal function, must be considered the first mandatory step owing to the high risk of underexposure related to its very long elimination half-
0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2005.11.012
F. Pea et al. / International Journal of Antimicrobial Agents 27 (2006) 344–350
life [11]. Subsequently, therapeutic drug monitoring (TDM) may be helpful in optimising antibiotic exposure in critically ill patients, as in this setting drug levels of antibiotics after administration of standard fixed dosages may often be unpredictable [12,13]. In a previous study retrospectively analysing the results from routine TDM of teicoplanin performed over a 7-year period at our hospital, we observed that within the first 4 days of therapy, appropriate loading doses (i.e. 400 mg every 12 h at least three times) were administered to only ca. onethird of patients (78 of 202). Interestingly, the percentage of patients receiving an appropriate loading was inversely correlated with their degree of renal function, decreasing from 60.4% in the case of normal renal function to 26.8% and 5.5% in cases of moderately or totally impaired renal function, respectively. The resulting suboptimal concentrations (<10 mg/L) still presented by most of these patients at Day 4 of treatment could have negatively affected the outcome of teicoplanin therapy [14]. On the basis of these findings, we planned a prospective study aimed at assessing the possible improvement in adequate clinical use of this glycopeptide within an implemented multidisciplinary, multifactorial, educational programme for optimal antibiotic use.
2. Patients and methods The objective of this study was to determine the effect of an interventional programme in improving the percentage of patients receiving appropriate pharmacodynamic exposure to antibiotics, using teicoplanin as a surrogate marker of good antibiotic use in clinical practice. Teicoplanin was considered suitable for this purpose owing to its peculiar pharmacokinetics and to the opportunity of comparing routine TDM results of the present prospective study with the historical results from a retrospective study [11]. 2.1. Interventional programme An antimicrobial treatment committee, which comprised infectious disease specialists, clinical pharmacologists, microbiologists and hospital epidemiologists, planned a sequential and multifactorial interventional programme on antibiotic policy at Udine University Hospital that started in April 2002. The programme was focused on various aspects, including: (1) a hospital-wide educational programme to be repeated twice per year regarding principles of good antimicrobial use; (2) semi-annual collegial discussion of microbiological reports on the incidence of different isolates and of their main resistance patterns; (3) hospitalwide daily active consultation of the infectious disease specialists; (4) optimisation over time of antimicrobial exposure in each single patient by means of real-time TDMguided adjustment of antibiotic dosage (defined as ‘active TDM’) carried out by the clinical pharmacologists; and (5)
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planning and implementation of collaborative clinical pharmacokinetic studies involving various field professionals aimed at optimising antimicrobial exposure in critically ill patients. 2.2. TDM of teicoplanin Blood samples for TDM of teicoplanin trough plasma concentrations (Cmin ) were collected immediately before the morning drug administration. After centrifugation at 3000 rpm for 10 min, plasma samples were analysed within 2 h by means of a fluorescence polarisation immunoassay (Opus Diagnostics, Fort Lee, NJ) using a TDx analyser (TDx, Abbott, Rome, Italy) [15,16]. The interday and intraday coefficients of variation of the assay were less than 10%. TDM of teicoplanin Cmin was not performed on each of the days of therapy, but the frequency depended both on the length of therapy and the patient’s pathophysiological status. 2.3. Markers of good teicoplanin use In recent years, TDM of teicoplanin has been increasingly highlighted as important [17–20]. Although it is generally accepted that Cmin > 10 mg/L may be appropriate for the standard of care, on the other hand Cmin > 20 mg/L is currently recommended for some severe settings, for example teicoplanin monotherapy [21], especially in immunocompromised hosts [22] and/or for the treatment of Staphylococcus aureus endocarditis and bone or prosthetic infections [18,19,23,24]. Noteworthy, in a retrospective study, favourable clinical outcome of S. aureus-related deep infections treated with teicoplanin was associated with pre-dose concentrations >20 mg/L [20,25]. Thus, at our institution appropriate teicoplanin use is considered as: (1) an initial loading dose of at least 6 mg/kg every 12 h for three doses regardless of renal function, with the intent of early achievement of Cmin > 10 mg/L; and (2) a variable maintenance dose aimed at maintaining Cmin at 10–30 mg/L, consistent both with in vitro susceptibility of the clinical isolate and with clinical requirements, and adjusted at least every 3–5 days on the basis of the patient’s renal function and serial TDM results. To take into account the eventual influence of differences in ward of admission on appropriate loading, patients were split into different groups according to their admission to medical wards, surgical wards, ICUs and haematological wards. To stratify patients by renal function, serum creatinine concentrations were determined at the same time as each TDM was performed and creatinine clearance (CLCr ) was then estimated on the basis of the Cockcroft and Gault formula [26]. Patients were considered to have normal renal function when CLCr was >50 mL/min, moderately impaired renal function when CLCr was 20–50 mL/min and total renal failure when CLCr was <20 mL/min.
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Table 1 Patient characteristics and treatments
Number (n, %) Gender (M/F) Age (years)a Body weight (kg)a Albuminaemia (g/dL)a Patients with normal renal function (n, %) Patients with moderately impaired renal function (n, %) Patients with totally impaired renal function (n, %) Days with teicoplanin therapyb Total TDM samples Number of TDM samples per patientb
Total patients
Medical wards
Surgical wards
ICUs
Haematological wards
605 370/235 61 ± 16 73 ± 16 3.03 ± 1.37 384 (63.5) 127 (21.0) 94 (15.5) 8 (3–107) 2697 4 (1–22)
182 (30.1) 101/81 66 ± 16 70 ± 14 3.08 ± 0.84 74 (40.7) 50 (27.5) 58 (31.9) 10 (3–107) 842 4 (1–21)
163 (26.9) 112/51 62 ± 15 73 ± 15 2.93 ± 0.68 121 (74.2) 27 (16.6) 15 (9.2) 11 (3–96) 808 4 (1–22)
131 (21.7) 94/37 63 ± 14 80 ± 18 2.60 ± 2.40 63 (48.1) 47 (35.9) 21 (16.0) 8 (3–74) 581 4 (1–12)
129 (21.3) 63/66 50 ± 14 70 ± 14 3.40 ± 0.50 126 (97.7) 3 (2.3) 0 (0.0) 6 (3–44) 466 3 (1–13)
ICUs, Intensive Care Units; TDM, therapeutic drug monitoring. a Data are expressed as mean ± standard deviation. b Data are expressed as median and range.
2.4. Statistical analysis Descriptive data were expressed as mean ± standard deviation (S.D.) or median and range depending on whether the data distribution was normal or non-normal, respectively. Statistical analysis comparing TDM data between different groups was performed using a parametric (paired or unpaired Student’s t-test, as appropriate) or a non-parametric (Mann–Whitney rank sum test) test for normally or nonnormally distributed data, respectively, using SigmaStat software (Systat Software Inc., Point Richmond, CA). Z-test and χ2 test were used for statistical comparison of percentages between two or more groups, respectively. A value of P < 0.05 was considered statistically significant.
3. Results Between July 2002 and June 2005, 605 patients undergoing teicoplanin TDM were prospectively included in this
study. The characteristics of the patients are shown in Table 1. Patients were almost equally distributed between medical wards, surgical wards, ICUs and haematological wards. The total number of teicoplanin TDM samples assayed was 2697 and the per-patient median number ranged between 3 and 4, with the maximum number varying according to the length of therapy. Comparison of patients receiving appropriate loading doses at the commencement of therapy, either as a whole and according to the degree of renal function, between the present study and the pre-interventional retrospective study are reported in Table 2. The trend over time of appropriate loading dose in the current study is reported in Table 3. The overall percentage of patients receiving appropriate loading doses in the present prospective study compared with the retrospective study was 66.6% versus 38.6%, respectively (P < 0.001). The proportion of patients receiving appropriate loading doses in the present study taking into account ward of admission is described in Table 4. The highest adherence was observed in haematological wards (97.7%).
Table 2 Patients receiving appropriate loading doses of teicoplanin Patient group
Present study
Retrospective study [11]
P (Z-test)
Whole group
403/605 (66.6%)
78/202 (38.6%)
<0.001
Stratified by renal function Normal Moderately impaired Totally impaired
301/384 (78.4%) 76/127 (59.8%) 26/94 (27.7%)
64/106 (60.4%) 11/41 (26.8%) 3/55 (5.5%)
0.004 <0.001 <0.001
Table 3 Trend over time of appropriate loading doses of teicoplanin in the 3-year period July 2002 to June 2005 Patient group
1st half year (July 2002–December 2002)
2nd half year (Jan 2003–June 2003)
2nd year (July 2003–June 2004)
3rd year (July 2004–June 2005)
Whole group
19/42 (45.2%)
80/124 (64.5%)
127/197 (64.5%)
177/242 (73.1%)
Stratified by renal function Normal Moderately impaired Totally impaired
14/17 (82.4%) 4/12 (33.3%) 1/13 (7.7%)
66/86 (76.7%%) 12/25 (48.0%) 2/13 (15.4%)
87/118 (73.7) 23/39 (59.0%) 17/40 (42.5%)
134/163 (82.2%) 37/51 (72.5%) 6/28 (21.4%)
F. Pea et al. / International Journal of Antimicrobial Agents 27 (2006) 344–350
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Table 4 Patients receiving appropriate loading doses of teicoplanin in relation to different hospital ward of admission Patient group
Medical wards
Surgical wards
ICUs
Haematological wards
Whole group
84/182 (46.2%)
101/163 (62.0%)
92/131 (70.2%)
126/129 (97.7%)
Stratified by renal function Normal Moderately impaired Totally impaired
53/74 (71.6%) 23/50 (46.0%) 8/58 (13.8%)
77/121 (63.6%) 17/27 (63.0%) 7/15 (46.7%)
48/63 (76.2%) 33/47 (70.2%) 11/21 (52.4%)
123/126 (97.6%) 3/3 (100%) 0/0
ICUs, Intensive Care Units.
With regard to patients receiving appropriate loading doses and undergoing TDM in the first 48 h of therapy (Fig. 1), those who received a loading dose (average of 5.53 mg/kg every 12 h for at least three doses) had significantly higher Cmin concentrations than those who did not receive a loading dose (average of 5.55 mg/kg/daily). The mean Cmin concentrations of teicoplanin in those patients who received a loading dose compared with those that did not were: 7.84 mg/L versus 4.40 mg/L on Day 1 (P < 0.001) and 12.19 mg/L versus 6.58 mg/L on Day 2 (P < 0.001). The trend over time of teicoplanin concentrations for the 605 patients in the current study compared with those for the 202 patients in the retrospective study are shown in Fig. 2. The time needed to achieve an average teicoplanin Cmin higher than 10 mg/L was 2 days in the current study compared with 5 days in the retrospective study. The percentages of patients with teicoplanin Cmin ≥ 10 mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. The profiles of teicoplanin Cmin over time stratified according to degree of renal function in the present study are shown in Fig. 3. The mean (± S.D.) daily maintenance dose needed to ensure comparable average Cmin from Day 5
Fig. 2. Comparison of mean (± standard deviation) trough plasma levels of teicoplanin (Cmin ) over time in critically ill patients between the current study and the retrospective study [11]. Dotted lines refer to the minimum (10 mg/L) and optimal (20 mg/L) concentrations recommended in serious infection.
onwards in patients with normal, or moderately or totally impaired renal function (mean Cmin ± S.D., 20.97 ± 6.99, 22.95 ± 7.72 and 20.71 ± 7.87 mg/L, respectively) was of 8.30 ± 3.30, 5.52 ± 2.78 and 4.45 ± 2.54 mg/kg, respectively.
4. Discussion
Fig. 1. Mean (± standard deviation) trough plasma levels of teicoplanin (Cmin ) during the first 2 days of therapy in patients receiving an appropriate loading dose compared with those not receiving an appropriate loading dose. Dotted line is the minimum concentration recommended in serious infection (10 mg/L).
Several authors have documented the positive impact that different types of educational programmes may have on antibiotic policy [27–33]. Consistent with this, our findings suggest that the multifactorial, multidisciplinary educational interventions were helpful in improving the appropriate use of teicoplanin. We believe that teicoplanin may be considered a valid surrogate marker for the assessment of proper antibiotic use in our hospital setting for several reasons. First, its very long elimination half-life renders the administration of loading doses at the commencement of therapy mandatory with the intent of rapidly achieving therapeutically effective concentrations. Second, loading must always be applied, even in patients with impaired renal function, considering its dependence only on volume of distribution and not on renal clearance. Third, the application of routine TDM
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Fig. 3. Mean (± standard deviation) trough plasma levels (Cmin ) and daily dose (mg/kg) of teicoplanin in critically ill patients stratified according to (A) normal (creatinine clearance (CLCr ) > 50 mL/min), (B) moderately impaired (CLCr of 20–50 mL/min) or (C) totally impaired (CLCr < 20 mL/min) renal function. Dotted lines refer to the minimum (10 mg/L) and optimal (20 mg/L) concentrations recommended in serious infection.
represents an effective way of obtaining a clear feedback for discriminating between proper and improper use. Fourth, the availability of a historical database previously used for a retrospective study [11] makes a post hoc assessment possible. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study [11], both when considered as a whole or when stratified according to
the degree of estimated renal function, with a consistently less marked inverse trend between adherence to appropriate loading and degree of renal function. Indeed, considering that the patients included in this prospective study presented similar baseline characteristics and distribution in terms of ward of admission to those included in the historical analysis, this is a very interesting finding, suggesting that clinicians progressively became more confident with this pharmacokinetic concept, even in the presence of renal failure, and that this positive approach was maintained over time in the subsequent 3 years. However, these overall positive results could be further improved considering that a significant between-ward difference in the frequency of proper loading was observed. Very high adherence to proper loading was documented especially in the ICUs and haematological wards. Interestingly, in the latter, in contrast to the medical wards, the appropriateness of loading seemed only marginally influenced by the patient’s degree of renal function. This could be related to the fact that intensive care specialists and haematologists probably perceive their patients as being at the highest risk of lifethreatening multidrug-resistant bacterial infections, therefore they are particularly careful not only at choosing the appropriate antimicrobial but also at applying the correct dosing regimen. Appropriate management of antibiotic use in these wards might also have benefitted from the constant consultancy of the infectious disease specialist, whose role in instituting programmes of antimicrobial stewardship is considered fundamental [34]. Additionally, the positive impact that the usefulness of very high loading doses of teicoplanin in patients with acute leukaemia may have had on haematologists’ habits reported in a recent collaborative study should not be overlooked [22]. Acute leukaemic patients may, in fact, present several pathophysiological and/or iatrogenic conditions that may enlarge the volume of distribution of hydrophilic antibiotics such as teicoplanin [13]. TDM performed within the first 48 h of therapy highlighted that optimal exposure to teicoplanin was rapidly ensured in most of the patients receiving appropriate loading doses. This might improve the prognosis of severe multidrugresistant Gram-positive infections, as early adequate antibiotic therapy was shown to affect the infection mortality rate in critically ill patients [35,36]. Although most of these studies primarily refer to choice of agent relative to the susceptibility of pathogens [2,37–39], a recent prospective study carried out in febrile, infected surgical ICU patients suggested that in the setting of appropriate antibiotic choice for an isolate, prompt initial administration of antibiotics may be crucial for survival [10]. Optimal exposure to teicoplanin throughout the whole therapeutic period was effectively ensured in most cases owing to the application of active TDM in each single patient. Indeed, optimisation of antibiotic exposure on the basis of pharmacokinetic/pharmacodynamic principles is currently considered very helpful both in improving therapeutic efficacy and in preventing the emergence of resistant pathogens
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[40]. However, although fundamental, this goal could be very difficult to achieve in critically ill patients without the support of active TDM, considering that many pathophysiological and/or iatrogenic conditions may be responsible for the altered disposition and large pharmacokinetic variability of antibiotics in this setting [13]. Thus, active TDM for individualisation of antimicrobial therapy in critically ill patients is currently advocated and recommended by several authors [13,35]. Interestingly, the finding of an almost direct linear relationship between the number of per-patient TDM samples and the length of therapy with teicoplanin appears to confirm that clinicians consider active TDM a useful tool in improving the quality of management of antimicrobial therapy. In conclusion, our findings suggest that continuous application of a multifactorial educational programme was efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin. Additionally, they confirm the usefulness of a multidisciplinary antimicrobial treatment team in helping the intensive care specialists and other specialists in the management both of per-ward and per-patient antibiotic policy. Of note, daily co-operation of the clinical pharmacologist with the infectious disease specialist and the clinical microbiologist, either by streamlining antimicrobial therapy or by being a cultural reference, may represent valuable support in improving antibiotic policies.
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The effect of multifactorial, multidisciplinary educational interventions on appropriate use of teicoplanin Federico Pea a,∗ , Pierluigi Viale b , Federica Pavan a , Marcello Tavio b , Donatella Poz a , Anna Beltrame b , Mario Furlanut a a
b
Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, P.le S. Maria della Misericordia 3, 33100 Udine, Italy Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine, Udine, Italy Received 29 September 2005; accepted 21 November 2005
Abstract The aim of this study was to determine the effect of multifactorial, multidisciplinary educational interventions over a 3-year period on the appropriate use of teicoplanin. Teicoplanin was considered a valid surrogate marker of good antibiotic use in clinical practice owing to its peculiar pharmacokinetics (i.e. necessity for an initial loading dose regardless of the patient’s renal function for early achievement of optimal exposure, namely Cmin ≥ 10 mg/L) and to the opportunity of comparing current routine therapeutic drug monitoring (TDM) results with those of a historical retrospective study. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study, both when considered as a whole (66.6% versus 38.6%, respectively; P < 0.001) or when stratified according to the degree of estimated renal function (78.4% versus 60.4% for creatinine clearance (CLCr ) >50 mL/min; 59.8% versus 26.8% for CLCr 20–50 mL/min; and 27.7% versus 5.5% for CLCr <20 mL/min). The highest adherence was observed in haematological wards (97.7%). The percentages of patients with teicoplanin Cmin ≥ 10 mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. Our findings suggest that continuous application of a multifactorial educational programme including active TDM may be efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin. © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Teicoplanin; Therapeutic drug monitoring; Loading dose; Antibiotic policy; Education
1. Introduction Infections due to multidrug-resistant pathogens frequently represent a major threat for severely ill hospitalised patients [1]. In recent years, several authors documented that the probability of survival in critically ill patients with infections may be significantly decreased in cases of inadequate empirical therapy [2,3]. Considering that Gram-positive cocci, particularly Staphylococcus spp. and Enterococcus spp., are among the most frequent hospital-acquired infection isolates in Intensive Care Unit (ICU) patients [4–6], often with a high incidence of multiresistance [7], antimicrobial regi∗
Corresponding author. Tel.: +39 0432 559 833; fax: +39 0432 559 833. E-mail address: [email protected] (F. Pea).
mens comprising adequate coverage against Gram-positive pathogens should be frequently considered. Glycopeptides, either vancomycin or teicoplanin, are still considered effective weapons for the treatment of documented or suspected hospital-acquired life-threatening multiresistant Gram-positive bacterial infections [8,9]. Interestingly, it has recently been demonstrated that in the setting of appropriate antibiotic choice, the role of prompt initial administration of antibiotics may be crucial for survival [10]. To ensure rapid therapeutically effective concentrations of teicoplanin, appropriate loading doses at the commencement of therapy, regardless of the patient’s renal function, must be considered the first mandatory step owing to the high risk of underexposure related to its very long elimination half-
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life [11]. Subsequently, therapeutic drug monitoring (TDM) may be helpful in optimising antibiotic exposure in critically ill patients, as in this setting drug levels of antibiotics after administration of standard fixed dosages may often be unpredictable [12,13]. In a previous study retrospectively analysing the results from routine TDM of teicoplanin performed over a 7-year period at our hospital, we observed that within the first 4 days of therapy, appropriate loading doses (i.e. 400 mg every 12 h at least three times) were administered to only ca. onethird of patients (78 of 202). Interestingly, the percentage of patients receiving an appropriate loading was inversely correlated with their degree of renal function, decreasing from 60.4% in the case of normal renal function to 26.8% and 5.5% in cases of moderately or totally impaired renal function, respectively. The resulting suboptimal concentrations (<10 mg/L) still presented by most of these patients at Day 4 of treatment could have negatively affected the outcome of teicoplanin therapy [14]. On the basis of these findings, we planned a prospective study aimed at assessing the possible improvement in adequate clinical use of this glycopeptide within an implemented multidisciplinary, multifactorial, educational programme for optimal antibiotic use.
2. Patients and methods The objective of this study was to determine the effect of an interventional programme in improving the percentage of patients receiving appropriate pharmacodynamic exposure to antibiotics, using teicoplanin as a surrogate marker of good antibiotic use in clinical practice. Teicoplanin was considered suitable for this purpose owing to its peculiar pharmacokinetics and to the opportunity of comparing routine TDM results of the present prospective study with the historical results from a retrospective study [11]. 2.1. Interventional programme An antimicrobial treatment committee, which comprised infectious disease specialists, clinical pharmacologists, microbiologists and hospital epidemiologists, planned a sequential and multifactorial interventional programme on antibiotic policy at Udine University Hospital that started in April 2002. The programme was focused on various aspects, including: (1) a hospital-wide educational programme to be repeated twice per year regarding principles of good antimicrobial use; (2) semi-annual collegial discussion of microbiological reports on the incidence of different isolates and of their main resistance patterns; (3) hospitalwide daily active consultation of the infectious disease specialists; (4) optimisation over time of antimicrobial exposure in each single patient by means of real-time TDMguided adjustment of antibiotic dosage (defined as ‘active TDM’) carried out by the clinical pharmacologists; and (5)
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planning and implementation of collaborative clinical pharmacokinetic studies involving various field professionals aimed at optimising antimicrobial exposure in critically ill patients. 2.2. TDM of teicoplanin Blood samples for TDM of teicoplanin trough plasma concentrations (Cmin ) were collected immediately before the morning drug administration. After centrifugation at 3000 rpm for 10 min, plasma samples were analysed within 2 h by means of a fluorescence polarisation immunoassay (Opus Diagnostics, Fort Lee, NJ) using a TDx analyser (TDx, Abbott, Rome, Italy) [15,16]. The interday and intraday coefficients of variation of the assay were less than 10%. TDM of teicoplanin Cmin was not performed on each of the days of therapy, but the frequency depended both on the length of therapy and the patient’s pathophysiological status. 2.3. Markers of good teicoplanin use In recent years, TDM of teicoplanin has been increasingly highlighted as important [17–20]. Although it is generally accepted that Cmin > 10 mg/L may be appropriate for the standard of care, on the other hand Cmin > 20 mg/L is currently recommended for some severe settings, for example teicoplanin monotherapy [21], especially in immunocompromised hosts [22] and/or for the treatment of Staphylococcus aureus endocarditis and bone or prosthetic infections [18,19,23,24]. Noteworthy, in a retrospective study, favourable clinical outcome of S. aureus-related deep infections treated with teicoplanin was associated with pre-dose concentrations >20 mg/L [20,25]. Thus, at our institution appropriate teicoplanin use is considered as: (1) an initial loading dose of at least 6 mg/kg every 12 h for three doses regardless of renal function, with the intent of early achievement of Cmin > 10 mg/L; and (2) a variable maintenance dose aimed at maintaining Cmin at 10–30 mg/L, consistent both with in vitro susceptibility of the clinical isolate and with clinical requirements, and adjusted at least every 3–5 days on the basis of the patient’s renal function and serial TDM results. To take into account the eventual influence of differences in ward of admission on appropriate loading, patients were split into different groups according to their admission to medical wards, surgical wards, ICUs and haematological wards. To stratify patients by renal function, serum creatinine concentrations were determined at the same time as each TDM was performed and creatinine clearance (CLCr ) was then estimated on the basis of the Cockcroft and Gault formula [26]. Patients were considered to have normal renal function when CLCr was >50 mL/min, moderately impaired renal function when CLCr was 20–50 mL/min and total renal failure when CLCr was <20 mL/min.
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Table 1 Patient characteristics and treatments
Number (n, %) Gender (M/F) Age (years)a Body weight (kg)a Albuminaemia (g/dL)a Patients with normal renal function (n, %) Patients with moderately impaired renal function (n, %) Patients with totally impaired renal function (n, %) Days with teicoplanin therapyb Total TDM samples Number of TDM samples per patientb
Total patients
Medical wards
Surgical wards
ICUs
Haematological wards
605 370/235 61 ± 16 73 ± 16 3.03 ± 1.37 384 (63.5) 127 (21.0) 94 (15.5) 8 (3–107) 2697 4 (1–22)
182 (30.1) 101/81 66 ± 16 70 ± 14 3.08 ± 0.84 74 (40.7) 50 (27.5) 58 (31.9) 10 (3–107) 842 4 (1–21)
163 (26.9) 112/51 62 ± 15 73 ± 15 2.93 ± 0.68 121 (74.2) 27 (16.6) 15 (9.2) 11 (3–96) 808 4 (1–22)
131 (21.7) 94/37 63 ± 14 80 ± 18 2.60 ± 2.40 63 (48.1) 47 (35.9) 21 (16.0) 8 (3–74) 581 4 (1–12)
129 (21.3) 63/66 50 ± 14 70 ± 14 3.40 ± 0.50 126 (97.7) 3 (2.3) 0 (0.0) 6 (3–44) 466 3 (1–13)
ICUs, Intensive Care Units; TDM, therapeutic drug monitoring. a Data are expressed as mean ± standard deviation. b Data are expressed as median and range.
2.4. Statistical analysis Descriptive data were expressed as mean ± standard deviation (S.D.) or median and range depending on whether the data distribution was normal or non-normal, respectively. Statistical analysis comparing TDM data between different groups was performed using a parametric (paired or unpaired Student’s t-test, as appropriate) or a non-parametric (Mann–Whitney rank sum test) test for normally or nonnormally distributed data, respectively, using SigmaStat software (Systat Software Inc., Point Richmond, CA). Z-test and χ2 test were used for statistical comparison of percentages between two or more groups, respectively. A value of P < 0.05 was considered statistically significant.
3. Results Between July 2002 and June 2005, 605 patients undergoing teicoplanin TDM were prospectively included in this
study. The characteristics of the patients are shown in Table 1. Patients were almost equally distributed between medical wards, surgical wards, ICUs and haematological wards. The total number of teicoplanin TDM samples assayed was 2697 and the per-patient median number ranged between 3 and 4, with the maximum number varying according to the length of therapy. Comparison of patients receiving appropriate loading doses at the commencement of therapy, either as a whole and according to the degree of renal function, between the present study and the pre-interventional retrospective study are reported in Table 2. The trend over time of appropriate loading dose in the current study is reported in Table 3. The overall percentage of patients receiving appropriate loading doses in the present prospective study compared with the retrospective study was 66.6% versus 38.6%, respectively (P < 0.001). The proportion of patients receiving appropriate loading doses in the present study taking into account ward of admission is described in Table 4. The highest adherence was observed in haematological wards (97.7%).
Table 2 Patients receiving appropriate loading doses of teicoplanin Patient group
Present study
Retrospective study [11]
P (Z-test)
Whole group
403/605 (66.6%)
78/202 (38.6%)
<0.001
Stratified by renal function Normal Moderately impaired Totally impaired
301/384 (78.4%) 76/127 (59.8%) 26/94 (27.7%)
64/106 (60.4%) 11/41 (26.8%) 3/55 (5.5%)
0.004 <0.001 <0.001
Table 3 Trend over time of appropriate loading doses of teicoplanin in the 3-year period July 2002 to June 2005 Patient group
1st half year (July 2002–December 2002)
2nd half year (Jan 2003–June 2003)
2nd year (July 2003–June 2004)
3rd year (July 2004–June 2005)
Whole group
19/42 (45.2%)
80/124 (64.5%)
127/197 (64.5%)
177/242 (73.1%)
Stratified by renal function Normal Moderately impaired Totally impaired
14/17 (82.4%) 4/12 (33.3%) 1/13 (7.7%)
66/86 (76.7%%) 12/25 (48.0%) 2/13 (15.4%)
87/118 (73.7) 23/39 (59.0%) 17/40 (42.5%)
134/163 (82.2%) 37/51 (72.5%) 6/28 (21.4%)
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Table 4 Patients receiving appropriate loading doses of teicoplanin in relation to different hospital ward of admission Patient group
Medical wards
Surgical wards
ICUs
Haematological wards
Whole group
84/182 (46.2%)
101/163 (62.0%)
92/131 (70.2%)
126/129 (97.7%)
Stratified by renal function Normal Moderately impaired Totally impaired
53/74 (71.6%) 23/50 (46.0%) 8/58 (13.8%)
77/121 (63.6%) 17/27 (63.0%) 7/15 (46.7%)
48/63 (76.2%) 33/47 (70.2%) 11/21 (52.4%)
123/126 (97.6%) 3/3 (100%) 0/0
ICUs, Intensive Care Units.
With regard to patients receiving appropriate loading doses and undergoing TDM in the first 48 h of therapy (Fig. 1), those who received a loading dose (average of 5.53 mg/kg every 12 h for at least three doses) had significantly higher Cmin concentrations than those who did not receive a loading dose (average of 5.55 mg/kg/daily). The mean Cmin concentrations of teicoplanin in those patients who received a loading dose compared with those that did not were: 7.84 mg/L versus 4.40 mg/L on Day 1 (P < 0.001) and 12.19 mg/L versus 6.58 mg/L on Day 2 (P < 0.001). The trend over time of teicoplanin concentrations for the 605 patients in the current study compared with those for the 202 patients in the retrospective study are shown in Fig. 2. The time needed to achieve an average teicoplanin Cmin higher than 10 mg/L was 2 days in the current study compared with 5 days in the retrospective study. The percentages of patients with teicoplanin Cmin ≥ 10 mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. The profiles of teicoplanin Cmin over time stratified according to degree of renal function in the present study are shown in Fig. 3. The mean (± S.D.) daily maintenance dose needed to ensure comparable average Cmin from Day 5
Fig. 2. Comparison of mean (± standard deviation) trough plasma levels of teicoplanin (Cmin ) over time in critically ill patients between the current study and the retrospective study [11]. Dotted lines refer to the minimum (10 mg/L) and optimal (20 mg/L) concentrations recommended in serious infection.
onwards in patients with normal, or moderately or totally impaired renal function (mean Cmin ± S.D., 20.97 ± 6.99, 22.95 ± 7.72 and 20.71 ± 7.87 mg/L, respectively) was of 8.30 ± 3.30, 5.52 ± 2.78 and 4.45 ± 2.54 mg/kg, respectively.
4. Discussion
Fig. 1. Mean (± standard deviation) trough plasma levels of teicoplanin (Cmin ) during the first 2 days of therapy in patients receiving an appropriate loading dose compared with those not receiving an appropriate loading dose. Dotted line is the minimum concentration recommended in serious infection (10 mg/L).
Several authors have documented the positive impact that different types of educational programmes may have on antibiotic policy [27–33]. Consistent with this, our findings suggest that the multifactorial, multidisciplinary educational interventions were helpful in improving the appropriate use of teicoplanin. We believe that teicoplanin may be considered a valid surrogate marker for the assessment of proper antibiotic use in our hospital setting for several reasons. First, its very long elimination half-life renders the administration of loading doses at the commencement of therapy mandatory with the intent of rapidly achieving therapeutically effective concentrations. Second, loading must always be applied, even in patients with impaired renal function, considering its dependence only on volume of distribution and not on renal clearance. Third, the application of routine TDM
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Fig. 3. Mean (± standard deviation) trough plasma levels (Cmin ) and daily dose (mg/kg) of teicoplanin in critically ill patients stratified according to (A) normal (creatinine clearance (CLCr ) > 50 mL/min), (B) moderately impaired (CLCr of 20–50 mL/min) or (C) totally impaired (CLCr < 20 mL/min) renal function. Dotted lines refer to the minimum (10 mg/L) and optimal (20 mg/L) concentrations recommended in serious infection.
represents an effective way of obtaining a clear feedback for discriminating between proper and improper use. Fourth, the availability of a historical database previously used for a retrospective study [11] makes a post hoc assessment possible. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study [11], both when considered as a whole or when stratified according to
the degree of estimated renal function, with a consistently less marked inverse trend between adherence to appropriate loading and degree of renal function. Indeed, considering that the patients included in this prospective study presented similar baseline characteristics and distribution in terms of ward of admission to those included in the historical analysis, this is a very interesting finding, suggesting that clinicians progressively became more confident with this pharmacokinetic concept, even in the presence of renal failure, and that this positive approach was maintained over time in the subsequent 3 years. However, these overall positive results could be further improved considering that a significant between-ward difference in the frequency of proper loading was observed. Very high adherence to proper loading was documented especially in the ICUs and haematological wards. Interestingly, in the latter, in contrast to the medical wards, the appropriateness of loading seemed only marginally influenced by the patient’s degree of renal function. This could be related to the fact that intensive care specialists and haematologists probably perceive their patients as being at the highest risk of lifethreatening multidrug-resistant bacterial infections, therefore they are particularly careful not only at choosing the appropriate antimicrobial but also at applying the correct dosing regimen. Appropriate management of antibiotic use in these wards might also have benefitted from the constant consultancy of the infectious disease specialist, whose role in instituting programmes of antimicrobial stewardship is considered fundamental [34]. Additionally, the positive impact that the usefulness of very high loading doses of teicoplanin in patients with acute leukaemia may have had on haematologists’ habits reported in a recent collaborative study should not be overlooked [22]. Acute leukaemic patients may, in fact, present several pathophysiological and/or iatrogenic conditions that may enlarge the volume of distribution of hydrophilic antibiotics such as teicoplanin [13]. TDM performed within the first 48 h of therapy highlighted that optimal exposure to teicoplanin was rapidly ensured in most of the patients receiving appropriate loading doses. This might improve the prognosis of severe multidrugresistant Gram-positive infections, as early adequate antibiotic therapy was shown to affect the infection mortality rate in critically ill patients [35,36]. Although most of these studies primarily refer to choice of agent relative to the susceptibility of pathogens [2,37–39], a recent prospective study carried out in febrile, infected surgical ICU patients suggested that in the setting of appropriate antibiotic choice for an isolate, prompt initial administration of antibiotics may be crucial for survival [10]. Optimal exposure to teicoplanin throughout the whole therapeutic period was effectively ensured in most cases owing to the application of active TDM in each single patient. Indeed, optimisation of antibiotic exposure on the basis of pharmacokinetic/pharmacodynamic principles is currently considered very helpful both in improving therapeutic efficacy and in preventing the emergence of resistant pathogens
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[40]. However, although fundamental, this goal could be very difficult to achieve in critically ill patients without the support of active TDM, considering that many pathophysiological and/or iatrogenic conditions may be responsible for the altered disposition and large pharmacokinetic variability of antibiotics in this setting [13]. Thus, active TDM for individualisation of antimicrobial therapy in critically ill patients is currently advocated and recommended by several authors [13,35]. Interestingly, the finding of an almost direct linear relationship between the number of per-patient TDM samples and the length of therapy with teicoplanin appears to confirm that clinicians consider active TDM a useful tool in improving the quality of management of antimicrobial therapy. In conclusion, our findings suggest that continuous application of a multifactorial educational programme was efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin. Additionally, they confirm the usefulness of a multidisciplinary antimicrobial treatment team in helping the intensive care specialists and other specialists in the management both of per-ward and per-patient antibiotic policy. Of note, daily co-operation of the clinical pharmacologist with the infectious disease specialist and the clinical microbiologist, either by streamlining antimicrobial therapy or by being a cultural reference, may represent valuable support in improving antibiotic policies.
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