A few years ago we started having difficulty clearing Coagulase-Negative Staphylococcal (CoNS) sepsis from the blood cultures of some babies in our NICU, children with CoNS also seemed to be sicker, and to more often have thrombocytopenia. It was at that time that I learnt about heteroresistance. This is a phenomenon, as I understand it, where within a colony of vancomycin susceptible CoNS there are a few individuals which are much less sensitive, sub-cultures of the original strain continue to show this heterogenicity of vancomycin sensitivity. This makes it difficult to eradicate the condition with vancomycin.
As a result, we started using linezolid as an alternative for a few cases, and for a short time, it even became our standard anti-CoNS antibiotic, but especially for babies presenting with moderate-to-severe illness severity and thrombocytopenia.
There was very little to base dosing on in the preterm, and little or no knowledge about toxicity in the newborn. There is apparently a risk of peripheral neuropathy in adults after prolonged use, which is usually reversible, so we were concerned that there were potential neurological impacts. The long term safety of many treatments is not clear in the preterm infant, which is not an excuse for introducing more interventions of unknown safety, but does help to put this in context.
We had actually used linezolid once or twice before this occurrence, as it is well absorbed orally, so we had decided, for some babies with difficult IV access and in whom the only indication for IV access was for administration of antibiotics, to finish their antistaphylococcal treatment with oral linezolid.
There does seem to be an increased risk of neurologic impairment and developmental delay in infants who have had a CoNS sepsis, but it is probably less important for that outcome than gram-negative sepsis. We decided we had better investigate the impact of treating CoNS with linezolid, so we decided to compare our outcomes with those of 2 other large Canadian NICUs in the CNN, Mount Sinai in Toronto and BC Children’s in Vancouver. Sicard M, et al. Neonatal and Neurodevelopmental Outcomes Following Linezolid for Coagulase-negative Staphylococcal Infection: Real World Evidence. Pediatr Infect Dis J. 2020. In the period covered, Sinai had not used linezolid at all, BCCH had used it a few times, and we treated 3/4 of our cases with the stuff.
The baseline data show that babies who received linezolid were indeed sicker, more getting vasopressors, and more receiving a transfusion of something (mostly platelets). We, therefore, corrected for these factors in the analysis of survival and of neurological impairment or developmental delay. In terms of survival, this was a bit lower in the infants who received linezolid in the first 30 days after the episode, but the difference was not great and disappeared after adjusting for severity of illness.
Long term neurological and developmental outcomes were very similar after adjusting for severity of illness. Even though there were more deaths in the very long term after linezolid use, as mentioned there was no difference in the first 30 days after using the medication, so it seems very unlikely to be causative.
Since this period our CoNS sepsis has again become less virulent, and we don’t seem to be having the heteroresistant strains any longer, so we now only use linezolid in rare cases. I wish I knew why changes like that happened!
Why not use linezolid more? It can be given orally, monitoring levels is fairly easy, and not clearly required. We now have about as much data about the safety of linezolid as about many other drugs that we use in the newborn; vancomycin, for example, is described as having about a 5% frequency of nephrotoxicity, and we have no idea about long term safety, but it seems no worse than linezolid from our study. A randomized comparison of vancomycin vs linezolid, examining long term outcomes in preterm infants with CoNS would be the best approach but seem unlikely to be done in the near future. Good quality registry RCTs could answer the question quickly and cheaply, but would still require some funding. In the meantime, observational studies like ours will help to allay some fears, but risk missing some adverse impacts, especially as we did not collect some data, for example acute creatinine changes.
I guess that the common response in such situations is that we have been using vancomycin for a long time, we think we know it, and its possible complications, and introducing a new agent, which does not have overwhelming advantages, is something we try and avoid.
Important study! I think we need more and large observational studies with short- and long-term outcome data in order to obtain safety data on the drugs we are using in the NICU.