Proper use of antibiotics: situation of linezolid at the intensive care unit of the Tunisian Military Hospital

Linezolid was introduced in clinical practice in the early 2000s. It was considered to be an ideal reserve drug for treatment of vancomycin-resistant Enterococcus spp. (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA). The aim of our study was to describe and evaluate the use of linezolid in clinical practice at the intensive care unit (ICU) of the Tunisian military hospital. This is a thirty-month retrospective study including patients treated with linezolid at the ICU of the Tunisian military hospital. Data collection was realized using the patients’ medical files and prescriptions. A pharmacist conducted an extended medication history and checked if an advice from an infectious disease-physician and a microbiological documentation were requested. A total of 80 patients were included. Forty-one per cent of indications were outside the Marketing Authorization (MA) criteria, and were mainly sepsis and postoperative mediastinitis (32% and 4% of total prescriptions, respectively). This antibiotic was used as a first-line therapy in 58% of cases. The advice from an infectious-disease physician was requested for 33% of prescriptions. Only 20% of infections were documented microbiologically, of which 35% were caused by methicillin resistant coagulase-negative Staphylococcus. Linezolid is an interesting therapeutic alternative in case of infections due to multi-resistant bacteria and/or complex clinical situations. Therefore, its prescription must be rationalized in order to slow down the emergence of resistance to this antibiotic. The high frequency of its use outside the MA criteria shows the importance of carrying out more clinical trials to evaluate its effectiveness and safety for new indications.


Introduction
Linezolid is a synthetic oxazolidinone. It is an antimicrobial agent that has good activity against most medically important Grampositive microorganisms resistant to methicillin and vancomycin. The Marketing Authorization (MA) allows linezolid for skin and soft tissue infections in addition to nosocomial and community-acquired pneumonia caused by sensitive Gram-positive bacteria. Given the need to evaluate antibiotics use and clinical practices, the prescription of linezolid at the Tunisian military hospital, one of the largest Tunisian hospitals, was investigated. The aims of our study were to judge the degree of conformity of linezolid prescriptions with the MA criteria, to evaluate the circumstances when this antibiotic was used and to specify its place in therapeutic strategy.

Methods
It is a thirty-month retrospective study (from January 1 st , 2013 to June 30th 2015). It was carried out in the intensive care unit (ICU) of the Tunisian military hospital. This is a 622-bed hospital.
Although the intensive care unit contains only 20 beds (3%), it has been found that it is the biggest consumer of linezolid. During the study's period, this unit consumed 81% of linezolid pockets (1409 among 1742 pockets). Treatment with linezolid in this period was the only inclusion criterion. There were no exclusion criteria. Data were collected using the patients' medical files in addition to registered prescriptions collected by the pharmacy's software. These data were about: demographic profile, indications for linezolid prescription, antibiotic therapeutic strategy, duration of treatment, advice from an infectious-disease physician and microbiological documentation of prescriptions. Statistical analysis was performed using Microsoft Excel 2007 software.

Results
The total number of patients included in this work was 80. The majority of them were men (sex-ratio (M/F) = 2.5). Mean age was 60 (range 19-87). The indications for linezolid are summarized in Table 1. Forty-one per cent of prescriptions were outside the MA criteria, and were mainly sepsis and postoperative mediastinitis (32% and 4% of total prescriptions, respectively). Linezolid therapy was prescribed as a first-line treatment in 46 cases (58%). It was used as second-line (42%) after the prescription of glycopeptides in 15% of cases only. This antibiotic was prescribed as a monotherapy (45%) or in association with another antibiotic (55%), including 20 bitherapies (45%) and 24 multitherapies (55%

Discussion
The Another study has shown that linezolid has superiority over vancomycin for this indication [3]. So, we conclude that the optimal treatment of nosocomial pneumonia caused by Gram-positive bacteria remains controversial. Linezolid turned out to be more effective than glycopeptides for the treatment of complicated skin This molecule can be administered per os. It has almost the same side effects as linezolid and a less potential for drug interactions [6].
In our study, 41% of prescriptions were outside the MA criteria, but 97% of these were justified with regard to current data from literature [7][8][9][10][11][12][13][14][15]. Sepsis microbiologically documented to be caused by Gram-positive bacteria (5/26) are mainly due to two germs: Staphylococcus aureus and coagulase-negative Staphylococcus (3 and 2 cases respectively). According to a multicenter epidemiological study conducted in the United States, it has been shown that these germs are the most implicated in nosocomial septicemia (20% and 31% of isolates, respectively) [16]. It should be noted that linezolid was used as a second-line therapy for the treatment of sepsis. In fact, this antimicrobial agent and vancomycin have almost the same effectiveness against Staphylococcus genus [7,8]. Moreover, the resistance of this genus to vancomycin is currently less described compared to Enterococcus genus which has an increasingly diminished sensitivity to vancomycin, daptomycin and even linezolid [9][10][11][12]. Mediastinitis is a common complication of cardiovascular surgeries. This infection can be caused by MRSA and is associated with high morbidity and mortality [17]. Tsuji et al showed that linezolid's concentration in the mediastinum and pleural space varies as in the serum and that the concentration in the mediastinum is the same as or greater than that in the serum [13].
Thus, linezolid is an interesting therapeutic alternative in mediastinitis due to MRSA.
In meningitis and endocarditis, this antibiotic was used as a bacteriostatic agent [14,15].  [19,20]. Given the lack of robust clinical studies that advocate the prescription of linezolid in these two indications, it should be used with caution in cases where another therapeutic alternative is not available.
One patient was treated with linezolid for an indication which is not The advice from an infectious-disease physician was requested for 33% of prescriptions versus 65% in the study of Aubin and al [18].
It should be noted that these cases (26) correspond to linezolid prescriptions received during the first six months of 2015. This is the period from which the Tunisian military hospital started using the validated prescriptions. These prescriptions require approval by an infectious-disease physician selected from a predetermined list in order to provide the antibiotic. Applied in Europe for more than five years, the program ´Antimicrobial stewardship´ has just started to be applied at the Tunisian military hospital [25]. This hospital is the first to apply this strategy in Tunisia. According to the results of a recent international study, only 13% of African countries are implementing this program versus 65% in Europe [26]. This is due mainly to a lack of funding and qualified staff (29% of cases).
Finally, we should mention that this study has limitations. The most important is its retrospective nature. Some data were not found in

Competing interests
The authors declare no competing interests.

Authors' contributions
All authors have read and agreed to the final version of this manuscript and have equally contributed to its content.