Participants
Sixty-four participants completed the survey, of which 14 (22%) were from academic hospitals, 25 (39%) from general hospitals, and 25 (39%) from teaching hospitals (Table 1). The median duration of professional work experience was 10 years (range 1–35). Most participants were hospital pharmacists (n = 38, 59%) or medical specialists (n = 15, 23%). The department of the participants was most frequently the hospital pharmacy (n = 45), followed by intensive care (n = 10) and microbiology and infectious diseases (n = 9).
Table 1
Characteristics of the participants
Department | Intensive Care (n = 10) | MMB and infect dis (n = 9) | Hospital Pharm. (n = 45) | Total (n = 64) |
Age (year) | | | | |
26–35 | 1 (10%) | 0 (0%) | 17 (37.8%) | 18 (28.1%) |
36–45 | 3 (30%) | 6 (66.7%) | 15 (33.3%) | 24 (37.5%) |
46–55 | 4 (40%) | 3 (33.3%) | 10 (22.2%) | 17 (26.6%) |
> 55 | 2 (20%) | 0 (0%) | 3 (6.7%) | 5 (7.8%) |
Hospital beds | | | | |
301–500 | 2 (20%) | 1 (11.1%) | 10 (22.2%) | 13 (20.3%) |
501–700 | 3 (30%) | 2 (22.2%) | 9 (20.0%) | 14 (21.9%) |
> 900 | 2 (20%) | 2 (22.2%) | 8 (17.8%) | 12 (18.8%) |
Missing | 3 (30%) | 4 (44.4%) | 18 (40.0%) | 25 (39.1%) |
ICU beds | | | | |
9–16 | 4 (40%) | 3 (33.3%) | 16 (35.6%) | 23 (35.9%) |
17–23 | 2 (20%) | 0 (0%) | 8 (17.8%) | 10 (15.6%) |
24–30 | 1 (10%) | 2 (22.2%) | 4 (8.9%) | 7 (10.9%) |
> 30 | 1 (10%) | 2 (22.2%) | 7 (15.6%) | 10 (15.6%) |
Missing | 2 (20%) | 2 (22.2%) | 10 (22.2%) | 14 (21.9%) |
Type of Hospital | | | | |
Academic | 2 (20%) | 4 (44.4%) | 8 (17.8%) | 14 (21.9%) |
General | 4 (40%) | 3 (33.3%) | 18 (40.0%) | 25 (39.1%) |
Teaching | 4 (40%) | 2 (22.2%) | 19 (42.2%) | 25 (39.1%) |
Profession | | | | |
Physician-assistant | 1 (10%) | 0 (0%) | 0 (0%) | 1 (1.6%) |
Resident | 0 (0%) | 0 (0%) | 5 (11.1%) | 5 (7.8%) |
Physician-microbiologist | 0 (0%) | 5 (55.6%) | 0 (0%) | 5 (7.8%) |
Medical Specialist | 8 (80%) | 4 (44.4%) | 3 (6.7%) | 15 (23.4%) |
Hospital Pharmacist | 1 (10%) | 0 (0%) | 37 (82.2%) | 38 (59.4%) |
Experience (years) | | | | |
Mean (SD) | 10.7 (8.5) | 9.7 (3.9) | 12 (9.10) | 11.4 (8.42) |
Median [Min, Max] | 10.5 [1, 25] | 10 [5, 15] | 10.0 [1, 35] | 10.0 [1, 35] |
Use of BLA TDM | | | | |
Never | 3 (30%) | 3 (33.3%) | 13 (28.9%) | 19 (29.7%) |
Rare | 2 (20%) | 2 (22.2%) | 16 (35.6%) | 20 (31.2%) |
Sometimes | 3 (30%) | 2 (22.2%) | 9 (20.0%) | 14 (21.9%) |
Regularly | 2 (20%) | 0 (0%) | 3 (6.7%) | 5 (7.8%) |
Often | 0 (0%) | 2 (22.2%) | 4 (8.9%) | 6 (9.4%) |
Use of Ciprofloxacin TDM | | | | |
Never | 6 (60%) | 5 (55.6%) | 32 (71.1%) | 43 (67.2%) |
Rare | 2 (20%) | 3 (33.3%) | 8 (17.8%) | 13 (20.3%) |
Sometimes | 1 (10%) | 0 (0%) | 4 (8.9%) | 5 (7.8%) |
Regularly | 0 (0%) | 1 (11.1%) | 1 (2.2%) | 2 (3.1%) |
Often | 1 (10%) | 0 (0%) | 0 (0%) | 1 (1.6%) |
BLA TDM Experience | | | | |
Beginner | 2 (20.0%) | 2 (22.2%) | 13 (28.9%) | 17 (26.6%) |
Average | 5 (50.0%) | 2 (22.2%) | 13 (28.9%) | 20 (31.2%) |
Advanced | 1 (10.0%) | 4 (44.4%) | 4 (8.9%) | 9 (14.1%) |
Expert | 1 (10.0%) | 0 (0%) | 6 (13.3%) | 7 (10.9%) |
Unknown | 1 (10.0%) | 1 (11.1%) | 9 (20.0%) | 11 (17.2%) |
Ciprofloxacin TDM Experience | | | | |
Beginner | 1 (10%) | 3 (33.3%) | 13 (28.9%) | 17 (26.6%) |
Average | 4 (40%) | 1 (11.1%) | 4 (8.9%) | 9 (14.1%) |
Advanced | 1 (10%) | 3 (33.3%) | 3 (6.7%) | 7 (10.9%) |
Expert | 1 (10%) | 0 (0%) | 4 (8.9%) | 5 (7.8%) |
Unknown | 3 (30%) | 2 (22.2%) | 21 (46.7%) | 26 (40.6%) |
Abbreviations: TDM: therapeutic drug monitoring, BLA: beta-lactam antibiotics, MMB and infect dis: Medical microbiology and infectious diseases, Hospital Pharm: Hospital Pharmacy |
Only 70% ever came into contact with TDM of beta-lactams with 31% of them indicating that this was seldom. With ciprofloxacin only 33% of the participants ever came into contact with TDM, of which 20% only seldom did.
Table 1: Characteristics of the participants
Barriers And Facilitators
For the implementation of beta-lactams TDM, 11 barriers and 4 facilitators were identified. For the implementation of ciprofloxacin TDM, 17 barriers and no facilitators were found. All beta-lactams barriers were also ciprofloxacin barriers. Table 2 describes all identified barriers and facilitators, and is a summary of all the questions described in supplementary table 1.
Table 2
Identified barriers and facilitators influencing the implementation of therapeutic drug monitoring for ICU patients (n = 64)
Factors | Barriers (question number) | Beta-lactams (%) | Ciprofloxacin (%) |
Procedure | Completeness of materials (3) | 39 | 47 |
| Knowledge (10/9) | 28/23* | 36/30* |
| Procedural clarity (1) | | 28 |
| Experience with TDM (45) | | 27 |
| Observability of outcomes (6) | | 20 |
Beliefs | Outcome expectations: TDM saves costs (20/44) | 36/20* | 38/22* |
| Personal benefits: TDM increases my workload (23) | 30 | 25 |
| Normative beliefs (15) | | 25 |
| Importance outcome expectations: TDM shortens ICU length of stay (29) | | 20 |
Organization | Formal ratification by management (30) | 55 | 72 |
| Unsettled organization (32) | 36 | 39 |
| Assigned coordinator (31) | 28 | 39 |
Literature | Evidence of effectiveness (41) | 53 | 58 |
| Evidence of cost-effectiveness (42) | 31 | 30 |
| Facilitators (question number) | | |
Procedure | Importance outcome expectations: TDM treats infection (18) | 92 | |
Beliefs | Professional obligation (12) | 84 | |
| Low complexity (4) | 81 | |
| Importance outcome expectations: TDM prevents side effects (19) | 81 | |
Data expressed as percentages representing the fraction of respondents that indicated that that the statement was a barrier or facilitator. The results of all questions are found in supplementary table 1. |
TDM, therapeutic drug monitoring; ICU, intensive care unit |
*Multiple questions addressed the same barrier |
Barriers
Multiple barriers were identified for the implementation of TDM of beta-lactams and ciprofloxacin in critically ill patients (Table 2). A substantial proportion of the participants indicated that they did not have all the information and materials to apply TDM for these antibiotics (39% beta-lactams, 47% ciprofloxacin). From the perspective of the participants, they explained that they did not have enough practical experience (28% beta-lactams, 36% ciprofloxacin) or, to a lesser degree, the required knowledge (23% beta-lactams, 30% ciprofloxacin). The respondents believed that TDM would not result in cost reduction (36% beta-lactams, 38% ciprofloxacin), would not be cost-effective (20% beta-lactams, 22% ciprofloxacin), and would increase their workload (30% beta-lactams, 25% ciprofloxacin). Furthermore, they indicated that lack of clear evidence of effectiveness (53% beta-lactams, 58% ciprofloxacin) and cost-effectiveness (31% beta-lactams, 30% ciprofloxacin) prohibits implementation. From the organization perspective, they further replied that there are mainly no formal agreements made by management (55% beta-lactams, 72% ciprofloxacin) followed by other factors in the organization preventing implementation (36% beta-lactams, 39% ciprofloxacin). A smaller number responded that there is no coordinator for the implementation of TDM for these antibiotics (28% beta-lactams, 39% ciprofloxacin).
More barriers were identified for ciprofloxacin TDM implementation: the responders found that the procedural clearness of TDM is unclear and that the procedures are unclear (both 28%) They also indicated that they felt hindered by little experience (27%). Furthermore, they responded that colleagues do not expect them to use TDM (25%), indicated that the outcome of TDM is not visible, and did not expect that it shortens ICU length of stay (both 20%).
Facilitators
The facilitators identified for implementation of beta-lactams TDM were that TDM is not complex to carry out (81%), that they perceived TDM to be one of their tasks (84%), that they believed that beta-lactams TDM prevent side-effects (81%), and that it improves treatment of infections (91%) (Table 2). There were no facilitators identified for implementation of ciprofloxacin TDM.
Eight respondents (13%) indicated that the COVID-19 pandemic increased the requests for beta-lactams TDM, whereas six respondents (9%) claimed that this increased for ciprofloxacin. Additionally, some responders (n = 9; 14%) indicated that the implementation of beta-lactams TDM was hampered by the COVID-19 pandemic, whereas 11% (n = 7) argued that this was a case for ciprofloxacin.
Qualitative Analysis
We also asked responders what they consider the greatest benefit and the main disadvantage of TDM of beta-lactams and ciprofloxacin combined. The most often mentioned disadvantages were ’the low availability of assays’ and ‘the absence of convincing evidence’ (both: n = 14; 21%). The greatest benefit was ‘the possible increased effectivity’(n = 29; 45%). The availability of assays, the costs and the complexity of sending blood samples to other laboratories were mostly named as the most important barriers for implementation. Eleven participants (17%) responded that patients with enhanced or diminished renal clearance should be considered for TDM. Eleven responded that all ICU patients should be considered, five participants indicated patients with overweight or underweight and four noted that it should be considered based on the micro-organism.
Availability Of Analysis
Around 28% of the participants reported that flucloxacillin could be analyzed for TDM purposes in their hospital (Fig. 1). Ceftazidime with 17% and meropenem with 16% followed closely. Ciprofloxacin was available in 14% of all hospitals. Cefotaxime was the least available of the beta-lactams with only 8% availability. None of the assays were available in general hospitals, except for flucloxacillin. In academic hospitals, the availability of assays was much more prevalent, with 41% availability compared to 6% in other hospitals.
Figure 1: Availability of therapeutic drug monitoring of beta-lactams and ciprofloxacin.
Pharmacodynamic Targets (Pdt)
Of all the participants, 21 answered possible PDT’s (Table 3). There was a great amount of variability in the answers for both beta-lactams and ciprofloxacin. For dosing TDM of beta-lactams 43% of the respondents indicate that 100% (f)T > 4xMIC should be achieved, compared to 38% that indicated that 100% (f)T > MIC should be targeted.
For ciprofloxacin, 57% indicated that they did not know what target to achieve. Of the responses, 29% answered that the target of AUC/MIC > 120 should be targeted, while 14% preferred to target fAUC/MIC > 100.
Table 3
Reported pharmacodynamic targets for therapeutic drug monitoring of beta-lactams and ciprofloxacin in ICU patients (n = 21)
Beta-lactams | |
50% (f)T > MIC | 14% |
100% (f)T > MIC | 38% |
100% (f)T > 4xMIC | 43% |
100% (f)T > MIC ECOFF | 10% |
Do not know | 24% |
Ciprofloxacin | |
AUC/MIC > 120 | 29% |
(f)AUC/MIC > 100 | 14% |
(f)AUC/MIC > 90 | 5% |
Cmax/MIC > 10 | 10% |
fCmax/MIC > 8 | 5% |
Do not know | 57% |
AUC, Area under the curve; (f), free fraction; T, time; MIC, Minimal inhibitory concentration, ECOFF, EUCAST epidemiological cut-off values; Cmax, Maximum concentration |