Clinical management issues of coagulase-negative staphylococcal sepsis in the neonatal intensive care unit

Abstract

Nosocomial sepsis is a major cause of morbidity in the neonatal intensive care unit (NICU), with coagulase-negative staphylococci (CONS) generally reported to be the most frequent causative micro-organisms. There is substantial evidence for the association between CONS sepsis and indwelling intravascular catheters, predominantly central venous catheters (CVCs). Due to advanced medical techniques survival of very and extremely low birth weight infants (VLBW and ELBW) has increased considerably and they are the category of infants at greatest risk of nosocomial sepsis. This thesis focuses on clinical management issues of coagulase-negative staphylococcal sepsis in the neonatal intensive care unit, in particular diagnostic aspects, clinical effects of antimicrobial therapy in relation to antimicrobial resistance, neurodevelopmental outcome and prevention. To avoid the use of vancomycin as empiric antimicrobial agent for neonatal CONS sepsis is an important subject of this thesis. We have clearly demonstrated that first generation cephalosporins, such as cefazolin, were clinically efficacious and that MIC values still remain in the susceptible range, despite their consistent use during more than two decades. Data from a second study revealed a striking discrepancy among mecA gene positive CONS blood isolates between universal resistance to oxacillin and apparent susceptibility to cefazolin and amoxicillin-clavulanate. The results of this study may explain the favourable response, although rarely reported, to beta-lactams, despite the fact that most CONS blood isolates are mecA positive. Using beta-lactams in neonatal CONS sepsis gives the opportunity to reserve vancomycin for selected cases and may postpone the emergence of vancomycin resistance. Another important topic of this thesis was the shortening of duration of antibiotic treatment. At first we showed that the removal of a central venous catheter is an important therapeutic measure in infants with clinical symptoms of sepsis. In another study we demonstrated that CONS are rapidly (within 48-72 hours after starting anti-staphylococcal treatment) cleared from the blood stream, and that infants show rapid clinical improvement with 24-48 hours. Finally, we demonstrated that 3 days instead of the generally used 7 days of antibiotic treatment was clinically efficacious in infants with uncomplicated CONS sepsis, in whom the central venous catheter was removed. A randomized controlled trial demonstrated the successful use of two doses of an anti-staphylococcal agent during the procedure of removal of a peripherally inserted central venous catheter to prevent CONS sepsis after removal, which is a new and important finding in case of prevention of CONS sepsis. Study of the neurodevelopmental outcome after CONS sepsis showed no cerebral white matter damage on MRI at term-equivalent age and no significant delay in cognitive and motor development at 15 months to 24 months corrected age.