The present study illustrates a rapid and worrying increase in linezolid prescriptions in a tertiary NICU over the past decade. The retrospective analysis of the 66 linezolid prescriptions in this NICU revealed that one third of these prescriptions were considered as inadequate.
Thanks to its wide bacterial spectrum, including Gram-positive bacteria and its excellent bioavailability, linezolid emerged in the early 2000s as a good alternative to vancomycin. In the specific population of neonates, literature data dealing with linezolid pharmacology, safety, effectiveness and tolerance in neonates is exponential thus demonstrating its growing importance (6, 8, 9, 13). In the study NICU, the first use of this drug was reported in 2014 and then increased yearly, raising our concern and leading to this work. Such increase has already been reported by other teams. For example, Buccelatto et al reported on a 3-fold increase in linezolid prescriptions from 2004 to 2011 in hospitalized children (10) while Bagga et al described a 5-fold increase in linezolid use between 2007 and 2014 in an American children’s hospital (11).
The reasons of this rapid increase are not totally understood. The hypothesis of Buccelatto et al was that it was due to an increase in glycopeptide heteroresistant or resistant staphylococci (10). Indeed, the presence of a decreased susceptibility to vancomycin is an emerging issue in CoNS strains involved in neonatal sepsis (14, 15) and linezolid has been reported as an efficient alternative in those situations(9). However, in our study only 2 strains harbored a documented resistance to vancomycin and no significant change in the bacterial epidemiology was noted during the study period so this hypothesis is not sufficient to explain the increase in linezolid prescriptions. Another situation in which linezolid was adequately prescribed in our study along with other ones is the need to obtain a correct pulmonary diffusion, for example in case of methicillin-resistant CoNS or S. aureus-related pneumonia (16). Of note, this situation concerned 14 cases (21%) in our cohort. Additional reasons to prescribe linezolid that are brought forth by prescribers in our study included: first-line treatment failure with persistent bacteremia despite adequate treatment, contraindication to first-line treatment (notably oliguric renal insufficiency) or impossible venous access. Such situations have already been discussed in the literature and considered as adequate (17).
However, in parallel to these situations, we also noted a 33% rate of linezolid prescriptions that were classified as inadequate as well as a disquieting rapid increase of these inadequate prescriptions, reaching more than 40% both in 2018 and 2019. The major situations of inadequate use in our cohort were the prescription in first-line in absence of contraindication to vancomycin or in second-line despite a non-optimal first-line treatment (insufficient vancomycin serum level and/or absence of removal of central line whereas it was if feasible).
The inadequate prescription of linezolid and its constant increase are of high concerns, first because it can lead to the selection and emergence of linezolid-resistant strains in NICU settings. Fortunately, hitherto we did not notice any emergence of bacterial resistance secondary to linezolid uses in our setting. However some authors have already reported such phenomenon (18, 19). A second concern related to the wide use of linezolid in NICUs is the possible side effects of this drug in neonates. As a matter of fact, linezolid is a relatively recent drug with limited data in neonates. Previous data in children suggest that linezolid could induce reversible myelosuppression (mostly thrombocytopenia but also anemia and leucopenia) (20), lactic acidosis (21), gut disorders (13) and in rare cases neuropathy (22). In our cohort no side effects were reported. This suggests that these side effects are limited especially in case of short linezolid course. However, we cannot exclude an underestimation of these side effects because there was no systematic biological analysis in patients treated with linezolid in the NICU study.
Due to the high and increasing number of inadequate linezolid use, as well as the possible risks related to this use, it is urgent to propose several ways for improvement. First, linezolid should be replaced when possible by another antibiotic drug. In the situations of infection with methicillin-susceptible CoNS or S. aureus it is obvious that the first choice has to be a penicillin M. Similarly, in case of penicillin-susceptible Enterococcus or Streptococcus, a penicillin A has to be prescribed. For methicillin-resistant Gram-positive bacteria, the choice is more difficult. Before 2014, linezolid was never used in the study NICU and rifampicin or fosfomycin were used in case of persistent bacteremia despite optimal vancomycin administration or in nosocomial pneumonia. Those drugs can still be considered in those situations, since literature data attest of their good efficiency in such indications (23–25). More recently, new drugs namely ceftarolin and ceftobiprole have been discovered and commercialized and can constitute very interesting alternatives. However, they have been rarely used in this population so data are lacking in the literature (26). Along with the choice of drugs, the removal of central line is recommended in case of persistent bacteremia and should not be forgotten. Finally the control of antibiotics’ use and the presence of a referring infectious disease specialist in NICUs may help to reduce antibiotic pressure (27), using for example care bundle methods of antibiotic stewardship as Ting et al implemented in 2014 in British Columbia Women's Hospital and Health Centre (28).
Our study presents some limitations. The retrospective classification of adequate/inadequate linezolid use was in some cases difficult due to lacking and/or not standardized data in the medical record. This study being monocentric, and even if our results are consistent with the literature, we cannot generalize our findings to all NICU settings. Finally, bacterial epidemiology of nosocomial pneumonia during the study period was not available so it was not possible to know if the increasing use of linezolid could be due to an increasing number of these infections.