This is one of the largest studies aimed primarily at comparing outcomes in neonates with CONS sepsis. Although non-inferiority of a restricted vancomycin policy could not be demonstrated (potentially due to insufficient sample size), the mean duration of sepsis among infants treated with empiric cloxacillin and gentamicin was comparable to that among infants treated with empiric vancomycin. Mortality was low in both groups of infants in this study. There was one death in an infant treated with empiric cloxacillin and gentamicin that may have been linked to CONS sepsis; however, insufficient clinical information was available to establish causality.
These results are consistent with previously published studies [1, 10, 11]. Karlowicz et al  reviewed all cases of late-onset sepsis, including 277 episodes of CONS sepsis, over a 10-year period in one institution. The number of episodes, duration and mortality rates were similar whether vancomycin and cefotaxime or cloxacillin and gentamicin were used empirically. However, no information regarding the presence or removal of a central venous line, sensitivity data or details about baseline characteristics of included infants were available, thus limiting generalizability. Matrai-Kovalskis et al  reviewed 127 episodes of positive blood cultures for CONS of which only 22 were considered true sepsis. Clinical signs were not part of the definition of sepsis. These episodes were compared to 105 episodes selected randomly from a sample of 210 considered contaminants. Infants in both groups were treated with ceftazidime+/- ampicillin or cloxacillin; vancomycin was reserved for confirmed cases of CONS. There was no difference in rates of recovery between the groups, although three infants in the "contaminant" group died and several received a full antibiotic course. Krediet et al  reviewed 66 cases of CONS sepsis, treated with cephalothin alone, vancomycin alone or cephalothin then vancomycin once resistance to oxacillin was confirmed. Mortality and duration of sepsis were similar between the 3 groups, even though CONS was resistant to oxacillin in 85% of cases. None of these studies reported differences in death rates between groups; however, they were not powered for death as an outcome. Although these data are reassuring, the limited sample size in the present study does not permit the demonstration of non-inferiority in mortality between the two patient groups.
Most CONS isolates recovered from infants in this study were resistant to oxacillin and/or gentamicin. Nevertheless, similar to Krediet et al's findings , we documented clinical improvement in more than half of the infants before the initiation of vancomycin, even in the face of oxacillin resistance. One possible explanation is that the CONS isolate represented a contaminant rather than true bacteremia. Although all study patients met the clinical criteria for sepsis, it is possible that their deterioration was due to other causes. Secondly, the susceptibility results based on phenotypic testing may indicate resistance despite the absence of the mecA gene for less commonly encountered species of CONS (e.g. S. lugdenensis). However, these species are rarely encountered in our hospital including the NICU, and we have previously shown that the disk diffusion method for oxacillin susceptibility testing correlates highly with the presence or absence of the mecA gene . Third, removal of the central line may lead to clearance of CONS bacteremia, even in the absence of antibiotic use. Finally, it may be that the addition of gentamicin to cloxacillin results in an in vitro synergistic antibiotic effect on staphylococci . However, a literature search failed to reveal any published studies demonstrating such a clinical benefit when patients are treated with combination therapy for infections due to CONS isolates that are resistant to oxacillin in vitro.
This study has several limitations. Although this is one of the largest studies evaluating outcomes in CONS sepsis in neonates, we undertook this study as part of a quality assurance process to compare similar time periods rather than a pre-determined number of sepsis episodes. Thus, the sample size limits the strength of our findings. Second, even with a clear definition of recovery from sepsis, it is difficult to be certain that sepsis had resolved. Not all infants had a documented repeat blood culture to confirm clearance of the organism, therefore duration of sepsis was recorded in days, rather than hours, which would have allowed for more precise comparison. We attempted to minimize this bias by having a single investigator responsible for assigning duration of sepsis based on a pre-specified definition for all infants. Third, the use of historical controls introduces the potential for bias, as there may be unaccounted for differences between infants in the two periods that could influence outcome. We chose comparison periods as close as possible in time to try to minimize this bias and baseline characteristics of included infants were similar between periods. A fourth potential limitation is the use of a single blood culture for infants exhibiting signs of sepsis. CONS is a frequent contaminant and Struthers et al  estimated that an additional 31% of infants were diagnosed as having CONS sepsis when diagnosis was based on only one blood culture as compared to two blood cultures. But, more recently, Sarkar et al  found no advantage in drawing two blood cultures for diagnosing sepsis in 216 neonates. We tried to limit the number of contaminants by careful preparation of the skin prior to drawing blood culture, taking the culture from peripheral sites rather than central lines, and considering the CONS to be a contaminant if the isolate was recovered after 48 hours or more of incubation. Furthermore, we included only infants with simultaneous clinical signs of sepsis. Using these criteria, six instances of CONS positive blood cultures were excluded from the study as likely contaminants. A final potential bias is the presence of a central venous line. Our data suggests a longer duration of sepsis when a central line was present, however there is no policy in our unit for line removal with sepsis. The presence of foreign material in the bloodstream allows for the formation of biofilm-incorporating microorganisms, which are very difficult to treat  and can prolong the duration of sepsis [14–16].
Reserving vancomycin for the treatment of sepsis caused by organisms confirmed to be oxacillin resistant is an important measure to control the spread of vancomycin resistant organisms. The results of this study suggest that empiric vancomycin use for late-onset neonatal sepsis may not be warranted in facilities with a low incidence of MRSA infections. Although we failed to demonstrate that a restricted vancomycin policy is not inferior in terms of duration of sepsis or mortality from CONS sepsis as compared to a non-restricted policy, we observed similar duration of sepsis (considering that duration estimate can only be accurate to within 1 day), and mortality was low in both groups. Given the high incidence but low mortality and morbidity from CONS sepsis in the NICU, vancomycin could be reserved for episodes of late-onset sepsis in which the implicated organism is confirmed to be oxacillin resistant. A policy change for empiric treatment of late-onset sepsis led to an important reduction in vancomycin use in our NICU. A prospective randomized controlled trial, powered to adequately assess similar morbidity and mortality rates is warranted to confirm these findings. Rubin et al  recommend that clinical practice guidelines should be developed in NICUs to ensure adequate blood sampling to decrease contamination, obtaining 2 blood cultures and possibly using adjunctive tests and information to help differentiate contaminants from pathogens. These guidelines would assist greatly in conducting such a trial. As well, routinely obtaining repeat blood cultures to document clearance of the organism would be helpful in defining length of sepsis and a central line removal policy would be beneficial in limiting bias between study groups.