Clinical Outcome of Cephalothin Versus Vancomycin Therapy in the Treatment of Coagulase-negative Staphylococcal Septicemia in Neonates: Relation to Methicillin Resistance and mec A Gene Carriage of Blood Isolates Tannette G. Krediet, MD*; Mark E. Jones, PhD§; Leo J. Gerards, MD*; and Andre´Fleer, MD‡ ABSTRACT. Objective. Coagulase-negative staphylo- already had recovered clinically before the switch, which cocci (CONS) are the most common causative agents in was based solely on susceptibility test results. neonatal nosocomial septicemia. Because of widespread Conclusions. Cephalothin was found to be clinically methicillin resistance among CONS, empiric therapy efficacious in the treatment of neonatal CONS septice- with vancomycin is recommended as the primary antibi- mia, despite a steadily increasing mec A gene carriage of otic regimen for these infections. In our unit, empiric CONS blood isolates in our neonatal intensive care unit treatment of nosocomially acquired septicemia consists and a corresponding high methicillin/oxacillin resis- of cephalothin and gentamicin, which are adjusted sub- tance. Hence, cephalothin remained the antibiotic of first sequently according to the determined bacterial suscep- choice in the treatment of CONS septicemia in our unit, tibility profile. Vancomycin is initiated only when the with vancomycin selected exclusively for cases not re- patient has been treated recently with cephalothin or sponding to initial cephalothin treatment, or for patients when intravascular lines or endotracheal tube are colo- developing CONS septicemia during or after recent nized with oxacillin/cephalothin-resistant CONS strains. cephalothin treatment. By applying this approach in our The aim of the present study was to evaluate the efficacy unit, we were able to reduce vancomycin use from 62% in of our antibiotic regimen for CONS septicemia, in rela- 1994 to 1995 to 21% in 1997. This shows that such a policy tion to methicillin-resistance and the carriage of mec A may result in an important reduction of vancomycin use, gene, encoding methicillin resistance, among CONS which may aid in postponing the threatening emergence blood isolates from our unit. of vancomycin resistance among Gram-positive cocci. Methods. Clinical symptoms of septicemia, clinical Pediatrics 1999;103(3). URL: http://www.pediatrics.org/ outcome, and laboratory parameters of septicemia (C- cgi/content/full/103/3/e29; neonatal septicemia, nosoco- reactive protein) were studied retrospectively in 66 pa- mial septicemia, coagulase-negative staphylococcus, ceph- tients with CONS septicemia. The diagnosis of septice- alothin, vancomycin, methicillin-resistance, mec A gene. mia was made by the attending neonatologist and was defined by clinical symptoms of septicemia in the pres- ence of a positive finding of a blood culture test, which ABBREVIATIONS. CONS, coagulase-negative staphylococci; was performed using a defined protocol. All CONS NICU, neonatal intensive care unit; CVC, central venous catheter; blood isolates were included to determine mec A gene NCCLS, National Committee for Clinical Laboratory Standards; carriage. CRP, C-reactive protein. Results. In the 66 patients, three treatment categories were distinguished: treatment with cephalothin (25 pa- uring the last 2 decades, coagulase-negative tients, 38%); with vancomycin (15 patients, 23%); and primary treatment with cephalothin, switched subse- staphylococci (CONS) have evolved as the quently to vancomycin (26 patients, 39%). It was found Dmost common causative agents of nosoco- that 92% of all CONS blood isolates (61/66) were mec mial septicemia in neonatal intensive care units A-positive. Concordance of mec A gene carriage with (NICUs).1–4 According to the National Nosocomial methicillin/oxacillin resistance was found in 56 of 66 Infections Surveillance System of the National Center isolates (85%); 10 of 61 (16%) isolates that were mec A- for Infectious Diseases, 58% of neonatal nosocomial positive were determined as oxacillin-susceptible. Al- bacteremia cases are caused by CONS. Similarly, the though 22 of the 25 blood isolates of the cephalothin- National Institute of Child Health and Human De- treated patients were mec A-positive, clinical recovery velopment Neonatal Research Network reported was uneventful. In the 26 patients in whom antibiotic therapy was switched from cephalothin to vancomycin, CONS as the causative agents in 55% of all cases of two strains were cephalothin-susceptible and 8 patients nosocomial bacteremia, with the rate of nosocomial bacteremia ranging from 11.5% to 32.4%. In our NICU, .70% of all nosocomial infections are caused From the Departments of *Neonatology and ‡Medical Microbiology, Wil- by CONS. Furthermore, the incidence of CONS sep- helmina Children’s Hospital, Utrecht University, and §Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Univer- ticemias has increased from 2.5% in 1988 to 15% at sity Hospital, Utrecht University, The Netherlands. present. This increase is most likely attributable to Received for publication May 13, 1998; accepted Sep 25, 1998. more aggressive, invasive therapeutic measures used Reprint requests to (T.G.K.) Department of Neonatology, Wilhelmina Chil- in NICUs, such as central venous catheters (CVCs), dren’s Hospital, Utrecht University, Box 18009, 3501 CA Utrecht, The Neth- erlands. arterial lines, artificial ventilation, and total paren- 4–6 PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad- teral nutrition for prolonged periods. Although emy of Pediatrics. vancomycin is recommended as the primary antibi- http://www.pediatrics.org/cgi/content/full/103/3/Downloaded from www.aappublications.org/newse29 by PEDIATRICSguest on September Vol. 27,103 2021 No. 3 March 1999 1of5 otic for nosocomial infections with CONS,1,3,7 in our ducted by a Vitek automated determination and susceptibility unit the combination of a first-generation cephalo- testing system (bioMe´rieux SA, Marcy-l’Etoile, France). sporin, cephalothin, and gentamicin is used. Ceph- alothin was chosen based on resistance patterns of RESULTS the most common causative microorganisms, CONS, During the study period, CONS septicemia was and Staphylococcus aureus. Gentamicin is added to diagnosed in 70 patients. A CVC was in situ in all this antibiotic regimen to cover Gram-negative or- patients. This CVC was either an umbilical vein cath- ganisms, because they cannot be excluded as caus- eter or a percutaneous silicone or polyurethane cath- ative agents at the moment of initiation of therapy. eter. The umbilical vein catheter was replaced by a During the last few years, a fivefold increase in use of percutaneous catheter within 7 days after birth. The vancomycin has been noted in our unit. This is at- policy in our NICU is that the CVC is not removed tributable to the increased reporting of methicillin when clinical signs of septicemia occur, but after resistance of CONS blood isolates from our neonatal antibiotic therapy is initiated and these clinical signs unit as a result of the introduction of methods of persist. The data of 4 patients, 2 of whom were antibiotic susceptibility testing based on guidelines treated with cephalothin and 2 with vancomycin, from the National Committee for Clinical Laboratory could not be evaluated because in these patients, the Standards (NCCLS).8 CVC was removed concurrent with initiation of an- One aim of the present study was to define more tibiotic therapy. Therefore, data of 66 patients with exactly the incidence of b-lactam, in particular meth- CONS septicemia, treated only with antibiotics, were icillin, resistance. To accomplish this, we conducted a evaluated. Patient demographics, clinical signs of molecular epidemiologic study of mec A gene car- septicemia, time to recovery, and CRP values are riage of the CONS blood isolates from the years 1994 shown in Table 1. Three treatment categories were and 1995. The mec A gene encodes penicillin-binding distinguished: patients treated with cephalothin; pa- protein 2a that determines methicillin resistance.9 tients treated with vancomycin; and patients treated The second aim of the study was to evaluate the initially with cephalothin, which subsequently was efficacy of our antibiotic regimen for CONS septice- switched to vancomycin. The reason for primary mia. This regimen featured prominently a first-gen- treatment with vancomycin instead of cephalothin eration cephalosporin, cephalothin, apparently with- according to the regimen used in our NICU was out ill consequences. For this reason, we studied the either recent treatment with cephalothin or coloniza- clinical outcome of cephalothin versus vancomycin tion with oxacillin/cephalothin resistant-CONS of therapy of CONS neonatal septicemia in relation to intravascular lines or endotracheal tube. Reasons for susceptibility to methicillin and cephalothin and mec switching from cephalothin to vancomycin were ox- A gene carriage of the CONS blood isolates. acillin/cephalothin resistance, as determined by the susceptibility test results; a negative clinical response PATIENTS AND METHODS to treatment with cephalothin, determined by a lack All patients with CONS septicemia during 1994 and 1995 were of clinical improvement; or a rise in CRP not ex- included in the study. Septicemia was defined by the concurrence plained by the physiologic delay in response to the of clinical symptoms of septicemia (apneic attacks, bradycardias, infection. Gentamicin, which was added to the anti- respiratory