Three-Year Multicenter Surveillance of Systemic Pneumococcal Infections in Children
Objective. To track antibiotic susceptibility of Streptococcus pneumoniae isolates obtained from children with systemic infections and determine outcome of treatment.
Design. A 3-year (September 1993 through August 1996) prospective surveillance study of all invasive pneumococcal infections in children.
Patients. Infants and children cared for at eight children's hospitals in the United States with culture-proven systemic pneumococcal infection.
Results. One thousand two hundred ninety-one episodes of systemic pneumococcal infection were identified in 1255 children. An underlying illness was present in the children for 27% of the episodes. The proportion of isolates that were nonsusceptible to penicillin or ceftriaxone increased annually and nearly doubled throughout the 3-year period; for the last year the percentages of isolates nonsusceptible to penicillin and ceftriaxone were 21% and 9.3%, respectively. There was no difference in mortality between patients with penicillin-susceptible or nonsusceptible isolates. Only 1 of 742 patients with bacteremia had a repeat blood culture that was positive >1 day after therapy was started. All 24 normal children with bacteremia attributable to isolates resistant to penicillin had resolution of their infection; the most common treatment regimen was a single dose of ceftriaxone followed by an oral antibiotic.
Conclusions. The percentage of pneumococcal isolates nonsusceptible to penicillin and ceftriaxone increased yearly among strains recovered from children with systemic infection. Because empiric antibiotic therapy already has changed for suspected pneumococcal infections, antibiotic resistance has not been associated with increased mortality. Careful monitoring of antibiotic susceptibility and outcome of therapy is necessary to continually reassess current recommendations for treatment.
During the past several years in the United States, as well as worldwide, isolates of Streptococcus pneumoniae that are resistant to antibiotics have been recovered with increasing frequency from patients with both systemic infections and infections of the upper respiratory tract.1,,2 Similarly, nasopharyngeal colonization by antibiotic-resistant S pneumoniae is steadily escalating.3–5 However, the proportion of pneumococcal isolates resistant to penicillin and other antibiotics varies greatly by geographic region both in the United States and other countries.
In general, pneumococcal isolates recovered from younger children or from upper respiratory sites are more likely to be resistant to antibiotics than are isolates recovered from older children or adults or those recovered from normally sterile sites.6,,7Furthermore, recent previous antibiotic use and day care attendance have been associated with antibiotic-resistant S pneumoniaein many studies.4,,5,8 Underlying illness and recent hospitalization also are risk factors in some studies.
The treatment of patients with pneumococcal infection has been complicated by the development of antibiotic resistance; except for bacterial meningitis, there is no consensus as to the most appropriate antibiotic choice(s).9,,10 The lack of clinical outcome data for various treatment regimens creates difficulty in determining the best antibiotic treatment. Another factor is the changing nature of this problem. Not only is the frequency of resistance increasing, but the degree of resistance (increasing minimal inhibitory concentration [MIC]) also is consistently becoming greater.2 This report describes systemic pneumococcal infections in children from eight children's hospitals in the United States during a 3-year period. The intent was to: 1) track antibiotic susceptibility for penicillin and ceftriaxone among S pneumoniae causing systemic infections in children, 2) evaluate risk factors for antibiotic resistance, and 3) determine outcome of treatment to the antibiotics administered in relation to antibiotic susceptibility.
Investigators from eight children's hospitals located in different regions throughout the United States prospectively identified all children evaluated at their respective centers (inpatients or outpatients) between September 1, 1993 and August 31, 1996 with systemic infections (meningitis, bacteremia, pneumonia, septic arthritis, cellulitis, peritonitis, and so forth) attributable toS pneumoniae. Patients were identified by reviewing the results of the microbiology laboratories at each institution. Systemic infections had to be documented by a positive culture from a normally sterile site, ie, a diagnosis of pneumococcal pneumonia required a positive culture of blood or pleural fluid. Isolates were identified asS pneumoniae by standard laboratory techniques. Clinical decisions regarding treatment were not necessarily supervised by the investigator. A standardized data form including demographic and clinical information was completed retrospectively for each episode of pneumococcal infection. Information was gathered from hospital records, office records, or from parents. Pneumococcal meningitis was defined as either a cerebrospinal fluid (CSF) culture which was positive forS pneumoniae or a CSF pleocytosis (>5 white blood cells/mm3) plus a blood culture positive for S pneumoniae. Pneumococcal pneumonia required a chest radiograph consistent with pneumonia in addition to the positive culture. A bacteriologic assessment was made when repeat cultures were obtained. Data were managed in the central office (Baylor College of Medicine) and any questions or discrepancies regarding a patient were resolved after discussion with the investigators or their designee. The institutional review boards at each institution approved the protocol.
All pneumococcal isolates from each center were sent to the central laboratory for processing (Infectious Disease Research Laboratory, Texas Children's Hospital, Houston, TX). Isolates were serotyped or serogrouped by the capsular swelling method using commercially available antisera (Statens Seruminstitut, Copenhagen, Denmark; Daco, Inc, Carpinteria, CA).7 MIC determinations for penicillin and ceftriaxone were performed by standard microbroth dilution with Mueller-Hinton media supplemented with 3% lysed horse blood.11 Susceptibility categories were determined by the 1997 National Committee for Clinical Laboratory Standards (NCCLS) guidelines for breakpoints (penicillin: ≤0.06 μg/mL = susceptible; 0.1–1.0 μg/mL = intermediate; ≥2.0 μg/mL = resistant; ceftriaxone: ≤0.5 μg/mL = susceptible; 1.0 μg/mL = intermediate; ≥2.0 μg/mL = resistant).12 Isolates in the intermediate or resistant categories were considered nonsusceptible.2
Dichotomous variables were analyzed by χ2 or χ2 test for trend. Multivariate analysis was performed by multiple logistic regression. True Epistat (Epistat Σ Services, Richardson, TX) was the statistical program used.
During the 3-year period 1291 episodes of systemic infection attributable to S pneumoniae occurred in 1255 children; 32 children had more than one pneumococcal infection during the study (4 had 3 episodes). In 27% of the episodes an underlying illness or condition was present (Table 1). In many instances a child fell into more than one category; this was particularly true for genetic disorders and congenital heart disease or central nervous system abnormalities. The three most common underlying conditions were a central nervous system disorder, heart disease (predominantly congenital heart disease), and malignancies. The central nervous system disorders included seizure disorders (n = 15), cerebral palsy (n = 12), a shunt in place (n = 8), encephalopathy (n = 6), head injury or skull fracture (n = 5), CSF leak (n = 4), previous meningitis (n = 2), meningomyelocele (n = 2), macrocephaly (n = 2), and 9 others. Only 1 category of a central nervous system disorder is counted, although many had multiple problems, ie, seizure disorder and encephalopathy. Patients with heart disease had a variety of congenital malformations: ventricular septal defect (n = 9), aortic stenosis (n = 5), atrioventricular canal (n = 5), pulmonary stenosis (n = 2), Tetralogy of Fallot (n = 3), and transposition of the great arteries (n = 2). Three children had undergone heart transplantation. Multiple other heart defects were encountered, some in association with other conditions such as premature birth (patent ductus arteriosus and pulmonary disease) or trisomy-21. Half of the children with recurrent infections did not have a readily identified defect in host defense.
Focus of Infection
Bacteremia alone accounted for >50% of the infections each year. Pneumonia and meningitis were the next most common diagnoses. For each year, the relative frequencies of the various diagnoses were nearly identical; bacteremia alone accounted for 57% to 58% of the systemic infections for each of the years. Thirteen of the 18 episodes of peritonitis occurred in children with renal disease. Other infections included skin and soft tissue infections, mastoiditis, endocarditis, epiglottitis, cerebellar abscess, central line infection, and appendicitis.
The age distribution of the children within the different categories of infections is shown in Table 2. Two-thirds of the children were <2 years of age. Thirty-one children (24 with one episode; 6 with 2 episodes; 1 with 3 episodes) with an underlying illness for which pneumococcal vaccine is recommended had received a pneumococcal vaccine before the pneumococcal infection. An additional 41 children with these underlying conditions (excluding the children with cancer for whom we do not have information on whether treatment has been completed) did not receive the pneumococcal vaccine.
Thirty-eight isolates were nonviable for serotyping or were not able to be typed with the antisera used. The distribution of the serotypes/serogroups for the 3 years of the study is shown in Table 3. Serotypes/serogroups 6, 9, 14, 19, and 23 accounted for >75% of the isolates. More than 95% of these isolates were in serotype/serogroups contained in the current pneumococcal polysaccharide vaccine. The distribution of serotypes/serogroups for the pneumococcal isolates from the 31 children who had received a pneumococcal vaccine was similar to the group in general.
The yearly proportion of isolates intermediate or resistant to penicillin (Fig 1A) or ceftriaxone (Fig 1B) is shown for each of the participating centers and in total. Eight isolates were not viable for antibiotic susceptibility tests. The overall percentages of isolates intermediate and resistant to penicillin were 10% and 4%, 9% and 8%, and 15% and 6% for years 1, 2, and 3, respectively. Penicillin-nonsusceptible isolates increased from 14% to 21% during the 3-year period (P = .009). The overall percentages of isolates intermediate and resistant to ceftriaxone were 2.6% and 0.5%, 4.9% and 1.2%, and 6.3% and 3.0% for years 1, 2, and 3, respectively. An increase in the proportion of ceftriaxone-nonsusceptible isolates occurred each year (threefold increase occurred during the 3 years) (P = .0003). By the third year of the study, there was a 50% increase in strains resistant to penicillin and a sixfold rise in strains resistant to ceftriaxone. More than 90% of the strains in the penicillin-nonsusceptible categories occurred in 5 serotypes/serogroups (types 6, 14, 19, 23, and 9). Although more systemic pneumococcal infections occurred during the winter months, there was no apparent relationship between season of the year and antibiotic susceptibility. There were no differences in the proportion of isolates nonsusceptible to penicillin among the three most common infection syndromes (bacteremia, pneumonia, and meningitis).
Risk Factors for Antibiotic Nonsusceptibility
The administration of an antibiotic to a child within 30 days of the time an isolate of S pneumoniae was recovered was highly associated with penicillin resistance. In 52% of episodes (115 children/220 episodes) of infection caused by S pneumoniaenonsusceptible to penicillin, the child had received an antibiotic within the previous 30 days compared with 28% (292/1058) of episodes because of penicillin-susceptible isolates (P < .000001). For the entire group, white children (108/525) also were more likely to have a penicillin-nonsusceptible isolate compared with non-white children (113/765) (P = .008). When only the children who have received a previous antibiotic are analyzed, a trend for white children to be more likely to have an infection because of a penicillin-nonsusceptible isolate remains when compared with the other groups combined (P = .12). Furthermore, when only children who had not received an antibiotic within the previous 30 days are considered, this same trend persists with respect to race (P = .09). Day care attendance was known for 96% of children ≤5 years old. Twenty-two percent of the isolates from children who attended day care were nonsusceptible to penicillin compared with 16% for isolates recovered from children who did not attend day care (P = .03). However, day care attendance in the absence of previous antibiotic use did not influence susceptibility to penicillin in a stratified analysis (Table 4). The highest proportion of isolates nonsusceptible to penicillin for children ≤5 years old occurred for those children who were both in day care and had received a previous antibiotic. Age, underlying illness, or hospitalizations within the previous 30 days were not associated with a greater risk for recovering nonsusceptible isolates.
A multivariate analysis was performed using the three variables: previous antibiotic therapy, day care attendance, and white versus non-white race associated with a penicillin-nonsusceptible isolate. Previous antibiotic therapy remained the most significant factor (odds ratio, 2.3; 95% confidence interval, 1.7–3.2). Race also remained a significant factor (odds ratio, 1.5; 95% confidence interval, 1.1–2.1). Day care attendance was not found to be a significant factor after adjusting for both previous antibiotic use and race.
Outcome of Therapy
The outcome of therapy with respect to complications and mortality was similar for the patients with penicillin-susceptible and penicillin-nonsusceptible isolates. Nineteen children died: 15 had meningitis, 3 had bacteremia, and 1 had pneumonia. Fifteen isolates were susceptible, 2 were intermediate, and 2 were resistant to penicillin. Mortality among those children with isolates that were nonsusceptible to penicillin (4/221; 1.81%) was no different from that among children with isolates that were penicillin susceptible (15/1062; 1.41%). Five children (4 with pneumonia) developed hemolytic-uremic syndrome. These cases were unrelated and attributable to serotypes 14 (n = 2), 3 (n = 2), and 7 (n = 1).
Another measure of the efficacy of therapy is bacterial eradication from normally sterile sites. Eighteen patients (bacteremia [n = 9], meningitis [n = 4], pneumonia with empyema [n= 3], endocarditis [n = 1], and ventriculoperitoneal shunt infection with pneumonia [n = 1]) had a repeat positive culture for S pneumoniae from a normally sterile site after the initiation of therapy. Overall, 11 of the isolates were susceptible, 2 were intermediate, and 5 were resistant to penicillin. Thirteen of these 18 children had serious underlying conditions. Fifteen of the positive repeat cultures occurred in cultures obtained within the first day after antibiotics were initiated by the parenteral route except for 1 case. Thereafter, repeat blood cultures were sterile. In 3 children, repeat positive cultures occurred beyond the first day. The first child with sickle cell disease had meningitis with positive blood and CSF cultures after 2 days of intravenous cefuroxime (50 mg/kg every 8 h) for treatment of pneumonia. His isolates had MIC of 2 μg/mL and 1 μg/mL for penicillin and ceftriaxone, respectively. A second child with meningitis and a lymphangioma near the mastoid/stylomastoid foramen had repeat CSF cultures that remained positive for 7 days (penicillin MIC, 2 μg/mL; ceftriaxone MIC, 0.5 μg/mL); delayed surgical drainage of the infected lymphangioma and mastoid bone was thought to be a major contributing factor to the persistently positive cultures. A third patient with a neuroectodermoid tumor and central vascular catheter had a positive blood culture 48 hours after the start of oxacillin therapy (penicillin MIC, 2 μg/mL; ceftriaxone MIC, 1 μg/mL).
Bacteremia alone represents the single most frequent type of invasive pneumococcal infection. Of the 742 episodes of pneumococcal bacteremia, 120 (16.2%) were because of penicillin-nonsusceptible isolates. The distribution of nonsusceptible isolates by MIC was: 0.1 to 1.0 μg/mL (n = 83), 2.0 μg/mL (n= 22), and ≥4.0 μg/mL (n = 15). A variety of antimicrobial regimens was administered to these children including one or more doses of vancomycin for 9% of children with strains susceptible to penicillin, and 12% for children with strains intermediate to penicillin. Of the 37 episodes occurring in the 36 patients whose isolates had penicillin MIC ≥2.0 μg/mL, 24 children did not have a serious underlying illness. Of these 24 children, 21 were ≤24 months old. All of the normal children were treated successfully. The most common antibiotic regimen in the these normal children was a single dose of intramuscular ceftriaxone followed by an oral antibiotic (n = 15). Three children had oral treatment only (amoxicillin-clavulanate [n = 2], cefprozil [n = 1]). The remainder had a variety of different regimens. Only 1 child received vancomycin (10 days). The isolates from 3 children had MIC for ceftriaxone equal to 2.0 μg/mL. Two of these children received a single dose of ceftriaxone followed by amoxicillin or amoxicillin-clavulanate. One child received a single dose of ceftriaxone without other therapy. Seven of these 24 patients had repeat blood cultures, all of which were negative at 24 hours (n = 6) or 72 hours (n = 1) after therapy was started.
Thirteen episodes of bacteremia attributable to isolates resistant to penicillin (MIC = 2.0 μg/mL [n = 8], MIC = 4 μg/mL [n = 4], MIC = 8 μg/mL [n = 1] occurred in 12 patients with serious underlying illnesses (malignancies [n = 5], congenital heart disease [n = 3], acquired immunodeficiency syndrome [n = 1], severe combined immunodeficiency [n = 1], sickle cell anemia [n = 1], Factor 10 deficiency [n = 1]). The median age of these patients was 3 years (range, 5 months-23 years). An extended-spectrum cephalosporin was administered in 12 of the episodes (median, 9 days; range, 1–14 days). Six patients received vancomycin for 7 to 14 days. In 8 episodes, blood cultures were repeated at 24 hours after antibiotics were initiated and were negative in each instance. One patient had a repeat blood culture drawn through a central vascular catheter that remained positive 48 hours after therapy was started; a blood culture drawn through the catheter at 72 hours was sterile. A second child with severe combined immune deficiency remained persistently febrile and received prolonged antibiotic therapy. A repeat blood culture obtained on day 11 of therapy was sterile.
S pneumoniae is the most common cause of invasive bacterial infection in children with an annual incidence between 45 to 145 cases/100 000 population of children <2 years old.13–15 Since the introduction of Haemophilus influenzae type b conjugate vaccines for infants, S pneumoniae has become the most common cause of morbidity and mortality because of bacterial meningitis in infants and children in the United States and other developed countries.16 Until 10 years ago almost all pneumococcal isolates were considered susceptible to penicillin and penicillin was the agent of choice for treating serious pneumococcal infections. Scattered cases of treatment failure for bacterial meningitis because of pneumococci that were not susceptible to penicillin were documented, but the numbers of cases were not enough to change the approach to empiric therapy of bacterial meningitis or other invasive infections possibly attributable toS pneumoniae.17–20 However, the increasing frequency of penicillin resistance and the emergence of cephalosporin resistance and multidrug resistance have required changes in the empiric approach to antibiotic selections when treating pneumococcal infections. This has been most readily documented for bacterial meningitis. Many reports have focused on treatment failures of pneumococcal meningitis associated with decreased susceptibility to the extended-spectrum cephalosporins.21–26 Most experts recommend including vancomycin, a drug generally effective in treating meningitis attributable to pneumococcal isolates that are resistant to cefotaxime or ceftriaxone, in the initial empiric regimen selected when treating a child with suspected bacterial meningitis.9,,10,27
In the 3-year surveillance period of our study, the frequency of penicillin resistance and ceftriaxone resistance increased steadily among the systemic isolates recovered from children. These data complement the experience of the Pneumococcal Sentinel Surveillance Working Group organized by the Centers for Disease Control and Prevention (CDC) during the years 1987 through 1994.28,,29The CDC Pneumococcal Sentinel study documented that during 1993 and 1994, 18.4% of isolates from children <6 years were penicillin nonsusceptible. This value is very similar to the 14% rate of nonsusceptible organisms we found in the first year of our multicenter surveillance study conducted in institutions separate from those participating in the CDC survey.
As in previous studies,3,,5,8 previous antibiotic use was associated with a greater risk for systemic pneumococcal infections caused by a penicillin-nonsusceptible isolate. The widespread use of antibiotics, particularly on an outpatient basis, is creating selective pressures which favor the emergence of antibiotic resistance in S pneumoniae as well as other microorganisms. Several groups have expressed this concern and have suggested strategies to curb inappropriate or excessive use of antibiotics.30,,31 It is necessary to educate the public as well as practitioners regarding this problem and the contributing factors. Developing new diagnostic tests to rapidly distinguish bacterial from viral infection is a major research priority and limiting antibiotic administration to those patients with a high likelihood of bacterial infection is an important goal. Practice guidelines have some impact on antibiotic use when these are thoughtfully developed and implemented.32,,33 Although changing practice habits is difficult, costly, and time-consuming, controlling antibiotic use is a national priority.34 The Centers for Disease Control and Prevention and the American Academy of Pediatrics have initiated major educational programs to promote the judicious use of antibiotics targeting both physicians and the public.35
Racial differences with respect to antibiotic resistance, similar to those reported by Hofman et al,6 were found in this study. White children were more likely than other racial groups to have a penicillin-nonsusceptible pneumococcus isolated. We did not find that day care attendance was an independent risk factor for recovering penicillin-nonsusceptible pneumococcal isolates. However, we did not consider the number of children within the day care centers which certainly is an important factor. The combination of previous antibiotic therapy and day care attendance led to the highest risk for antibiotic resistance in the children 5 years old or younger.
The most common serotypes/serogroups of S pneumoniaerecovered from this large number of children were distributed as in most previous reports.2,,13,14 Virtually all of the isolates nonsusceptible to penicillin fell within 5 of these serotypes/serogroups as has been generally noted.2,,6,28Children with underlying illnesses or who were immunocompromised had the same distribution of serotypes/serogroups as those recovered from normal children (data not shown). Weisholtz et al36 found that for patients of any age, with underlying conditions associated with impaired host defense, serotype/serogroup distributions were different than for isolates recovered from otherwise normal hosts. However, they found immunocompromised children generally had infections attributable to serotypes contained in the pneumococcal vaccine. Our data support the current constituents of the conjugate pneumococcal vaccines under investigation which would be directed against the most common serotypes/serogroups of S pneumoniae recovered from normal or immunocompromised children with systemic pneumococcal infections.37,,38
Twenty-seven percent of the children in our study had an underlying illness. The most common illnesses were a central nervous system disorder, congenital heart disease, and a malignancy. For some of these conditions pneumococcal vaccination is not routinely recommended in children.39,,40 Further studies are needed to determine if the incidence of systemic pneumococcal infection is substantially greater in children with these underlying conditions (eg, cardiovascular, genetic, and central nervous system disorders) than in normal children. If this is the case, expanding the indications for administering the current pneumococcal vaccine should be considered.
Few studies have addressed the outcome of treating pneumococcal infections outside the central nervous system in relation to penicillin susceptibility. The earliest reports discussed predominantly infections because of isolates with intermediate susceptibility to penicillin, and demonstrated that high-dose penicillin would adequately treat pneumonia or bacteremia attributable to such strains.41–43 However, these findings may not be applicable for isolates with MIC in the higher ranges (MIC ≥2 μg/mL) or in immunocompromised patients.
The impact of antibiotic resistance on the outcome of S pneumoniae bacteremia is difficult to assess from our study. The overall mortality from bacteremia was 3/742 or 0.4%. Two of the three isolates from these patients were penicillin susceptible; one was intermediate to penicillin. No patient with a penicillin-resistant isolate causing bacteremia received penicillin therapy alone initially, accordingly the effectiveness of penicillin for the treatment of pneumococcal bacteremia, even attributable to isolates with penicillin MIC between 0.1 to 2.0 μg/mL, cannot be evaluated. Persistent bacteremia was not documented in any patient with an isolate having an MIC >4.0 μg/mL for ceftriaxone. After standard doses of cefotaxime and ceftriaxone, serum levels of 100 to 200 μg/mL are achieved.44,,45 Blood stream isolates of S pneumoniae with MIC up to 8 μg/mL for extended-spectrum cephalosporins might be cleared readily in otherwise normal children with parenteral administration of these antibiotics. However, clinical experience documenting successful therapy for this level of susceptibility has not been reported.
Assessing outcome of therapy in children with underlying illness is even more difficult. When progressive illness and fatal outcome occur in high risk patients it may be difficult to distinguish a treatment failure from the natural history of infection.46 In our study, 13 episodes of pneumococcal bacteremia attributable to penicillin-resistant isolates occurred in 12 children with underlying illnesses which would diminish host response to infection. In only 1 case was there any delay in sterilization of blood cultures and this was likely related to an infected central catheter as well as the host defense problem. One additional child had persistent fever but without documentation that this was because of continued bacteremia or another focus of infection. These children received a variety of antibiotic combinations, therefore, it is not possible to determine the efficacy of a single agent such as ceftriaxone or cefotaxime from these data.
In one study of adults with pneumococcal bacteremia, mortality was no different for patients infected with penicillin-susceptible strains compared with those whose strains were nonsusceptible (mostly intermediate) to penicillin.47 However, duration of hospitalization was longer for the group of patients with nonsusceptible organisms. In another investigation in which invasive pneumococcal infections in patients with and without HIV infections were assessed, mortality was not influenced by resistance to penicillin.48 Investigators from Spain also did not find any difference in mortality between patients infected with penicillin-susceptible versus nonsusceptible (primarily intermediate) pneumococci including patients with cancer and neutropenia.49,,50 Friedland found that the course of pneumococcal pneumonia was similar among 25 children with isolates intermediate to penicillin compared with 53 children with penicillin-susceptible isolates.51 However, if as expected, the degree of penicillin and cephalosporin resistance increases further, the results of these studies will not be applicable in the future.
The Committee on Infectious Diseases of the American Academy of Pediatrics has developed guidelines for the therapy of children with serious infections caused by S pneumoniae; these are the most up-to-date recommendations for the antibiotic treatment of infections attributable to antibiotic resistant pneumococci.27 Undoubtedly, these recommendations will undergo modification as greater experience is accumulated with the treatment and outcome of pneumococcal infections because of isolates with higher levels of resistance. Continued surveillance and monitoring of the outcome of therapy are essential.
This study was supported in part by a grant from Roche Laboratories.
We thank Linda Lamberth and Rebekah Lichenstein for technical support and Constance Rothermel, PhD, for her support. We also acknowledge the help of the following individuals: Tracye Paris, RN; Susana Aragon, RN; Timothy Postula; Michelene Ortenzo; Nancy C. Tucker, RN; and Kathyann Marsh, RN, MSN.
- Received October 24, 1997.
- Accepted February 27, 1998.
Reprint requests to (S.L.K.) Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
- MIC =
- minimal inhibitory concentration •
- CSF =
- cerebrospinal fluid •
- CDC =
- Centers for Disease Control and Prevention
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- Copyright © 1998 American Academy of Pediatrics