PEDIATRICS Vol. 120 No. 5 November 2007, pp. 937-945 (doi:10.1542/peds.2007-0956)
ARTICLE |
Evaluation and Treatment of Community-Acquired Staphylococcus aureus Infections in Term and Late-Preterm Previously Healthy Neonates
a Department of Pediatrics
b Sections of Neonatology
d Infectious Diseases, Baylor College of Medicine, Houston, Texas
c Department of Neonatology
e Infectious Disease Service, Texas Children's Hospital, Houston, Texas
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. We describe the evaluation and treatment of neonatal community-acquired Staphylococcus aureus disease in the era of community-acquired methicillin-resistant S aureus.
METHODS. We retrospectively reviewed the evaluation and treatment of 126 community-acquired S aureus infections of term and late-preterm previously healthy neonates who were 
30 days of age between August 2001 and July 2006 at Texas Children's Hospital.
RESULTS. S aureus infections included 43 pustulosis, 68 cellulitis/abscess, and 15 invasive infections. We found 84 methicillin-resistant and 42 methicillin-susceptible S aureus isolates. Twenty-one patients received outpatient antibiotics before hospital presentation. Systemic infection evaluation included urine, blood, and cerebrospinal fluid cultures in 79, 102, and 84 neonates, respectively. Culture revealed S aureus urinary tract infections in 1, S aureus bacteremias in 6, and aseptic cerebrospinal fluid pleocytosis of unclear cause in 11 neonates. Physicians admitted 106, transferred 5 to other hospitals, and discharged 15 afebrile patients with topical or oral antibiotics. Clindamycin was the predominant antistaphylococcal intravenous and oral antibiotic for pustulosis and cellulitis/abscess infections. One patient with systemic S aureus and herpes simplex virus infection died. At discharge after inpatient treatment, physicians prescribed no antibiotics for 43 patients and oral or topical antibiotics for 62 patients. Outpatient treatment failed for 1 patient who was discharged after intravenous therapy and was readmitted. Eighty percent (16 of 20) of patients with mastitis alone completed treatment with outpatient oral antibiotics.
CONCLUSIONS. Evaluation and treatment strategies for neonatal community-acquired S aureus disease are varied at our hospital. Prospective studies are needed to determine optimal management strategies.
Key Words: community-acquired Staphylococcus aureus • methicillin resistance • infant • newborn • therapy
Abbreviations: CA—community-acquired • MRSA—methicillin-resistant Staphylococcus aureus • TCH—Texas Children's Hospital • SBI—serious bacterial infection • CSF—cerebrospinal fluid • UTI—urinary tract infection • CFU—colony-forming units • WBC—white blood cell • PFGE—pulsed-field gel electrophoresis • HSV—herpes simplex virus • MSSA—methicillin-susceptible Staphylococcus aureus
taphylococcus aureus is a frequent neonatal pathogen that causes a variety of infections.1 Community-acquired (CA) methicillin-resistant S aureus (MRSA) isolates have been documented in nosocomially transmitted infections in the NICU as have CA infections in previously healthy neonates at Texas Children's Hospital (TCH).2,3 Postpartum women in endemic areas are also at risk for S aureus skin infections, including mastitis, and cesarean incision infections after an uncomplicated pregnancy and delivery.3–5
The increasing prevalence of neonatal and maternal CA S aureus infections in Houston and other major metropolitan areas throughout the United States underscores the importance of rapidly identifying potentially infected neonates and instituting effective therapy.3–8 Treatment recommendations for CA S aureus disease in previously healthy neonates are limited.1,8 For example, there are no clear guidelines regarding the decision to use local versus systemic antibiotics or oral versus parenteral therapy; empiric antibiotic selection; duration of therapy; inpatient versus outpatient treatment; and the indications for an evaluation for a serious bacterial infection (SBI) obtaining blood, urine, and cerebrospinal fluid (CSF) for culture.
Although multicenter, randomized, controlled trials are needed to determine optimally the safety and efficacy of various protocols, accumulated experience in the evaluation and treatment of these infections in centers with a high prevalence such as TCH is 1 currently available source of guidance. In this report, we describe the evaluation and treatment of CA S aureus disease in neonates who presented to TCH.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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As previously described,3 we prospectively identified TCH patients with CA S aureus infections and collected their S aureus isolates from the clinical microbiology laboratory. CA organisms were isolated (1) within 48 hours of hospitalization; (2) during an outpatient visit; or (3) after 48 hours of hospitalization but clinical evidence suggested a CA infection, such as symptoms present at hospital admission. Exclusion criteria were (1) underlying illness predisposing to frequent hospitalizations or medical visits, (2) indwelling catheters or percutaneous medical devices, and (3) hospitalization within the past year excluding birth.9 The Infectious Disease Research Laboratory coded and froze the S aureus specimens in horse blood at –80°C. Antibiotic susceptibilities to oxacillin, clindamycin, erythromycin, gentamicin, trimethoprim-sulfamethoxazole, and vancomycin were determined by disk diffusion and categorized by Clinical and Laboratory Standards Institute guidelines.10 Inducible resistance to clindamycin was evaluated by D test.10 A research nurse recorded demographic and clinical information from medical charts into an electronic database using a standardized form. The Baylor College of Medicine Institutional Review Board approved this study.
Patients who were 30 days of age at onset of symptoms and were seen at TCH between August 1, 2001, and July 31, 2006, were selected from the database. We identified previously healthy neonates who were born at 
36 weeks’ gestation, were treated for S aureus infection, and presented after nursery discharge. "Previously healthy" was defined as no hospitalizations since birth and no surgeries except circumcision. A data collection form was developed to include more detailed information regarding the maternal history, clinical presentation and manifestations, treatment, and outcome. Data were entered into a separate database. This population included 89 neonates whose clinical presentation and isolates were previously described3 and 37 neonates who were seen in the subsequent 18 months.
Neonates were classified by the type of skin and soft tissue manifestation. Infections extending beyond skin and soft tissue structures were classified as invasive. Lesions that contained pus <1 cm in diameter were considered pustules. Larger pus-filled lesions were classified as abscesses. Pustulosis was considered local when only 1 region of the body was involved versus diffuse when >1 region of the body (eg, groin and arm) was affected (Fig 1). Urinary tract infection (UTI) was defined as >1000 colony-forming units (CFU) of bacteria per mL when obtained from a catheterized specimen, unless other evidence indicated an infection. CSF pleocytosis was defined as white blood cell (WBC) count of >22/mm3 11 after decreasing the WBC count by 1 for every 1000 red blood cells per mm3. Fever was defined as a temperature 38°C by any route. In the emergency center, rectal temperatures were obtained.
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Pulsed-Field Gel Electrophoresis (PFGE)
PFGE was performed for isolates that infected neonates with CSF pleocytosis, and strain relationships were determined as previously described.12–14
Statistical Analysis
Statistical analysis was performed using Fisher's exact test, 
2, or 2 for trend for dichotomous variables or Student's t test for comparison of means by using GraphPad Prism 4.0 (GraphPad, San Diego, CA). A Welch's correction was applied for populations with unequal variance. Analyses were 2-tailed, and P< .05 was considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Population characteristics are described in Table 1. Symptoms began earlier for patients with pustulosis than for those with cellulitis/abscess or invasive infections (P < .01). Fever at presentation was more likely as the severity of disease increased (pustulosis versus cellulitis/abscess: P < .01; cellulitis/abscess versus invasive: P = .02; pustulosis versus invasive: P < .01). The admission status and treatment for different disease manifestations are described in Fig 2.
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Pretreatment
Known antibacterial treatments before hospital presentation included topical (n = 8), oral (n = 9), and intramuscular ceftriaxone (n = 1) and oral and topical combinations (n = 3). Topical medications included mupirocin, bacitracin, Neosporin, and erythromycin eye ointment. Amoxicillin, amoxicillin/clavulanate, azithromycin, cephalexin, and clindamycin were oral medications used. One patient received amoxicillin solely for UTI prophylaxis. The child who was treated the longest before hospital presentation was initially prescribed 7 days of oral clindamycin for a diaper area pustulosis without culture, but treatment was extended to 10 days for a recurrence after the last dose. He was admitted with mastitis that required drainage, and the infecting isolate expressed constitutive clindamycin resistance.
Disposition
After evaluation, 15 (12%) patients were discharged from TCH to continue outpatient treatment, and the remaining patients were admitted (Fig 2). No patient who was discharged from the emergency center was febrile or underwent an SBI evaluation. Two children were treated before presentation with oral antibiotics (1 for UTI prophylaxis), and 1 child was treated with topical antibiotic therapy. Ten children were treated with topical antibiotics alone. Five children were treated with oral antibiotics with or without topical medications for abdominal/groin area infections. One infant with a perirectal abscess underwent incision and drainage in the emergency center before discharge. Documented duration of prescribed outpatient treatment ranged from 7 to 14 days (n = 4) for topical and 7 to 12 days (n = 4) for oral antibiotic therapy. Two additional patients were discharged from the hospital without antibiotics. One patient was recalled for admission because of a positive skin-culture result. One patient initially presented with decreased movement and pain at the right shoulder and temperature of 100°F. He had worsening symptoms and was subsequently admitted with osteomyelitis and septic arthritis.
Initial Evaluation
All cases with the exception of 3 invasive cases were evaluated by culture and Gram stain of the material from the primary site of infection. The Gram stain revealed Gram-positive cocci for 79 (65%) of 121 patients. Potential pathogens other than S aureus that were isolated from primary infection site cultures included Klebsiella species (n = 12), Escherichia coli (n = 9), Enterobacter species (n = 6), Clostridium species (n = 2), Enterococcus species (n = 2), Serratia species (n = 1), Proteus species (n = 1), Pseudomonas species (n = 1), Pantoea species (n = 1), Acinetobacter species (n = 1), Bacillus species (n = 1), and Propionibacterium species (n = 1). Cultures from patients with drainage procedures contained other organisms less frequently than those from patients without drainage procedures (9 of 49 [18%] vs 29 of 77 [38%]; P = .03). Four infants received antibiotic coverage for bacterial co-infection with Klebsiella species or Enterobacter species at the primary S aureus infection site. There was no relationship between the initial WBC count or absolute neutrophil count and the likelihood of a diagnosis of invasive disease. When the percentage of immature neutrophils was compared with total neutrophil count, patients with invasive infections had increased ratios compared with patients with pustulosis and cellulitis/abscess; patients with cellulitis/abscess had increased ratios compared with patients with pustulosis; however, the sensitivity for invasive infection using a threshold of 10% was only 67%.
Many neonates underwent evaluation for SBI (Table 1). One uncircumcised boy with phimosis had 10000 CFU/mL Enterobacter species isolated from the urine; no initial urinalysis was obtained. His groin pustulosis included penile lesions, and his pustular culture grew both S aureus and Enterobacter species. Another uncircumcised boy had a urine culture with only 1000 CFU/mL S aureus but subsequently had purulent material aspirated from a perinephric abscess, which also grew MRSA. A third circumcised boy had >100000 CFU/mL S aureus isolated from the urine in addition to S aureus isolated from synovial fluid associated with septic arthritis; the initial urinalysis revealed 11 to 20 WBCs per high-power field. Two additional boys were treated but did not meet the UTI criteria.
CSF Pleocytosis
None of 84 CSF cultures isolated S aureus. Eleven infants were found to have CSF pleocytosis (Table 2). Disease severity, season, ethnicity, gender, age, and the presence of bacteremia or UTI were not related to the CSF WBC count. Two infants were treated for the CSF pleocytosis despite negative culture results because they received an antibiotic before their lumbar punctures were performed. Only 4 (36%) patients had a history of fever at the time of presentation. Only 1 patient had a CSF viral evaluation; both the viral culture and herpes simplex virus (HSV) polymerase chain reaction were negative. Seven (70%) of 10 available isolates from the primary infection site had a PFGE pattern consistent with USA300.
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Antibiotic Selection
Intravenous antibiotic selection is described in Table 1. Empiric antibiotics were initiated within 2 days of treatment onset. Definitive antibiotics were the final antistaphylococcal coverage chosen in patients who were hospitalized for >4 days at TCH.
The predominant antistaphylococcal monotherapy empiric choice for pustulosis and cellulitis/abscess was clindamycin for 75% (18 of 24) and 58% (31 of 53), respectively. All patients who had invasive manifestations and were empirically treated for S aureus with 1 exception received vancomycin; 33% also received nafcillin or clindamycin. Eighty-nine (71%) patients were treated with gentamicin, ampicillin, or cephalosporins for synergy or empiric coverage for other bacteria. The presence of documented fever had no specific relationship to antibiotic choice. Patients with cellulitis/abscess only in the upper body were more likely to be treated with mono antistaphylococcal therapy, usually clindamycin, than patients with lower body involvement (94% [32 of 34] vs 64% [21 of 33]; P = .003).
Early Discharge Versus Full Inpatient Therapy
Sixty-two patients were discharged after inpatient therapy to complete treatment with oral and/or topical antibiotics (ie, early discharge; Fig 2). Patients with pustulosis and cellulitis/abscess were more likely to have early discharge with oral or topical treatment than patients with invasive infections (P < .001 and P = .002, respectively). Only 1 patient with invasive disease was discharged on oral antibiotic therapy. This patient had septic shock and trunk cellulitis/abscess and completed 15 days of inpatient therapy before discharge with 7 days of clindamycin. Patients with pustulosis were more likely to be treated with topical therapy only after early discharge than were patients with cellulitis/abscess (P = .04). Eighty percent (16 of 20) of patients with mastitis alone completed treatment with outpatient oral antibiotics. Four inpatients (3 with pustulosis and 1 with cellulitis/abscess) received topical antibiotics as their sole inpatient antistaphylococcal antibiotic. Some patients had additional diagnoses that affected the location of care and duration of hospitalization.
Oral Antibiotic Choice After Inpatient Therapy
Clindamycin was the most commonly used oral antibiotic for both MRSA (32 of 33 [97%]) and methicillin-susceptible S aureus (MSSA; 8 of 16 [50%]) infection. Five patients were treated with cephalexin, and 2 patients were treated with amoxicillin/clavulanate. Three patients who were older than 21 days at discharge were treated with trimethoprim-sulfamethoxazole.
Treatment Length
Table 1 describes the length of effective treatment for patients who received antistaphylococcal systemic therapy. Pretreatment with oral antibiotic therapy is not included because the therapy was presumed to be ineffective. Patients who were transferred to other institutions and 1 patient who died were not included in Table 1.
Outcome
Only 1 patient is known to have had a treatment failure after evaluation at TCH. He presented with mastitis and chest cellulitis that measured 2.5 x 2 cm at 18 days of age to the TCH emergency center. He received cephalexin before his initial presentation to TCH. Blood, urine, and CSF cultures were negative. Ampicillin, gentamicin, and vancomycin were initiated. He was transferred to another facility by family request. After 72 hours of intravenous ampicillin, gentamicin, and clindamycin and an attempted aspiration, the patient was discharged on oral clindamycin. He returned to TCH 4 days after discharge, at 25 days of age, with a 5 x 4 cm mastitis and was admitted on intravenous clindamycin. The next day, a mastotomy was performed with removal of 8 mL of purulent material that grew MRSA that was susceptible to clindamycin. He was discharged at 31 days of age after completing his entire intravenous antibiotic course.
Five patients had a second S aureus infection after an initial neonatal CA S aureus infection. All infections occurred >1 month after the final treatment day and therefore are considered reinfection, not treatment failure. Neonate 1 had an initial MRSA omphalitis and presented at 9 months of age with MRSA osteomyelitis of the femur and distal thumb complicated by UTI, bacteremia, CSF pleocytosis (11 WBCs per mm3), and pericardial effusion. Neonate 2, with MRSA mastitis, developed another cellulitis (no culture obtained) at 5 months of age and an MRSA hand infection at 2 years of age. Neonate 3 initially presented with MSSA groin pustulosis and developed an MSSA otitis externa, otitis media, and early mastoiditis at 7 months of age. Neonate 4 had MRSA mastitis and at 2 months of age developed an MRSA dacryocystitis and preseptal cellulitis. Neonate 5 had an MRSA sacral abscess as a neonate and developed an MRSA scalp abscess at 9 months of age. Other children may have experienced a second infection or treatment failure but were treated elsewhere. For 3 patients, the isolates from the first and second infections had identical susceptibility patterns. Neonate 2 had an initial isolate that was resistant whereas the second isolate was susceptible to erythromycin. Neonate 5 had an initial isolate that was constitutively resistant to clindamycin, whereas the second isolate was susceptible to clindamycin. One additional patient with an extensive family history of skin and soft tissue infections initially had diffuse MRSA pustulosis involving the ears, axilla, and groin and developed a culture-negative humerus osteomyelitis and septic arthritis at 7 months of age.
Viral Infection
Thirty-two patients were evaluated for viral infection. Seventeen patients were evaluated for HSV by specific testing, and 9 patients were treated with acyclovir pending laboratory results. Patients who were evaluated or treated for HSV presented with cellulitis/abscess (n = 6), pustulosis (n = 11), and overwhelming liver failure (n = 1). The only patient who was found to have infection with HSV (type 1) also had overwhelming S aureus infection and died. Three infants had positive nasal wash culture results (rhinovirus, enterovirus, and respiratory syncytial virus).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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No consensus guidelines exist regarding the appropriate evaluation and treatment of previously healthy term and late-preterm neonates with CA S aureus infections, especially those caused by CA-MRSA isolates. This is the first study to describe the evaluation and treatment of CA–S aureus infections in the previously healthy neonatal population since the prevalence of CA-MRSA strains began increasing throughout the United States.
S aureus pustulosis may be difficult to distinguish visually from cutaneous HSV infection and normal newborn rashes, including erythema toxicum neonatorum and pustular melanosis. Although Gram stain and eosinophil stain (Wright stain) may be helpful, bacterial culture is the gold standard to diagnose S aureus infection. In our population, 44% of children with culture-positive S aureus pustular lesions had a negative Gram stain. The indication for routine HSV culture in the evaluation of pustulosis requires additional clarification.
Although the mean percentage of immature neutrophils was significantly lower in patients with noninvasive compared with invasive infections, the SDs are wide. Although the percentage of immature neutrophils has been used to differentiate healthy neonates from neonates with group B Streptococcus infection at birth,15 this measure is inadequate to predict invasive disease in any single previously healthy neonate with a known S aureus infection.
Neonates at TCH with skin and soft tissue S aureus infections were frequently evaluated for SBI. No patients with pustulosis had a systemic S aureus infection identified by SBI evaluation, and some patients with pustulosis received no SBI evaluation. Multiple attempts may be needed to obtain these cultures, and contamination may occur. In addition, urine and CSF evaluation may require sampling near the infected area when the patient has a groin-area infection. Some infants required sedation and ultrasound guidance to obtain CSF. The urine culture with 10000 CFU/mL Enterobacter species from 1 neonate may represent contamination from the skin and a tight phimosis. Therefore, term or late-preterm neonates with an unremarkable medical/surgical history, a localized area of pustulosis, no systemic symptoms, and no fever may not require SBI evaluation. A blood culture alone is probably all that is required for neonates who meet these criteria but with diffuse pustulosis involving multiple skin regions. We recommend that all neonates with infections that are more severe than diffuse pustulosis and those with systemic symptoms or fever continue to be evaluated for bacterial infection by blood, urine, and CSF culture until results of prospective studies are available.
In this study, 11 neonates had CSF pleocytosis with negative CSF bacterial culture results. Four infants had CSF pleocytosis with adjusted WBC counts >100/mm3. The cause or pathogenesis of this pleocytosis is unknown. The meningeal inflammation may have a pathogenesis similar to the mononuclear aseptic meningitis described concurrent with UTI in infants. Potential mechanisms include known or as yet unidentified proinflammatory molecules that are produced by S aureus and can cross the intact blood-brain barrier or a concurrent viral meningitis.16,17 Because only 1 patient had a CSF evaluation for viral infection that was negative, the possibility of viral meningitis cannot be excluded.
As our experience with CA S aureus infections has increased, treating patients with local pustulosis in the outpatient setting with topical antibiotic therapy alone seems to be reasonable as was preliminarily recommended by some experts.1,8 We recommend admitting all neonates with infections that are more severe than pustulosis and those who receive any evaluation for bacterial infection of the blood, urine, or CSF. Empiric antibiotics should be based on the local susceptibility pattern of CA S aureus isolates; clindamycin with or without gentamicin for patients with noninvasive disease and vancomycin, nafcillin, and gentamicin for patients with invasive infections are commonly used in our setting, where <10% of CA S aureus isolates are resistant to clindamycin.18
It is essential that criteria for the length of inpatient therapy be established for patients with noninvasive infections who are discharged to continue treatment at home. These criteria should include resolution of systemic symptoms and fever, improvement in the disease, and that any systemic bacterial cultures obtained not isolate pathogens after 48 hours of incubation. Other factors to consider include the availability of antibacterial susceptibility results and parental cooperation to adjust therapy to the most appropriate antibiotic choice after discharge, if necessary. Patients with invasive infections should complete antibiotic treatment intravenously. Some patients who require a prolonged treatment course (eg, osteomyelitis) may be candidates for home intravenous antibiotics.
Forty-nine neonates were treated with oral antibiotics after initial intravenous therapy. Amoxicillin-clavulanate and cephalexin have adequate oral bioavailability in the neonate.19,20 Clindamycin has adequate oral bioavailability when administered to infants 1 to 6 months of age.21 Although similar information is not available for neonates, clindamycin is approved for oral administration in neonatal infection.22 Because trimethoprim-sulfamethoxazole may increase the risk for kernicterus by displacing bilirubin in the first few weeks of age, its use should be delayed beyond the immediate neonatal period.23–25 This issue may be important in areas of increasing clindamycin resistance. Linezolid is another oral antibiotic alternative that is approved for neonatal use26 and may be considered when the S aureus isolate is resistant to other oral antibiotic choices. This medication should be given under close supervision by an infectious disease expert.
We found only 1 patient with an outpatient treatment failure on oral antibiotics. Possible explanations for his treatment failure include poor antibiotic compliance, poor oral antibiotic absorption with inadequate levels to penetrate the abscess site, and the need for adequate drainage. Other children may have experienced outpatient treatment failure but were treated by a non-TCH health care provider and the chart was not available to us. A comprehensive follow-up program for neonates is imperative when treatment is initiated or completed in the outpatient setting to monitor carefully the response to therapy.
Clinical studies are needed to determine duration of therapy for noninvasive infections, because subjective durations of 5, 7, or 10 days are often prescribed. As highlighted in Table 1, the average oral prescription length after intravenous antibiotics was 7 days for both patients with pustulosis and patients with cellulitis/abscess despite clearly different disease severity.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Practitioners at our institution are using varied evaluation and treatment strategies for neonatal CA S aureus disease, and prospective trials with close follow-up are needed to determine the optimal management strategy, including duration of treatment based on response to therapy in this vulnerable population.
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ACKNOWLEDGMENTS |
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This study was supported in part by a grant from Pfizer, Inc.
We thank Linda B. Lamberth for technical assistance.
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FOOTNOTES |
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Accepted May 30, 2007.
Address correspondence to Sheldon L. Kaplan, MD, Texas Children's Hospital, Mail Code 3-2371, 6621 Fannin St, Houston, TX 77030. E-mail: skaplan{at}bcm.tmc.edu
Financial Disclosure: Dr Kaplan received a grant from Pfizer for the Staphylococcus aureus study. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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