Russell J McCulloh, MD

Staphylococcal scalded skin syndrome (SSSS) is an exfoliative toxin-mediated dermatitis that predominantly occurs in young children. Multiple recent reports indicate a rising incidence of this disease.^1-4 Recommended treatment for SSSS includes antistaphylococcal antibiotics and supportive care measures.^5,6 Elimination or reduction of the toxin-producing Staphylococcus aureus is thought to help limit disease progression and promote recovery. Experts advocate for the use of antibiotics even when there is no apparent focal source of infection, such as an abscess.^6,7

Several factors may affect antibiotic selection, including the desire to inhibit toxin production and to target the causative pathogen in a bactericidal fashion. Because SSSS is toxin mediated, clindamycin is often recommended because of its inhibition of toxin synthesis.^5,8 The clinical utility of adding other antibiotics to clindamycin for coverage of methicillin-sensitive S aureus (MSSA) or methicillin-resistant S aureus (MRSA) is uncertain. Several studies report MSSA to be the predominant pathogen identified by culture^2,9; however, SSSS caused by MRSA has been reported.^9-11 Additionally, bactericidal antibiotics (eg, nafcillin) have been considered to hold potential clinical advantage as compared with bacteriostatic antibiotics (eg, clindamycin), even though clinical studies have not clearly demonstrated this advantage in the general population.^12,13 Some experts recommend additional MRSA or MSSA coverage (such as vancomycin or nafcillin) in patients with high illness severity or nonresponse to therapy, or in areas where there is high prevalence of staphylococcal resistance to clindamycin.^5,7,9,14 Alternatively, for areas with low MRSA prevalence, monotherapy with an anti-MSSA antibiotic is another potential option. No recent studies have compared patient outcomes among antibiotic regimens in children with SSSS.

Knowledge of the outcomes associated with different antibiotic regimens for children hospitalized with SSSS is needed and could be used to improve patient outcomes and potentially promote antibiotic stewardship. In this study, our objectives were to (1) describe antibiotic regimens given to children hospitalized with SSSS, and (2) examine the association of three antibiotic regimens commonly used for SSSS (clindamycin monotherapy, clindamycin plus additional MSSA coverage, and clindamycin plus additional MRSA coverage) with patient outcomes of length of stay (LOS), treatment failure, and cost in a large cohort of children at US children’s hospitals.

We conducted a multicenter, retrospective cohort study utilizing data within the Pediatric Health Information System (PHIS) database from July 1, 2011, to June 30, 2016. Thirty-five free-standing tertiary care US children’s hospitals within 24 states were included. The Children’s Hospital Association (Lenexa, Kansas) maintains the PHIS database, which contains de-identified patient information, including diagnoses (with International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification [ICD-9-CM, ICD-10-CM]), demographics, procedures, and daily billing records. Data quality and reliability are confirmed by participating institutions and the Children’s Hospital Association.¹⁵ The local institutional review board (IRB) deemed the study exempt from formal IRB review, as patient information was de-identified.

Study Population

We included hospitalized children aged newborn to 18 years with a primary or secondary diagnosis of SSSS (ICD-9, 695.81; ICD-10, L00). Children whose primary presentation and admission were to a PHIS hospital were included; children transferred from another hospital were excluded. The following exclusion criteria were based on previously published methodology.¹⁶ Children with complex chronic medical conditions as classified by Feudtner et al¹⁷ were excluded, since these children may require a different treatment approach than the general pediatric population. In order to decrease diagnostic ambiguity, we excluded children if an alternative dermatologic diagnosis was recorded as a principal or secondary diagnosis (eg, Stevens-Johnson syndrome or scarlet fever).¹⁶ Finally, hospitals with fewer than 10 children with SSSS during the study period were excluded.

Antibiotic Regimen Groups

We used PHIS daily billing codes to determine the antibiotics received by the study population. Children were classified into antibiotic regimen groups based on whether they received specific antibiotic combinations. Antibiotics received on any day during the hospitalization, including in the emergency department (ED), were used to assign patients to regimen groups. Antibiotics were classified into regimen groups based on consensus among study investigators, which included two board-certified pediatric infectious diseases specialists (A.C., R.M.). Antibiotic group definitions are listed in Table 1. Oral and intravenous (IV) therapies were grouped together for clindamycin, cephalexin/cefazolin, and linezolid because of good oral bioavailability in most situations.¹⁸ The three most common antistaphylococcal groups were chosen for further analysis: clindamycin alone, clindamycin plus MSSA coverage, and clindamycin plus MRSA coverage. The clindamycin group was defined as children with receipt of oral or IV clindamycin. Children who received clindamycin with additional MSSA coverage, such as cefazolin or nafcillin, were categorized as the clindamycin plus MSSA group. Children who received clindamycin with additional MRSA coverage, such as vancomycin or linezolid, were categorized as the clindamycin plus MRSA group. We chose not to include children who received the above regimens plus other antibiotics with partial antistaphylococcal activity, such as ampicillin, gentamicin, or ceftriaxone, in the clindamycin plus MSSA and clindamycin plus MRSA groups. We excluded these antibiotics to decrease the heterogeneity in the definition of regimen groups and allow a more direct comparison for effectiveness.

Covariates

Covariates included age, sex, ethnicity and/or race, payer type, level of care, illness severity, and region. The variable definitions below are in keeping with a prior study of SSSS.¹⁶ Age was categorized as: birth to 59 days, 2 to 11 months, 1 to 4 years (preschool age), 5 to 10 years (school age), and 11 to 18 years (adolescent). We examined infants younger than 60 days separately from older infants because this population may warrant additional treatment considerations. Race and ethnicity were categorized as White (non-Hispanic), African American (non-Hispanic), Hispanic, or other. Payer types included government, private, or other. Level of care was assigned as either intensive care or acute care. Illness severity was assigned using the All Patient Refined Diagnosis Related Group (APR-DRG; 3M Corporation, St. Paul, Minnesota) severity levels.¹⁹ In line with a prior study,¹⁶ we defined “low illness severity” as the APR-DRG minor (1) classification. The moderate (2), major (3), and extreme (4) classifications were defined as “moderate to high illness severity,” since there were very few classifications of major or extreme (<5%) illness severity. We categorized hospitals into the following US regions: Northeast, Midwest, South, and West.

Outcome Measures

The primary outcome was hospital LOS in days, and secondary outcomes were treatment failure and hospital costs. Hospital LOS was chosen as the primary outcome to represent the time needed for the child to show clinical improvement. Treatment failure was defined as a same-cause 14-day ED revisit or hospital readmission, and these were determined to be same-cause if a diagnosis for SSSS (ICD-9, 695.81; ICD-10, L00) was documented for the return encounter. The 14-day interval for readmission and ED revisit was chosen to measure any relapse of symptoms after completion of antibiotic therapy, similar to a prior study of treatment failure in skin and soft tissue infections.²⁰ Total costs of the hospitalization were estimated from charges using hospital- and year-specific cost-to-charge ratios. Subcategories of cost, including clinical, pharmacy, imaging, laboratory, supply, and other, were also compared among the three groups.

Statistical Analysis

Demographic and clinical characteristics of children were summarized using frequencies and percentages for categorical variables and medians with interquartile ranges (IQRs) for continuous variables. These were compared across antibiotic groups using chi-square and Kruskal–Wallis tests, respectively. In unadjusted analyses, outcomes were compared across antibiotic regimen groups using these same statistical tests. In order to account for patient clustering within hospitals, generalized linear mixed-effects models were used to model outcomes with a random intercept for each hospital. Models were adjusted for SSSS being listed as a principal or secondary diagnosis, race, illness severity, and level of care. We log-transformed LOS and cost data prior to modeling because of the nonnormal distributions for these data. Owing to the inability to measure the number of antibiotic doses, and to reduce the possibility of including children who received few regimen-defined combination antibiotics, a post hoc sensitivity analysis was performed. This analysis used an alternative definition for antibiotic regimen groups, for which children admitted for 2 or more calendar days must have received regimen-specified antibiotics on at least 2 days of the admission. Additionally, outcomes were stratified by low and moderate/high illness severity and compared across the three antibiotic regimen groups. All analyses were performed with SAS (SAS 9.4; SAS Institute, Cary, North Carolina), and P values of less than .05 were considered statistically significant.

Overall, 1,815 hospitalized children with SSSS were identified in the PHIS database, and after application of the exclusion criteria, 1,259 children remained, with 1,247 (99%) receiving antibiotics (Figure). The antibiotic regimens received by these children are described in Table 1. Of these, 828 children (66%) received one of the three most common antistaphylococcal regimens (clindamycin, clindamycin + MSSA, and clindamycin + MRSA) and were included for further analysis.

Characteristics of the 828 children are presented in Table 2. Most children (82%) were aged 4 years or younger, and distributions of age, sex, and insurance payer were similar among children receiving the three regimens. Thirty-two percent had moderate to high illness severity, and 3.5% required management in the intensive care setting. Of the three antibiotic regimens, clindamycin monotherapy was most common (47%), followed by clindamycin plus MSSA coverage (33%), and clindamycin plus MRSA coverage (20%). A higher proportion of children in the clindamycin plus MRSA group were African American and were hospitalized in the South. Children receiving clindamycin plus MRSA coverage had higher illness severity (44%) as compared with clindamycin monotherapy (28%) and clindamycin plus MSSA coverage (32%) (P = .001). Additionally, a larger proportion of children treated with clindamycin plus MRSA coverage were managed in the intensive care setting as compared with the clindamycin plus MSSA or clindamycin monotherapy groups.

Among the 828 children with SSSS, the median LOS was 2 days (IQR, 2-3), and treatment failure was 1.1% (95% CI, 0.4-1.8). After adjustment for illness severity, race, payer, and region (Table 3), the three antibiotic regimens were not associated with significant differences in LOS or treatment failure. Costs were significantly different among the three antibiotic regimens. Clindamycin plus MRSA coverage was associated with the greatest costs, whereas clindamycin monotherapy was associated with the lowest costs (mean, $5,348 vs $4,839, respectively; P < .001) (Table 3). In a sensitivity analysis using an alternative antibiotic regimen definition, we found results in line with the primary analysis, with no statistically significant differences in LOS (P = .44) or treatment failure (P = .54), but significant differences in cost (P < .001). Additionally, the same findings were present for LOS, treatment failure, and cost when outcomes were stratified by illness severity (Appendix Table). However, significant contributors to the higher cost in the clindamycin plus MRSA group did vary by illness severity stratification. Laboratory, supply, and pharmacy cost categories differed significantly among antibiotic groups for the low illness severity strata, whereas pharmacy was the only significant cost category difference in moderate/high illness severity.

Clindamycin monotherapy, clindamycin plus MSSA coverage, and clindamycin plus MRSA coverage are the most commonly administered antistaphylococcal antibiotic regimens for children hospitalized with SSSS at US children’s hospitals. Our multicenter study found that, across these antistaphylococcal antibiotic regimens, there were no associated differences in hospital LOS or treatment failure. However, the antibiotic regimens were associated with significant differences in overall hospital costs. These findings suggest that the use of clindamycin with additional MSSA or MRSA antibiotic coverage for children with SSSS may not be associated with additional clinical benefit, as compared with clindamycin monotherapy, and could potentially be more costly.

Prior literature describing LOS in relation to antibiotic use for children with SSSS is limited. Authors of a recent case series of 21 children in Philadelphia reported approximately 50% of children received clindamycin monotherapy or combination therapy, but patient outcomes such as LOS were not described.⁹ Clindamycin use and outcomes have been described in smaller studies and case reports of SSSS, which reported positive outcomes such as patient recovery and lack of disease recurrence.^2,9,21 A small retrospective, comparative effectiveness study of 30 neonates with SSSS examined beta-lactamase–resistant penicillin use with and without cephalosporins. They found no effect on LOS, but findings were limited by a small sample size.²² Our study cohort included relatively few neonates, and thus our findings may not be applicable to this population subgroup. We chose not to include regimens with third-generation cephalosporins or ampicillin, which may have limited the number of included neonates, because these antibiotics are frequently administered during evaluation for invasive bacterial infections.²³ We found a very low occurrence of treatment failure in our study cohort across all three groups, which is consistent with other studies of SSSS that report an overall good prognosis and low recurrence and/or readmission rates.^6,16,24 The low prevalence of treatment failure, however, precluded our ability to detect small differences among antibiotic regimen groups that may exist.

We observed that cost differed significantly across antibiotic regimen groups, with lowest cost associated with clindamycin monotherapy in adjusted analysis despite similar LOS. Even with our illness-severity adjustment, there may have been other unmeasured factors resulting in the higher cost associated with the combination groups. Hence, we also examined cost breakdown with a stratified analysis by illness severity. We found that pharmacy costs were significantly different among antibiotic groups in both illness severity strata, whereas those with low illness severity also differed by laboratory and supply costs. Thus, pharmacy cost differences may be the largest driver in the cost differential among groups. Lower cost in the clindamycin monotherapy group is likely due to administration of a single antibiotic. The reason for supply and laboratory cost differences is uncertain, but higher cost in the clindamycin plus MRSA group could possibly be from laboratory testing related to drug monitoring (eg, renal function testing or drug levels). While other studies have reported costs for hospitalized children with SSSS associated with different patient characteristics or diagnostic testing,^1,16 to our knowledge, no other studies have reported cost related to antibiotic regimens for SSSS. As healthcare reimbursements shift to value-based models, identifying treatment regimens with equal efficacy but lower cost will become increasingly important. Future studies should also examine other covariates and outcomes, such as oral vs parenteral antibiotic use, use of monitoring laboratories related to antibiotic choice, and adverse drug effects.

Several strengths and additional limitations apply to our study. Our study is one of the few to describe outcomes associated with antibiotic regimens for children with SSSS. With the PHIS database, we were able to include a large number of children with SSSS from children’s hospitals across the United States. Although the PHIS database affords these strengths, there are limitations inherent to administrative data. Children with SSSS were identified by documented ICD-9 and ICD-10 diagnostic codes, which might lead to misclassification. However, misclassification is less likely because only one ICD-9 and ICD-10 code exists for SSSS, and the characteristics of this condition are specific. Also, diagnostic codes for other dermatologic conditions (eg, scarlet fever) were excluded to further reduce the chance of misclassification. A limitation to our use of PHIS billing codes was the inability to confirm the dosage of antibiotics given, the number of doses, or whether antibiotics were prescribed upon discharge. Another limitation is that children whose antibiotic therapy was changed during hospitalization (eg, from clindamycin monotherapy to cefazolin monotherapy) were categorized into the combination groups. However, the sensitivity analysis performed based on a stricter antibiotic group definition (receipt of both antibiotics on at least 2 calendar days) did not alter the outcomes, which is reassuring. We were unable to assess the use of targeted antibiotic therapy because clinical data (eg, microbiology results) were not available. However, this may be less important because some literature suggests that cultures for S aureus are obtained infrequently² and may be difficult to interpret when obtained,²⁵ since culture growth can represent colonization rather than causative strains. An additional limitation is that administrative data do not include certain clinical outcomes, such as fever duration or degree of skin involvement, which could have differed among the groups. Last, the PHIS database only captures revisits or readmissions to PHIS hospitals, and so we are unable to exclude the possibility of a child being seen at or readmitted to another hospital.

Due to the observational design of this study and potential for incomplete measurement of illness severity, we recommend a future prospective trial with randomization to confirm these findings. One possible reason that LOS did not differ among groups is that the burden of clindamycin-resistant strains in our cohort could be low, and the addition of MSSA or MRSA coverage does not result in a clinically important increase in S aureus coverage. However, pooled pediatric hospital antibiogram data suggest the overall rate of clindamycin resistance is close to 20% in hospitals located in all US regions.²⁶ Limited studies also suggest that MSSA may be the predominant pathogen associated with SSSS.^2,9 To address this, future randomized trials could compare the effectiveness of clindamycin monotherapy to MSSA-specific agents like cefazolin or nafcillin. Unfortunately, anti-MSSA monotherapy was not evaluated in our study because very few children received this treatment. Using monotherapy as opposed to multiple antibiotics has the potential to promote antibiotic stewardship for antistaphylococcal antibiotics in the management of SSSS. Reducing unnecessary antibiotic use not only potentially affects antibiotic resistance, but could also benefit patients in reducing possible side effects, cost, and IV catheter complications.²⁷ However, acknowledging our study limitations, our findings should be applied cautiously in clinical settings, in the context of local antibiogram data, individual culture results, and specific patient factors. The local clindamycin resistance rate for both MSSA and MRSA should be considered. Many antibiotics chosen to treat MRSA—such as vancomycin and trimethoprim/sulfamethoxazole—will also have anti-MSSA activity and may have lower local resistance rates than clindamycin. Practitioners may also consider how each antibiotic kills bacteria; for example, beta-lactams rely on bacterial replication, but clindamycin does not. Each factor should influence how empiric treatment, whether monotherapy or combination, is chosen for children with SSSS.

In this large, multicenter cohort of hospitalized children with SSSS, we found that the addition of MSSA or MRSA coverage to clindamycin monotherapy was not associated with differences in outcomes of hospital LOS and treatment failure. Furthermore, clindamycin monotherapy was associated with lower overall cost. Prospective randomized studies are needed to confirm these findings and assess whether clindamycin monotherapy, monotherapy with an anti-MSSA antibiotic, or alternative regimens are most effective for treatment of children with SSSS.

Staphylococcal scalded skin syndrome (SSSS) is an exfoliative toxin-mediated dermatitis that predominantly occurs in young children. Multiple recent reports indicate a rising incidence of this disease.^1-4 Recommended treatment for SSSS includes antistaphylococcal antibiotics and supportive care measures.^5,6 Elimination or reduction of the toxin-producing Staphylococcus aureus is thought to help limit disease progression and promote recovery. Experts advocate for the use of antibiotics even when there is no apparent focal source of infection, such as an abscess.^6,7

Several factors may affect antibiotic selection, including the desire to inhibit toxin production and to target the causative pathogen in a bactericidal fashion. Because SSSS is toxin mediated, clindamycin is often recommended because of its inhibition of toxin synthesis.^5,8 The clinical utility of adding other antibiotics to clindamycin for coverage of methicillin-sensitive S aureus (MSSA) or methicillin-resistant S aureus (MRSA) is uncertain. Several studies report MSSA to be the predominant pathogen identified by culture^2,9; however, SSSS caused by MRSA has been reported.^9-11 Additionally, bactericidal antibiotics (eg, nafcillin) have been considered to hold potential clinical advantage as compared with bacteriostatic antibiotics (eg, clindamycin), even though clinical studies have not clearly demonstrated this advantage in the general population.^12,13 Some experts recommend additional MRSA or MSSA coverage (such as vancomycin or nafcillin) in patients with high illness severity or nonresponse to therapy, or in areas where there is high prevalence of staphylococcal resistance to clindamycin.^5,7,9,14 Alternatively, for areas with low MRSA prevalence, monotherapy with an anti-MSSA antibiotic is another potential option. No recent studies have compared patient outcomes among antibiotic regimens in children with SSSS.

Knowledge of the outcomes associated with different antibiotic regimens for children hospitalized with SSSS is needed and could be used to improve patient outcomes and potentially promote antibiotic stewardship. In this study, our objectives were to (1) describe antibiotic regimens given to children hospitalized with SSSS, and (2) examine the association of three antibiotic regimens commonly used for SSSS (clindamycin monotherapy, clindamycin plus additional MSSA coverage, and clindamycin plus additional MRSA coverage) with patient outcomes of length of stay (LOS), treatment failure, and cost in a large cohort of children at US children’s hospitals.

We conducted a multicenter, retrospective cohort study utilizing data within the Pediatric Health Information System (PHIS) database from July 1, 2011, to June 30, 2016. Thirty-five free-standing tertiary care US children’s hospitals within 24 states were included. The Children’s Hospital Association (Lenexa, Kansas) maintains the PHIS database, which contains de-identified patient information, including diagnoses (with International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification [ICD-9-CM, ICD-10-CM]), demographics, procedures, and daily billing records. Data quality and reliability are confirmed by participating institutions and the Children’s Hospital Association.¹⁵ The local institutional review board (IRB) deemed the study exempt from formal IRB review, as patient information was de-identified.

Study Population

We included hospitalized children aged newborn to 18 years with a primary or secondary diagnosis of SSSS (ICD-9, 695.81; ICD-10, L00). Children whose primary presentation and admission were to a PHIS hospital were included; children transferred from another hospital were excluded. The following exclusion criteria were based on previously published methodology.¹⁶ Children with complex chronic medical conditions as classified by Feudtner et al¹⁷ were excluded, since these children may require a different treatment approach than the general pediatric population. In order to decrease diagnostic ambiguity, we excluded children if an alternative dermatologic diagnosis was recorded as a principal or secondary diagnosis (eg, Stevens-Johnson syndrome or scarlet fever).¹⁶ Finally, hospitals with fewer than 10 children with SSSS during the study period were excluded.

Antibiotic Regimen Groups

We used PHIS daily billing codes to determine the antibiotics received by the study population. Children were classified into antibiotic regimen groups based on whether they received specific antibiotic combinations. Antibiotics received on any day during the hospitalization, including in the emergency department (ED), were used to assign patients to regimen groups. Antibiotics were classified into regimen groups based on consensus among study investigators, which included two board-certified pediatric infectious diseases specialists (A.C., R.M.). Antibiotic group definitions are listed in Table 1. Oral and intravenous (IV) therapies were grouped together for clindamycin, cephalexin/cefazolin, and linezolid because of good oral bioavailability in most situations.¹⁸ The three most common antistaphylococcal groups were chosen for further analysis: clindamycin alone, clindamycin plus MSSA coverage, and clindamycin plus MRSA coverage. The clindamycin group was defined as children with receipt of oral or IV clindamycin. Children who received clindamycin with additional MSSA coverage, such as cefazolin or nafcillin, were categorized as the clindamycin plus MSSA group. Children who received clindamycin with additional MRSA coverage, such as vancomycin or linezolid, were categorized as the clindamycin plus MRSA group. We chose not to include children who received the above regimens plus other antibiotics with partial antistaphylococcal activity, such as ampicillin, gentamicin, or ceftriaxone, in the clindamycin plus MSSA and clindamycin plus MRSA groups. We excluded these antibiotics to decrease the heterogeneity in the definition of regimen groups and allow a more direct comparison for effectiveness.

Covariates

Covariates included age, sex, ethnicity and/or race, payer type, level of care, illness severity, and region. The variable definitions below are in keeping with a prior study of SSSS.¹⁶ Age was categorized as: birth to 59 days, 2 to 11 months, 1 to 4 years (preschool age), 5 to 10 years (school age), and 11 to 18 years (adolescent). We examined infants younger than 60 days separately from older infants because this population may warrant additional treatment considerations. Race and ethnicity were categorized as White (non-Hispanic), African American (non-Hispanic), Hispanic, or other. Payer types included government, private, or other. Level of care was assigned as either intensive care or acute care. Illness severity was assigned using the All Patient Refined Diagnosis Related Group (APR-DRG; 3M Corporation, St. Paul, Minnesota) severity levels.¹⁹ In line with a prior study,¹⁶ we defined “low illness severity” as the APR-DRG minor (1) classification. The moderate (2), major (3), and extreme (4) classifications were defined as “moderate to high illness severity,” since there were very few classifications of major or extreme (<5%) illness severity. We categorized hospitals into the following US regions: Northeast, Midwest, South, and West.

Outcome Measures

The primary outcome was hospital LOS in days, and secondary outcomes were treatment failure and hospital costs. Hospital LOS was chosen as the primary outcome to represent the time needed for the child to show clinical improvement. Treatment failure was defined as a same-cause 14-day ED revisit or hospital readmission, and these were determined to be same-cause if a diagnosis for SSSS (ICD-9, 695.81; ICD-10, L00) was documented for the return encounter. The 14-day interval for readmission and ED revisit was chosen to measure any relapse of symptoms after completion of antibiotic therapy, similar to a prior study of treatment failure in skin and soft tissue infections.²⁰ Total costs of the hospitalization were estimated from charges using hospital- and year-specific cost-to-charge ratios. Subcategories of cost, including clinical, pharmacy, imaging, laboratory, supply, and other, were also compared among the three groups.

Statistical Analysis

Demographic and clinical characteristics of children were summarized using frequencies and percentages for categorical variables and medians with interquartile ranges (IQRs) for continuous variables. These were compared across antibiotic groups using chi-square and Kruskal–Wallis tests, respectively. In unadjusted analyses, outcomes were compared across antibiotic regimen groups using these same statistical tests. In order to account for patient clustering within hospitals, generalized linear mixed-effects models were used to model outcomes with a random intercept for each hospital. Models were adjusted for SSSS being listed as a principal or secondary diagnosis, race, illness severity, and level of care. We log-transformed LOS and cost data prior to modeling because of the nonnormal distributions for these data. Owing to the inability to measure the number of antibiotic doses, and to reduce the possibility of including children who received few regimen-defined combination antibiotics, a post hoc sensitivity analysis was performed. This analysis used an alternative definition for antibiotic regimen groups, for which children admitted for 2 or more calendar days must have received regimen-specified antibiotics on at least 2 days of the admission. Additionally, outcomes were stratified by low and moderate/high illness severity and compared across the three antibiotic regimen groups. All analyses were performed with SAS (SAS 9.4; SAS Institute, Cary, North Carolina), and P values of less than .05 were considered statistically significant.

Overall, 1,815 hospitalized children with SSSS were identified in the PHIS database, and after application of the exclusion criteria, 1,259 children remained, with 1,247 (99%) receiving antibiotics (Figure). The antibiotic regimens received by these children are described in Table 1. Of these, 828 children (66%) received one of the three most common antistaphylococcal regimens (clindamycin, clindamycin + MSSA, and clindamycin + MRSA) and were included for further analysis.

Characteristics of the 828 children are presented in Table 2. Most children (82%) were aged 4 years or younger, and distributions of age, sex, and insurance payer were similar among children receiving the three regimens. Thirty-two percent had moderate to high illness severity, and 3.5% required management in the intensive care setting. Of the three antibiotic regimens, clindamycin monotherapy was most common (47%), followed by clindamycin plus MSSA coverage (33%), and clindamycin plus MRSA coverage (20%). A higher proportion of children in the clindamycin plus MRSA group were African American and were hospitalized in the South. Children receiving clindamycin plus MRSA coverage had higher illness severity (44%) as compared with clindamycin monotherapy (28%) and clindamycin plus MSSA coverage (32%) (P = .001). Additionally, a larger proportion of children treated with clindamycin plus MRSA coverage were managed in the intensive care setting as compared with the clindamycin plus MSSA or clindamycin monotherapy groups.

Among the 828 children with SSSS, the median LOS was 2 days (IQR, 2-3), and treatment failure was 1.1% (95% CI, 0.4-1.8). After adjustment for illness severity, race, payer, and region (Table 3), the three antibiotic regimens were not associated with significant differences in LOS or treatment failure. Costs were significantly different among the three antibiotic regimens. Clindamycin plus MRSA coverage was associated with the greatest costs, whereas clindamycin monotherapy was associated with the lowest costs (mean, $5,348 vs $4,839, respectively; P < .001) (Table 3). In a sensitivity analysis using an alternative antibiotic regimen definition, we found results in line with the primary analysis, with no statistically significant differences in LOS (P = .44) or treatment failure (P = .54), but significant differences in cost (P < .001). Additionally, the same findings were present for LOS, treatment failure, and cost when outcomes were stratified by illness severity (Appendix Table). However, significant contributors to the higher cost in the clindamycin plus MRSA group did vary by illness severity stratification. Laboratory, supply, and pharmacy cost categories differed significantly among antibiotic groups for the low illness severity strata, whereas pharmacy was the only significant cost category difference in moderate/high illness severity.

Clindamycin monotherapy, clindamycin plus MSSA coverage, and clindamycin plus MRSA coverage are the most commonly administered antistaphylococcal antibiotic regimens for children hospitalized with SSSS at US children’s hospitals. Our multicenter study found that, across these antistaphylococcal antibiotic regimens, there were no associated differences in hospital LOS or treatment failure. However, the antibiotic regimens were associated with significant differences in overall hospital costs. These findings suggest that the use of clindamycin with additional MSSA or MRSA antibiotic coverage for children with SSSS may not be associated with additional clinical benefit, as compared with clindamycin monotherapy, and could potentially be more costly.

Prior literature describing LOS in relation to antibiotic use for children with SSSS is limited. Authors of a recent case series of 21 children in Philadelphia reported approximately 50% of children received clindamycin monotherapy or combination therapy, but patient outcomes such as LOS were not described.⁹ Clindamycin use and outcomes have been described in smaller studies and case reports of SSSS, which reported positive outcomes such as patient recovery and lack of disease recurrence.^2,9,21 A small retrospective, comparative effectiveness study of 30 neonates with SSSS examined beta-lactamase–resistant penicillin use with and without cephalosporins. They found no effect on LOS, but findings were limited by a small sample size.²² Our study cohort included relatively few neonates, and thus our findings may not be applicable to this population subgroup. We chose not to include regimens with third-generation cephalosporins or ampicillin, which may have limited the number of included neonates, because these antibiotics are frequently administered during evaluation for invasive bacterial infections.²³ We found a very low occurrence of treatment failure in our study cohort across all three groups, which is consistent with other studies of SSSS that report an overall good prognosis and low recurrence and/or readmission rates.^6,16,24 The low prevalence of treatment failure, however, precluded our ability to detect small differences among antibiotic regimen groups that may exist.

We observed that cost differed significantly across antibiotic regimen groups, with lowest cost associated with clindamycin monotherapy in adjusted analysis despite similar LOS. Even with our illness-severity adjustment, there may have been other unmeasured factors resulting in the higher cost associated with the combination groups. Hence, we also examined cost breakdown with a stratified analysis by illness severity. We found that pharmacy costs were significantly different among antibiotic groups in both illness severity strata, whereas those with low illness severity also differed by laboratory and supply costs. Thus, pharmacy cost differences may be the largest driver in the cost differential among groups. Lower cost in the clindamycin monotherapy group is likely due to administration of a single antibiotic. The reason for supply and laboratory cost differences is uncertain, but higher cost in the clindamycin plus MRSA group could possibly be from laboratory testing related to drug monitoring (eg, renal function testing or drug levels). While other studies have reported costs for hospitalized children with SSSS associated with different patient characteristics or diagnostic testing,^1,16 to our knowledge, no other studies have reported cost related to antibiotic regimens for SSSS. As healthcare reimbursements shift to value-based models, identifying treatment regimens with equal efficacy but lower cost will become increasingly important. Future studies should also examine other covariates and outcomes, such as oral vs parenteral antibiotic use, use of monitoring laboratories related to antibiotic choice, and adverse drug effects.

Several strengths and additional limitations apply to our study. Our study is one of the few to describe outcomes associated with antibiotic regimens for children with SSSS. With the PHIS database, we were able to include a large number of children with SSSS from children’s hospitals across the United States. Although the PHIS database affords these strengths, there are limitations inherent to administrative data. Children with SSSS were identified by documented ICD-9 and ICD-10 diagnostic codes, which might lead to misclassification. However, misclassification is less likely because only one ICD-9 and ICD-10 code exists for SSSS, and the characteristics of this condition are specific. Also, diagnostic codes for other dermatologic conditions (eg, scarlet fever) were excluded to further reduce the chance of misclassification. A limitation to our use of PHIS billing codes was the inability to confirm the dosage of antibiotics given, the number of doses, or whether antibiotics were prescribed upon discharge. Another limitation is that children whose antibiotic therapy was changed during hospitalization (eg, from clindamycin monotherapy to cefazolin monotherapy) were categorized into the combination groups. However, the sensitivity analysis performed based on a stricter antibiotic group definition (receipt of both antibiotics on at least 2 calendar days) did not alter the outcomes, which is reassuring. We were unable to assess the use of targeted antibiotic therapy because clinical data (eg, microbiology results) were not available. However, this may be less important because some literature suggests that cultures for S aureus are obtained infrequently² and may be difficult to interpret when obtained,²⁵ since culture growth can represent colonization rather than causative strains. An additional limitation is that administrative data do not include certain clinical outcomes, such as fever duration or degree of skin involvement, which could have differed among the groups. Last, the PHIS database only captures revisits or readmissions to PHIS hospitals, and so we are unable to exclude the possibility of a child being seen at or readmitted to another hospital.

Due to the observational design of this study and potential for incomplete measurement of illness severity, we recommend a future prospective trial with randomization to confirm these findings. One possible reason that LOS did not differ among groups is that the burden of clindamycin-resistant strains in our cohort could be low, and the addition of MSSA or MRSA coverage does not result in a clinically important increase in S aureus coverage. However, pooled pediatric hospital antibiogram data suggest the overall rate of clindamycin resistance is close to 20% in hospitals located in all US regions.²⁶ Limited studies also suggest that MSSA may be the predominant pathogen associated with SSSS.^2,9 To address this, future randomized trials could compare the effectiveness of clindamycin monotherapy to MSSA-specific agents like cefazolin or nafcillin. Unfortunately, anti-MSSA monotherapy was not evaluated in our study because very few children received this treatment. Using monotherapy as opposed to multiple antibiotics has the potential to promote antibiotic stewardship for antistaphylococcal antibiotics in the management of SSSS. Reducing unnecessary antibiotic use not only potentially affects antibiotic resistance, but could also benefit patients in reducing possible side effects, cost, and IV catheter complications.²⁷ However, acknowledging our study limitations, our findings should be applied cautiously in clinical settings, in the context of local antibiogram data, individual culture results, and specific patient factors. The local clindamycin resistance rate for both MSSA and MRSA should be considered. Many antibiotics chosen to treat MRSA—such as vancomycin and trimethoprim/sulfamethoxazole—will also have anti-MSSA activity and may have lower local resistance rates than clindamycin. Practitioners may also consider how each antibiotic kills bacteria; for example, beta-lactams rely on bacterial replication, but clindamycin does not. Each factor should influence how empiric treatment, whether monotherapy or combination, is chosen for children with SSSS.

In this large, multicenter cohort of hospitalized children with SSSS, we found that the addition of MSSA or MRSA coverage to clindamycin monotherapy was not associated with differences in outcomes of hospital LOS and treatment failure. Furthermore, clindamycin monotherapy was associated with lower overall cost. Prospective randomized studies are needed to confirm these findings and assess whether clindamycin monotherapy, monotherapy with an anti-MSSA antibiotic, or alternative regimens are most effective for treatment of children with SSSS.

Staphylococcal scalded skin syndrome (SSSS) is an exfoliative toxin-mediated dermatitis that predominantly occurs in young children. Multiple recent reports indicate a rising incidence of this disease.^1-4 Recommended treatment for SSSS includes antistaphylococcal antibiotics and supportive care measures.^5,6 Elimination or reduction of the toxin-producing Staphylococcus aureus is thought to help limit disease progression and promote recovery. Experts advocate for the use of antibiotics even when there is no apparent focal source of infection, such as an abscess.^6,7

Several factors may affect antibiotic selection, including the desire to inhibit toxin production and to target the causative pathogen in a bactericidal fashion. Because SSSS is toxin mediated, clindamycin is often recommended because of its inhibition of toxin synthesis.^5,8 The clinical utility of adding other antibiotics to clindamycin for coverage of methicillin-sensitive S aureus (MSSA) or methicillin-resistant S aureus (MRSA) is uncertain. Several studies report MSSA to be the predominant pathogen identified by culture^2,9; however, SSSS caused by MRSA has been reported.^9-11 Additionally, bactericidal antibiotics (eg, nafcillin) have been considered to hold potential clinical advantage as compared with bacteriostatic antibiotics (eg, clindamycin), even though clinical studies have not clearly demonstrated this advantage in the general population.^12,13 Some experts recommend additional MRSA or MSSA coverage (such as vancomycin or nafcillin) in patients with high illness severity or nonresponse to therapy, or in areas where there is high prevalence of staphylococcal resistance to clindamycin.^5,7,9,14 Alternatively, for areas with low MRSA prevalence, monotherapy with an anti-MSSA antibiotic is another potential option. No recent studies have compared patient outcomes among antibiotic regimens in children with SSSS.

Knowledge of the outcomes associated with different antibiotic regimens for children hospitalized with SSSS is needed and could be used to improve patient outcomes and potentially promote antibiotic stewardship. In this study, our objectives were to (1) describe antibiotic regimens given to children hospitalized with SSSS, and (2) examine the association of three antibiotic regimens commonly used for SSSS (clindamycin monotherapy, clindamycin plus additional MSSA coverage, and clindamycin plus additional MRSA coverage) with patient outcomes of length of stay (LOS), treatment failure, and cost in a large cohort of children at US children’s hospitals.

We conducted a multicenter, retrospective cohort study utilizing data within the Pediatric Health Information System (PHIS) database from July 1, 2011, to June 30, 2016. Thirty-five free-standing tertiary care US children’s hospitals within 24 states were included. The Children’s Hospital Association (Lenexa, Kansas) maintains the PHIS database, which contains de-identified patient information, including diagnoses (with International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification [ICD-9-CM, ICD-10-CM]), demographics, procedures, and daily billing records. Data quality and reliability are confirmed by participating institutions and the Children’s Hospital Association.¹⁵ The local institutional review board (IRB) deemed the study exempt from formal IRB review, as patient information was de-identified.

Study Population

We included hospitalized children aged newborn to 18 years with a primary or secondary diagnosis of SSSS (ICD-9, 695.81; ICD-10, L00). Children whose primary presentation and admission were to a PHIS hospital were included; children transferred from another hospital were excluded. The following exclusion criteria were based on previously published methodology.¹⁶ Children with complex chronic medical conditions as classified by Feudtner et al¹⁷ were excluded, since these children may require a different treatment approach than the general pediatric population. In order to decrease diagnostic ambiguity, we excluded children if an alternative dermatologic diagnosis was recorded as a principal or secondary diagnosis (eg, Stevens-Johnson syndrome or scarlet fever).¹⁶ Finally, hospitals with fewer than 10 children with SSSS during the study period were excluded.

Antibiotic Regimen Groups

We used PHIS daily billing codes to determine the antibiotics received by the study population. Children were classified into antibiotic regimen groups based on whether they received specific antibiotic combinations. Antibiotics received on any day during the hospitalization, including in the emergency department (ED), were used to assign patients to regimen groups. Antibiotics were classified into regimen groups based on consensus among study investigators, which included two board-certified pediatric infectious diseases specialists (A.C., R.M.). Antibiotic group definitions are listed in Table 1. Oral and intravenous (IV) therapies were grouped together for clindamycin, cephalexin/cefazolin, and linezolid because of good oral bioavailability in most situations.¹⁸ The three most common antistaphylococcal groups were chosen for further analysis: clindamycin alone, clindamycin plus MSSA coverage, and clindamycin plus MRSA coverage. The clindamycin group was defined as children with receipt of oral or IV clindamycin. Children who received clindamycin with additional MSSA coverage, such as cefazolin or nafcillin, were categorized as the clindamycin plus MSSA group. Children who received clindamycin with additional MRSA coverage, such as vancomycin or linezolid, were categorized as the clindamycin plus MRSA group. We chose not to include children who received the above regimens plus other antibiotics with partial antistaphylococcal activity, such as ampicillin, gentamicin, or ceftriaxone, in the clindamycin plus MSSA and clindamycin plus MRSA groups. We excluded these antibiotics to decrease the heterogeneity in the definition of regimen groups and allow a more direct comparison for effectiveness.

Covariates

Covariates included age, sex, ethnicity and/or race, payer type, level of care, illness severity, and region. The variable definitions below are in keeping with a prior study of SSSS.¹⁶ Age was categorized as: birth to 59 days, 2 to 11 months, 1 to 4 years (preschool age), 5 to 10 years (school age), and 11 to 18 years (adolescent). We examined infants younger than 60 days separately from older infants because this population may warrant additional treatment considerations. Race and ethnicity were categorized as White (non-Hispanic), African American (non-Hispanic), Hispanic, or other. Payer types included government, private, or other. Level of care was assigned as either intensive care or acute care. Illness severity was assigned using the All Patient Refined Diagnosis Related Group (APR-DRG; 3M Corporation, St. Paul, Minnesota) severity levels.¹⁹ In line with a prior study,¹⁶ we defined “low illness severity” as the APR-DRG minor (1) classification. The moderate (2), major (3), and extreme (4) classifications were defined as “moderate to high illness severity,” since there were very few classifications of major or extreme (<5%) illness severity. We categorized hospitals into the following US regions: Northeast, Midwest, South, and West.

Outcome Measures

The primary outcome was hospital LOS in days, and secondary outcomes were treatment failure and hospital costs. Hospital LOS was chosen as the primary outcome to represent the time needed for the child to show clinical improvement. Treatment failure was defined as a same-cause 14-day ED revisit or hospital readmission, and these were determined to be same-cause if a diagnosis for SSSS (ICD-9, 695.81; ICD-10, L00) was documented for the return encounter. The 14-day interval for readmission and ED revisit was chosen to measure any relapse of symptoms after completion of antibiotic therapy, similar to a prior study of treatment failure in skin and soft tissue infections.²⁰ Total costs of the hospitalization were estimated from charges using hospital- and year-specific cost-to-charge ratios. Subcategories of cost, including clinical, pharmacy, imaging, laboratory, supply, and other, were also compared among the three groups.

Statistical Analysis

Demographic and clinical characteristics of children were summarized using frequencies and percentages for categorical variables and medians with interquartile ranges (IQRs) for continuous variables. These were compared across antibiotic groups using chi-square and Kruskal–Wallis tests, respectively. In unadjusted analyses, outcomes were compared across antibiotic regimen groups using these same statistical tests. In order to account for patient clustering within hospitals, generalized linear mixed-effects models were used to model outcomes with a random intercept for each hospital. Models were adjusted for SSSS being listed as a principal or secondary diagnosis, race, illness severity, and level of care. We log-transformed LOS and cost data prior to modeling because of the nonnormal distributions for these data. Owing to the inability to measure the number of antibiotic doses, and to reduce the possibility of including children who received few regimen-defined combination antibiotics, a post hoc sensitivity analysis was performed. This analysis used an alternative definition for antibiotic regimen groups, for which children admitted for 2 or more calendar days must have received regimen-specified antibiotics on at least 2 days of the admission. Additionally, outcomes were stratified by low and moderate/high illness severity and compared across the three antibiotic regimen groups. All analyses were performed with SAS (SAS 9.4; SAS Institute, Cary, North Carolina), and P values of less than .05 were considered statistically significant.

Overall, 1,815 hospitalized children with SSSS were identified in the PHIS database, and after application of the exclusion criteria, 1,259 children remained, with 1,247 (99%) receiving antibiotics (Figure). The antibiotic regimens received by these children are described in Table 1. Of these, 828 children (66%) received one of the three most common antistaphylococcal regimens (clindamycin, clindamycin + MSSA, and clindamycin + MRSA) and were included for further analysis.

Characteristics of the 828 children are presented in Table 2. Most children (82%) were aged 4 years or younger, and distributions of age, sex, and insurance payer were similar among children receiving the three regimens. Thirty-two percent had moderate to high illness severity, and 3.5% required management in the intensive care setting. Of the three antibiotic regimens, clindamycin monotherapy was most common (47%), followed by clindamycin plus MSSA coverage (33%), and clindamycin plus MRSA coverage (20%). A higher proportion of children in the clindamycin plus MRSA group were African American and were hospitalized in the South. Children receiving clindamycin plus MRSA coverage had higher illness severity (44%) as compared with clindamycin monotherapy (28%) and clindamycin plus MSSA coverage (32%) (P = .001). Additionally, a larger proportion of children treated with clindamycin plus MRSA coverage were managed in the intensive care setting as compared with the clindamycin plus MSSA or clindamycin monotherapy groups.

Among the 828 children with SSSS, the median LOS was 2 days (IQR, 2-3), and treatment failure was 1.1% (95% CI, 0.4-1.8). After adjustment for illness severity, race, payer, and region (Table 3), the three antibiotic regimens were not associated with significant differences in LOS or treatment failure. Costs were significantly different among the three antibiotic regimens. Clindamycin plus MRSA coverage was associated with the greatest costs, whereas clindamycin monotherapy was associated with the lowest costs (mean, $5,348 vs $4,839, respectively; P < .001) (Table 3). In a sensitivity analysis using an alternative antibiotic regimen definition, we found results in line with the primary analysis, with no statistically significant differences in LOS (P = .44) or treatment failure (P = .54), but significant differences in cost (P < .001). Additionally, the same findings were present for LOS, treatment failure, and cost when outcomes were stratified by illness severity (Appendix Table). However, significant contributors to the higher cost in the clindamycin plus MRSA group did vary by illness severity stratification. Laboratory, supply, and pharmacy cost categories differed significantly among antibiotic groups for the low illness severity strata, whereas pharmacy was the only significant cost category difference in moderate/high illness severity.

Clindamycin monotherapy, clindamycin plus MSSA coverage, and clindamycin plus MRSA coverage are the most commonly administered antistaphylococcal antibiotic regimens for children hospitalized with SSSS at US children’s hospitals. Our multicenter study found that, across these antistaphylococcal antibiotic regimens, there were no associated differences in hospital LOS or treatment failure. However, the antibiotic regimens were associated with significant differences in overall hospital costs. These findings suggest that the use of clindamycin with additional MSSA or MRSA antibiotic coverage for children with SSSS may not be associated with additional clinical benefit, as compared with clindamycin monotherapy, and could potentially be more costly.

Prior literature describing LOS in relation to antibiotic use for children with SSSS is limited. Authors of a recent case series of 21 children in Philadelphia reported approximately 50% of children received clindamycin monotherapy or combination therapy, but patient outcomes such as LOS were not described.⁹ Clindamycin use and outcomes have been described in smaller studies and case reports of SSSS, which reported positive outcomes such as patient recovery and lack of disease recurrence.^2,9,21 A small retrospective, comparative effectiveness study of 30 neonates with SSSS examined beta-lactamase–resistant penicillin use with and without cephalosporins. They found no effect on LOS, but findings were limited by a small sample size.²² Our study cohort included relatively few neonates, and thus our findings may not be applicable to this population subgroup. We chose not to include regimens with third-generation cephalosporins or ampicillin, which may have limited the number of included neonates, because these antibiotics are frequently administered during evaluation for invasive bacterial infections.²³ We found a very low occurrence of treatment failure in our study cohort across all three groups, which is consistent with other studies of SSSS that report an overall good prognosis and low recurrence and/or readmission rates.^6,16,24 The low prevalence of treatment failure, however, precluded our ability to detect small differences among antibiotic regimen groups that may exist.

We observed that cost differed significantly across antibiotic regimen groups, with lowest cost associated with clindamycin monotherapy in adjusted analysis despite similar LOS. Even with our illness-severity adjustment, there may have been other unmeasured factors resulting in the higher cost associated with the combination groups. Hence, we also examined cost breakdown with a stratified analysis by illness severity. We found that pharmacy costs were significantly different among antibiotic groups in both illness severity strata, whereas those with low illness severity also differed by laboratory and supply costs. Thus, pharmacy cost differences may be the largest driver in the cost differential among groups. Lower cost in the clindamycin monotherapy group is likely due to administration of a single antibiotic. The reason for supply and laboratory cost differences is uncertain, but higher cost in the clindamycin plus MRSA group could possibly be from laboratory testing related to drug monitoring (eg, renal function testing or drug levels). While other studies have reported costs for hospitalized children with SSSS associated with different patient characteristics or diagnostic testing,^1,16 to our knowledge, no other studies have reported cost related to antibiotic regimens for SSSS. As healthcare reimbursements shift to value-based models, identifying treatment regimens with equal efficacy but lower cost will become increasingly important. Future studies should also examine other covariates and outcomes, such as oral vs parenteral antibiotic use, use of monitoring laboratories related to antibiotic choice, and adverse drug effects.

Several strengths and additional limitations apply to our study. Our study is one of the few to describe outcomes associated with antibiotic regimens for children with SSSS. With the PHIS database, we were able to include a large number of children with SSSS from children’s hospitals across the United States. Although the PHIS database affords these strengths, there are limitations inherent to administrative data. Children with SSSS were identified by documented ICD-9 and ICD-10 diagnostic codes, which might lead to misclassification. However, misclassification is less likely because only one ICD-9 and ICD-10 code exists for SSSS, and the characteristics of this condition are specific. Also, diagnostic codes for other dermatologic conditions (eg, scarlet fever) were excluded to further reduce the chance of misclassification. A limitation to our use of PHIS billing codes was the inability to confirm the dosage of antibiotics given, the number of doses, or whether antibiotics were prescribed upon discharge. Another limitation is that children whose antibiotic therapy was changed during hospitalization (eg, from clindamycin monotherapy to cefazolin monotherapy) were categorized into the combination groups. However, the sensitivity analysis performed based on a stricter antibiotic group definition (receipt of both antibiotics on at least 2 calendar days) did not alter the outcomes, which is reassuring. We were unable to assess the use of targeted antibiotic therapy because clinical data (eg, microbiology results) were not available. However, this may be less important because some literature suggests that cultures for S aureus are obtained infrequently² and may be difficult to interpret when obtained,²⁵ since culture growth can represent colonization rather than causative strains. An additional limitation is that administrative data do not include certain clinical outcomes, such as fever duration or degree of skin involvement, which could have differed among the groups. Last, the PHIS database only captures revisits or readmissions to PHIS hospitals, and so we are unable to exclude the possibility of a child being seen at or readmitted to another hospital.

Due to the observational design of this study and potential for incomplete measurement of illness severity, we recommend a future prospective trial with randomization to confirm these findings. One possible reason that LOS did not differ among groups is that the burden of clindamycin-resistant strains in our cohort could be low, and the addition of MSSA or MRSA coverage does not result in a clinically important increase in S aureus coverage. However, pooled pediatric hospital antibiogram data suggest the overall rate of clindamycin resistance is close to 20% in hospitals located in all US regions.²⁶ Limited studies also suggest that MSSA may be the predominant pathogen associated with SSSS.^2,9 To address this, future randomized trials could compare the effectiveness of clindamycin monotherapy to MSSA-specific agents like cefazolin or nafcillin. Unfortunately, anti-MSSA monotherapy was not evaluated in our study because very few children received this treatment. Using monotherapy as opposed to multiple antibiotics has the potential to promote antibiotic stewardship for antistaphylococcal antibiotics in the management of SSSS. Reducing unnecessary antibiotic use not only potentially affects antibiotic resistance, but could also benefit patients in reducing possible side effects, cost, and IV catheter complications.²⁷ However, acknowledging our study limitations, our findings should be applied cautiously in clinical settings, in the context of local antibiogram data, individual culture results, and specific patient factors. The local clindamycin resistance rate for both MSSA and MRSA should be considered. Many antibiotics chosen to treat MRSA—such as vancomycin and trimethoprim/sulfamethoxazole—will also have anti-MSSA activity and may have lower local resistance rates than clindamycin. Practitioners may also consider how each antibiotic kills bacteria; for example, beta-lactams rely on bacterial replication, but clindamycin does not. Each factor should influence how empiric treatment, whether monotherapy or combination, is chosen for children with SSSS.

In this large, multicenter cohort of hospitalized children with SSSS, we found that the addition of MSSA or MRSA coverage to clindamycin monotherapy was not associated with differences in outcomes of hospital LOS and treatment failure. Furthermore, clindamycin monotherapy was associated with lower overall cost. Prospective randomized studies are needed to confirm these findings and assess whether clindamycin monotherapy, monotherapy with an anti-MSSA antibiotic, or alternative regimens are most effective for treatment of children with SSSS.

Febrile infants 60 days of age or younger pose a significant diagnostic challenge for clinicians. Most of these infants are well appearing and do not have localizing signs or symptoms of infection, yet they may have serious bacterial infections (SBI) such as urinary tract infection (UTI), bacteremia, and meningitis. While urinalysis is highly sensitive for predicting UTI,¹ older clinical decision rules and biomarkers such as white blood cell (WBC) count, absolute neutrophil count (ANC), and C-reactive protein (CRP) lack both appropriate sensitivity and specificity for identifying bacteremia and meningitis (ie, invasive bacterial infection [IBI]),^2,3 which affect approximately 2.4% and 0.9% of febrile infants during the first 2 months of life, respectively.⁴ The lack of accurate diagnostic markers can drive overuse of laboratory testing, antibiotics, and hospitalization despite the low rates of these infections. As a result, procalcitonin (PCT) has generated interest because of its potential to serve as a more accurate biomarker for bacterial infections. This review summarizes recent literature on the diagnostic utility of PCT in the identification of IBI in febrile young infants 60 days or younger.

Procalcitonin is undetectable in noninflammatory states but can be detected in the blood within 4 to 6 hours after initial bacterial infection.⁵ Its production is stimulated throughout various tissues of the body by cytokines such as interleukin-6 and tumor necrosis factor, which are produced in response to bacterial infections. Interferon-γ, which is produced in response to viral infections, attenuates PCT production. While these characteristics suggest promise for PCT as a more specific screening test for underlying bacterial infection, there are caveats. PCT levels are physiologically elevated in the first 48 hours of life and vary with gestational age, factors that should be considered when interpreting results.⁶ Additionally, PCT levels can rise in other inflammatory states such as autoimmune conditions and certain malignancies,⁵ though these states are unlikely to confound the evaluation of febrile young infants.

Because of PCT’s potential to be more specific than other commonly used biomarkers, multiple studies have evaluated its performance characteristics in febrile young infants. Gomez et al retrospectively evaluated 1,112 well-appearing infants younger than 3 months with fever without a source in seven European emergency departments (EDs).⁷ Overall, 23 infants (2.1%) had IBI (1 with meningitis). A PCT level of 0.5 ng/mL or greater was the only independent risk factor for IBI (adjusted odds ratio, 21.69; 95% CI, 7.93-59.28). Four infants with IBI had a PCT level less than 0.5 ng/mL, and none of these four had meningitis. PCT was superior to CRP, ANC, and WBC in detecting IBI (area under the curve [AUC], 0.825; 95% CI, 0.698-0.952). PCT was the also the best marker for identifying IBI among 451 infants with a normal urine dipstick and fever detected ≤6 hours before presentation (AUC, 0.819; 95% CI, 0.551-1.087).

In the largest prospective study to date evaluating the diagnostic accuracy of PCT in febrile young infants, Milcent et al studied 2,047 previously healthy infants aged 7-91 days admitted for fever from 15 French EDs.⁸ In total, 21 (1%) had an IBI (8 with meningitis). PCT performed better than CRP, ANC, and WBC for the detection of IBI with an AUC of 0.91 (95% CI, 0.83-0.99). In a multivariable model, a PCT level of 0.3 ng/mL or greater was the only independent risk factor for IBI with an adjusted odds ratio of 40.3 (95% CI, 5.0-332). Only one infant with IBI had a PCT level less than 0.3 ng/mL. This infant was 83 days old, had 4 hours of fever, and became afebrile spontaneously prior to the blood culture revealing Streptococcus pneumoniae. PCT also performed better than CRP in the detection of IBI in infants 7-30 days of age and those with fever for less than 6 hours, though both subgroups had small numbers of infants with IBI. The authors determined that a PCT level of 0.3 ng/mL was the optimal cutoff for ruling out IBI; this cutoff had a sensitivity of 90% and negative likelihood ratio (LR) of 0.1 (Table). In contrast, the more commonly studied PCT cutoff of 0.5 ng/mL increased the negative LR to 0.2. The authors suggested that PCT, when used in the context of history, exam, and tests such as urinalysis, could identify infants at low risk of IBI.

Gomez et al conducted a prospective, single-center study of well-appearing infants with fever without a source and negative urine dipsticks.⁹ They identified IBI in 9 of 196 infants (4.5%) 21 days or younger and 13 of 1,331 infants (1.0%) 22-90 days old. PCT was superior to CRP and ANC for IBI detection in both age groups. However, in infants 21 days or younger, both the positive and negative LRs for PCT levels of 0.5 ng/mL or greater were poor (Table). Differences in results from the prior two studies^7,8 may be related to smaller sample size and differences in patient population because this study included infants younger than 7 days and a higher proportion of infants presenting within 6 hours of fever.

PCT has also been incorporated into clinical decision rules for febrile young infants, primarily to identify those at low risk of either IBI or SBI. The Step-by-Step approach¹⁰ classified well-appearing febrile infants 90 days or younger as having a high risk of IBI if they were ill appearing, younger than 21 days old, had a positive urine dipstick or a PCT level of 0.5 ng/mL or greater, and classified them as intermediate risk if they had a CRP level greater than 20 mg/L or ANC level greater than 10,000/µL. The remaining infants were classified as low risk and could be managed as outpatients without lumbar puncture or empiric antibiotics. Of note, derivation of this rule excluded patients with respiratory signs or symptoms. In a prospective validation study with 2,185 infants from 11 European EDs, 87 (4.0%) had an IBI (10 with bacterial meningitis). Sequentially identifying patients as high risk using general appearance, age, and urine dipstick alone identified 80% of infants with IBI and 90% of those with bacterial meningitis. The remaining case of meningitis would have been detected by an elevated PCT. A total of 7 of 991 infants (0.7%) classified as low risk had an IBI and none had meningitis. Six of these infants had a fever duration of less than 2 hours, which would not be enough time for PCT to rise. The Step-by-Step approach, with a sensitivity of 92% and negative LR of 0.17, performed well in the ability to rule out IBI.

A clinical prediction rule developed by the Pediatric Emergency Care Applied Research Network (PECARN) found that urinalysis, ANC, and PCT performed well in identifying infants 60 days or younger at low risk for SBI and IBI.¹¹ This prospective observational study of 1,821 infants 60 days or younger in 26 US EDs found 170 (9.3%) with SBI and 30 (1.6%) with IBI; 10 had bacterial meningitis. Only one patient with IBI was classified as low risk, a 30-day-old whose blood culture grew Enterobacter cloacae and who had a negative repeat blood culture prior to antibiotic treatment. Together, a negative urinalysis, ANC of 4,090/µL or less, and PCT level of 1.71 ng/mL or less were excellent in predicting infants at low risk for both SBI and IBI, with a sensitivity of 97% and negative LR of 0.05 for the outcome of IBI. When applying these variables with “rounded cutoffs” of PCT levels less than 0.5 ng/mL (chosen by the authors because it is a more commonly used cutoff) and ANC of 4,000/µL or less to identify infants at low risk for SBI, their performance was similar to nonrounded cutoffs. Data for the rule with rounded cutoffs in identifying infants at low risk for IBI were not presented. The PECARN study was limited by the small numbers of infants with IBIs, and the authors recommended caution when applying the rule to infants 28 days or younger.

Older clinical decision rules without PCT, such as the Rochester and modified Philadelphia criteria, use clinical and laboratory features to assess risk of IBI.³ Recent studies have evaluated these criteria in cohorts with larger numbers of infants with IBI since the derivation studies included mostly infants with SBI and small numbers with IBI.³ Gomez et al demonstrated that the Rochester criteria had lower sensitivity and higher negative LR than the Step-by-Step approach in IBI detection.¹⁰ In a case-control study of 135 cases of IBI with 249 matched controls, Aronson et al reported that the modified Philadelphia criteria had higher sensitivity but lower specificity than the Rochester criteria for IBI detection.¹² The ability of the Rochester and modified Philadelphia criteria to rule out IBI, as demonstrated by the negative LR (range 0.2-0.4), was inferior to the negative LRs documented by Milcent et al⁸ (PCT cutoff value of 0.3 ng/mL), the Step-by-Step approach,¹⁰ and the PECARN rule¹¹ (range 0.05-0.17; Table). However, clinical decision rules with and without PCT suffer similar limitations in having poor specificity in identifying infants likely to have IBI.

Several key knowledge gaps around PCT use for diagnosing neonatal infections exist. First, the optimal use of PCT in context with other biomarkers and clinical decision rules remains uncertain. A meta-analysis of 28 studies involving over 2,600 infants that compared PCT level (with and without CRP) with isolated CRP and presepsin levels found that PCT in combination with CRP had greater diagnostic accuracy than either PCT or CRP alone, which highlights a potential opportunity for prospective study.¹³ Second, more data are needed on the use of PCT in the ≤ 28-day age group given the increased risk of both IBI and neonatal herpes simplex virus infection (HSV), compared with that in the second month of life. Neonatal HSV poses diagnostic challenges because half of infants will initially present as afebrile,¹⁴ and delays in initiating antiviral treatment dramatically increase the risk of permanent disability or death.¹⁵ There have been no prospective studies evaluating PCT use as part of neonatal HSV evaluations.

In summary, PCT can play an important adjunctive diagnostic role in the evaluation of febrile young infants, especially during the second month of life when outpatient management is more likely to be considered. PCT is superior to other inflammatory markers in identifying IBI, though the optimal cutoffs to maximize sensitivity and specificity are uncertain. Its performance characteristics, both alone and within clinical decision rules, can help clinicians better identify children at low risk for IBI when compared with clinical decision rules without PCT. PCT measurement can help clinicians miss fewer infants with IBI and identify infants for whom safely doing less is an appropriate option, which can ultimately reduce costs and hospitalizations. PCT may be particularly helpful when the clinical history is difficult to assess or when other diagnostic test results are missing or give conflicting results. Centers that use PCT will need to ensure that results are available within a short turnaround time (a few hours) in order to meaningfully affect care. Future studies of PCT in febrile infant evaluations should focus on identifying optimal strategies for incorporating this biomarker into risk assessments that present information to parents in a way that enables them to understand their child’s risk of a serious infection.

Febrile infants 60 days of age or younger pose a significant diagnostic challenge for clinicians. Most of these infants are well appearing and do not have localizing signs or symptoms of infection, yet they may have serious bacterial infections (SBI) such as urinary tract infection (UTI), bacteremia, and meningitis. While urinalysis is highly sensitive for predicting UTI,¹ older clinical decision rules and biomarkers such as white blood cell (WBC) count, absolute neutrophil count (ANC), and C-reactive protein (CRP) lack both appropriate sensitivity and specificity for identifying bacteremia and meningitis (ie, invasive bacterial infection [IBI]),^2,3 which affect approximately 2.4% and 0.9% of febrile infants during the first 2 months of life, respectively.⁴ The lack of accurate diagnostic markers can drive overuse of laboratory testing, antibiotics, and hospitalization despite the low rates of these infections. As a result, procalcitonin (PCT) has generated interest because of its potential to serve as a more accurate biomarker for bacterial infections. This review summarizes recent literature on the diagnostic utility of PCT in the identification of IBI in febrile young infants 60 days or younger.

Procalcitonin is undetectable in noninflammatory states but can be detected in the blood within 4 to 6 hours after initial bacterial infection.⁵ Its production is stimulated throughout various tissues of the body by cytokines such as interleukin-6 and tumor necrosis factor, which are produced in response to bacterial infections. Interferon-γ, which is produced in response to viral infections, attenuates PCT production. While these characteristics suggest promise for PCT as a more specific screening test for underlying bacterial infection, there are caveats. PCT levels are physiologically elevated in the first 48 hours of life and vary with gestational age, factors that should be considered when interpreting results.⁶ Additionally, PCT levels can rise in other inflammatory states such as autoimmune conditions and certain malignancies,⁵ though these states are unlikely to confound the evaluation of febrile young infants.

Because of PCT’s potential to be more specific than other commonly used biomarkers, multiple studies have evaluated its performance characteristics in febrile young infants. Gomez et al retrospectively evaluated 1,112 well-appearing infants younger than 3 months with fever without a source in seven European emergency departments (EDs).⁷ Overall, 23 infants (2.1%) had IBI (1 with meningitis). A PCT level of 0.5 ng/mL or greater was the only independent risk factor for IBI (adjusted odds ratio, 21.69; 95% CI, 7.93-59.28). Four infants with IBI had a PCT level less than 0.5 ng/mL, and none of these four had meningitis. PCT was superior to CRP, ANC, and WBC in detecting IBI (area under the curve [AUC], 0.825; 95% CI, 0.698-0.952). PCT was the also the best marker for identifying IBI among 451 infants with a normal urine dipstick and fever detected ≤6 hours before presentation (AUC, 0.819; 95% CI, 0.551-1.087).

In the largest prospective study to date evaluating the diagnostic accuracy of PCT in febrile young infants, Milcent et al studied 2,047 previously healthy infants aged 7-91 days admitted for fever from 15 French EDs.⁸ In total, 21 (1%) had an IBI (8 with meningitis). PCT performed better than CRP, ANC, and WBC for the detection of IBI with an AUC of 0.91 (95% CI, 0.83-0.99). In a multivariable model, a PCT level of 0.3 ng/mL or greater was the only independent risk factor for IBI with an adjusted odds ratio of 40.3 (95% CI, 5.0-332). Only one infant with IBI had a PCT level less than 0.3 ng/mL. This infant was 83 days old, had 4 hours of fever, and became afebrile spontaneously prior to the blood culture revealing Streptococcus pneumoniae. PCT also performed better than CRP in the detection of IBI in infants 7-30 days of age and those with fever for less than 6 hours, though both subgroups had small numbers of infants with IBI. The authors determined that a PCT level of 0.3 ng/mL was the optimal cutoff for ruling out IBI; this cutoff had a sensitivity of 90% and negative likelihood ratio (LR) of 0.1 (Table). In contrast, the more commonly studied PCT cutoff of 0.5 ng/mL increased the negative LR to 0.2. The authors suggested that PCT, when used in the context of history, exam, and tests such as urinalysis, could identify infants at low risk of IBI.

Gomez et al conducted a prospective, single-center study of well-appearing infants with fever without a source and negative urine dipsticks.⁹ They identified IBI in 9 of 196 infants (4.5%) 21 days or younger and 13 of 1,331 infants (1.0%) 22-90 days old. PCT was superior to CRP and ANC for IBI detection in both age groups. However, in infants 21 days or younger, both the positive and negative LRs for PCT levels of 0.5 ng/mL or greater were poor (Table). Differences in results from the prior two studies^7,8 may be related to smaller sample size and differences in patient population because this study included infants younger than 7 days and a higher proportion of infants presenting within 6 hours of fever.

PCT has also been incorporated into clinical decision rules for febrile young infants, primarily to identify those at low risk of either IBI or SBI. The Step-by-Step approach¹⁰ classified well-appearing febrile infants 90 days or younger as having a high risk of IBI if they were ill appearing, younger than 21 days old, had a positive urine dipstick or a PCT level of 0.5 ng/mL or greater, and classified them as intermediate risk if they had a CRP level greater than 20 mg/L or ANC level greater than 10,000/µL. The remaining infants were classified as low risk and could be managed as outpatients without lumbar puncture or empiric antibiotics. Of note, derivation of this rule excluded patients with respiratory signs or symptoms. In a prospective validation study with 2,185 infants from 11 European EDs, 87 (4.0%) had an IBI (10 with bacterial meningitis). Sequentially identifying patients as high risk using general appearance, age, and urine dipstick alone identified 80% of infants with IBI and 90% of those with bacterial meningitis. The remaining case of meningitis would have been detected by an elevated PCT. A total of 7 of 991 infants (0.7%) classified as low risk had an IBI and none had meningitis. Six of these infants had a fever duration of less than 2 hours, which would not be enough time for PCT to rise. The Step-by-Step approach, with a sensitivity of 92% and negative LR of 0.17, performed well in the ability to rule out IBI.

A clinical prediction rule developed by the Pediatric Emergency Care Applied Research Network (PECARN) found that urinalysis, ANC, and PCT performed well in identifying infants 60 days or younger at low risk for SBI and IBI.¹¹ This prospective observational study of 1,821 infants 60 days or younger in 26 US EDs found 170 (9.3%) with SBI and 30 (1.6%) with IBI; 10 had bacterial meningitis. Only one patient with IBI was classified as low risk, a 30-day-old whose blood culture grew Enterobacter cloacae and who had a negative repeat blood culture prior to antibiotic treatment. Together, a negative urinalysis, ANC of 4,090/µL or less, and PCT level of 1.71 ng/mL or less were excellent in predicting infants at low risk for both SBI and IBI, with a sensitivity of 97% and negative LR of 0.05 for the outcome of IBI. When applying these variables with “rounded cutoffs” of PCT levels less than 0.5 ng/mL (chosen by the authors because it is a more commonly used cutoff) and ANC of 4,000/µL or less to identify infants at low risk for SBI, their performance was similar to nonrounded cutoffs. Data for the rule with rounded cutoffs in identifying infants at low risk for IBI were not presented. The PECARN study was limited by the small numbers of infants with IBIs, and the authors recommended caution when applying the rule to infants 28 days or younger.

Older clinical decision rules without PCT, such as the Rochester and modified Philadelphia criteria, use clinical and laboratory features to assess risk of IBI.³ Recent studies have evaluated these criteria in cohorts with larger numbers of infants with IBI since the derivation studies included mostly infants with SBI and small numbers with IBI.³ Gomez et al demonstrated that the Rochester criteria had lower sensitivity and higher negative LR than the Step-by-Step approach in IBI detection.¹⁰ In a case-control study of 135 cases of IBI with 249 matched controls, Aronson et al reported that the modified Philadelphia criteria had higher sensitivity but lower specificity than the Rochester criteria for IBI detection.¹² The ability of the Rochester and modified Philadelphia criteria to rule out IBI, as demonstrated by the negative LR (range 0.2-0.4), was inferior to the negative LRs documented by Milcent et al⁸ (PCT cutoff value of 0.3 ng/mL), the Step-by-Step approach,¹⁰ and the PECARN rule¹¹ (range 0.05-0.17; Table). However, clinical decision rules with and without PCT suffer similar limitations in having poor specificity in identifying infants likely to have IBI.

Several key knowledge gaps around PCT use for diagnosing neonatal infections exist. First, the optimal use of PCT in context with other biomarkers and clinical decision rules remains uncertain. A meta-analysis of 28 studies involving over 2,600 infants that compared PCT level (with and without CRP) with isolated CRP and presepsin levels found that PCT in combination with CRP had greater diagnostic accuracy than either PCT or CRP alone, which highlights a potential opportunity for prospective study.¹³ Second, more data are needed on the use of PCT in the ≤ 28-day age group given the increased risk of both IBI and neonatal herpes simplex virus infection (HSV), compared with that in the second month of life. Neonatal HSV poses diagnostic challenges because half of infants will initially present as afebrile,¹⁴ and delays in initiating antiviral treatment dramatically increase the risk of permanent disability or death.¹⁵ There have been no prospective studies evaluating PCT use as part of neonatal HSV evaluations.

In summary, PCT can play an important adjunctive diagnostic role in the evaluation of febrile young infants, especially during the second month of life when outpatient management is more likely to be considered. PCT is superior to other inflammatory markers in identifying IBI, though the optimal cutoffs to maximize sensitivity and specificity are uncertain. Its performance characteristics, both alone and within clinical decision rules, can help clinicians better identify children at low risk for IBI when compared with clinical decision rules without PCT. PCT measurement can help clinicians miss fewer infants with IBI and identify infants for whom safely doing less is an appropriate option, which can ultimately reduce costs and hospitalizations. PCT may be particularly helpful when the clinical history is difficult to assess or when other diagnostic test results are missing or give conflicting results. Centers that use PCT will need to ensure that results are available within a short turnaround time (a few hours) in order to meaningfully affect care. Future studies of PCT in febrile infant evaluations should focus on identifying optimal strategies for incorporating this biomarker into risk assessments that present information to parents in a way that enables them to understand their child’s risk of a serious infection.

Febrile infants 60 days of age or younger pose a significant diagnostic challenge for clinicians. Most of these infants are well appearing and do not have localizing signs or symptoms of infection, yet they may have serious bacterial infections (SBI) such as urinary tract infection (UTI), bacteremia, and meningitis. While urinalysis is highly sensitive for predicting UTI,¹ older clinical decision rules and biomarkers such as white blood cell (WBC) count, absolute neutrophil count (ANC), and C-reactive protein (CRP) lack both appropriate sensitivity and specificity for identifying bacteremia and meningitis (ie, invasive bacterial infection [IBI]),^2,3 which affect approximately 2.4% and 0.9% of febrile infants during the first 2 months of life, respectively.⁴ The lack of accurate diagnostic markers can drive overuse of laboratory testing, antibiotics, and hospitalization despite the low rates of these infections. As a result, procalcitonin (PCT) has generated interest because of its potential to serve as a more accurate biomarker for bacterial infections. This review summarizes recent literature on the diagnostic utility of PCT in the identification of IBI in febrile young infants 60 days or younger.

Procalcitonin is undetectable in noninflammatory states but can be detected in the blood within 4 to 6 hours after initial bacterial infection.⁵ Its production is stimulated throughout various tissues of the body by cytokines such as interleukin-6 and tumor necrosis factor, which are produced in response to bacterial infections. Interferon-γ, which is produced in response to viral infections, attenuates PCT production. While these characteristics suggest promise for PCT as a more specific screening test for underlying bacterial infection, there are caveats. PCT levels are physiologically elevated in the first 48 hours of life and vary with gestational age, factors that should be considered when interpreting results.⁶ Additionally, PCT levels can rise in other inflammatory states such as autoimmune conditions and certain malignancies,⁵ though these states are unlikely to confound the evaluation of febrile young infants.

Because of PCT’s potential to be more specific than other commonly used biomarkers, multiple studies have evaluated its performance characteristics in febrile young infants. Gomez et al retrospectively evaluated 1,112 well-appearing infants younger than 3 months with fever without a source in seven European emergency departments (EDs).⁷ Overall, 23 infants (2.1%) had IBI (1 with meningitis). A PCT level of 0.5 ng/mL or greater was the only independent risk factor for IBI (adjusted odds ratio, 21.69; 95% CI, 7.93-59.28). Four infants with IBI had a PCT level less than 0.5 ng/mL, and none of these four had meningitis. PCT was superior to CRP, ANC, and WBC in detecting IBI (area under the curve [AUC], 0.825; 95% CI, 0.698-0.952). PCT was the also the best marker for identifying IBI among 451 infants with a normal urine dipstick and fever detected ≤6 hours before presentation (AUC, 0.819; 95% CI, 0.551-1.087).

In the largest prospective study to date evaluating the diagnostic accuracy of PCT in febrile young infants, Milcent et al studied 2,047 previously healthy infants aged 7-91 days admitted for fever from 15 French EDs.⁸ In total, 21 (1%) had an IBI (8 with meningitis). PCT performed better than CRP, ANC, and WBC for the detection of IBI with an AUC of 0.91 (95% CI, 0.83-0.99). In a multivariable model, a PCT level of 0.3 ng/mL or greater was the only independent risk factor for IBI with an adjusted odds ratio of 40.3 (95% CI, 5.0-332). Only one infant with IBI had a PCT level less than 0.3 ng/mL. This infant was 83 days old, had 4 hours of fever, and became afebrile spontaneously prior to the blood culture revealing Streptococcus pneumoniae. PCT also performed better than CRP in the detection of IBI in infants 7-30 days of age and those with fever for less than 6 hours, though both subgroups had small numbers of infants with IBI. The authors determined that a PCT level of 0.3 ng/mL was the optimal cutoff for ruling out IBI; this cutoff had a sensitivity of 90% and negative likelihood ratio (LR) of 0.1 (Table). In contrast, the more commonly studied PCT cutoff of 0.5 ng/mL increased the negative LR to 0.2. The authors suggested that PCT, when used in the context of history, exam, and tests such as urinalysis, could identify infants at low risk of IBI.

Gomez et al conducted a prospective, single-center study of well-appearing infants with fever without a source and negative urine dipsticks.⁹ They identified IBI in 9 of 196 infants (4.5%) 21 days or younger and 13 of 1,331 infants (1.0%) 22-90 days old. PCT was superior to CRP and ANC for IBI detection in both age groups. However, in infants 21 days or younger, both the positive and negative LRs for PCT levels of 0.5 ng/mL or greater were poor (Table). Differences in results from the prior two studies^7,8 may be related to smaller sample size and differences in patient population because this study included infants younger than 7 days and a higher proportion of infants presenting within 6 hours of fever.

PCT has also been incorporated into clinical decision rules for febrile young infants, primarily to identify those at low risk of either IBI or SBI. The Step-by-Step approach¹⁰ classified well-appearing febrile infants 90 days or younger as having a high risk of IBI if they were ill appearing, younger than 21 days old, had a positive urine dipstick or a PCT level of 0.5 ng/mL or greater, and classified them as intermediate risk if they had a CRP level greater than 20 mg/L or ANC level greater than 10,000/µL. The remaining infants were classified as low risk and could be managed as outpatients without lumbar puncture or empiric antibiotics. Of note, derivation of this rule excluded patients with respiratory signs or symptoms. In a prospective validation study with 2,185 infants from 11 European EDs, 87 (4.0%) had an IBI (10 with bacterial meningitis). Sequentially identifying patients as high risk using general appearance, age, and urine dipstick alone identified 80% of infants with IBI and 90% of those with bacterial meningitis. The remaining case of meningitis would have been detected by an elevated PCT. A total of 7 of 991 infants (0.7%) classified as low risk had an IBI and none had meningitis. Six of these infants had a fever duration of less than 2 hours, which would not be enough time for PCT to rise. The Step-by-Step approach, with a sensitivity of 92% and negative LR of 0.17, performed well in the ability to rule out IBI.

A clinical prediction rule developed by the Pediatric Emergency Care Applied Research Network (PECARN) found that urinalysis, ANC, and PCT performed well in identifying infants 60 days or younger at low risk for SBI and IBI.¹¹ This prospective observational study of 1,821 infants 60 days or younger in 26 US EDs found 170 (9.3%) with SBI and 30 (1.6%) with IBI; 10 had bacterial meningitis. Only one patient with IBI was classified as low risk, a 30-day-old whose blood culture grew Enterobacter cloacae and who had a negative repeat blood culture prior to antibiotic treatment. Together, a negative urinalysis, ANC of 4,090/µL or less, and PCT level of 1.71 ng/mL or less were excellent in predicting infants at low risk for both SBI and IBI, with a sensitivity of 97% and negative LR of 0.05 for the outcome of IBI. When applying these variables with “rounded cutoffs” of PCT levels less than 0.5 ng/mL (chosen by the authors because it is a more commonly used cutoff) and ANC of 4,000/µL or less to identify infants at low risk for SBI, their performance was similar to nonrounded cutoffs. Data for the rule with rounded cutoffs in identifying infants at low risk for IBI were not presented. The PECARN study was limited by the small numbers of infants with IBIs, and the authors recommended caution when applying the rule to infants 28 days or younger.

Older clinical decision rules without PCT, such as the Rochester and modified Philadelphia criteria, use clinical and laboratory features to assess risk of IBI.³ Recent studies have evaluated these criteria in cohorts with larger numbers of infants with IBI since the derivation studies included mostly infants with SBI and small numbers with IBI.³ Gomez et al demonstrated that the Rochester criteria had lower sensitivity and higher negative LR than the Step-by-Step approach in IBI detection.¹⁰ In a case-control study of 135 cases of IBI with 249 matched controls, Aronson et al reported that the modified Philadelphia criteria had higher sensitivity but lower specificity than the Rochester criteria for IBI detection.¹² The ability of the Rochester and modified Philadelphia criteria to rule out IBI, as demonstrated by the negative LR (range 0.2-0.4), was inferior to the negative LRs documented by Milcent et al⁸ (PCT cutoff value of 0.3 ng/mL), the Step-by-Step approach,¹⁰ and the PECARN rule¹¹ (range 0.05-0.17; Table). However, clinical decision rules with and without PCT suffer similar limitations in having poor specificity in identifying infants likely to have IBI.

Several key knowledge gaps around PCT use for diagnosing neonatal infections exist. First, the optimal use of PCT in context with other biomarkers and clinical decision rules remains uncertain. A meta-analysis of 28 studies involving over 2,600 infants that compared PCT level (with and without CRP) with isolated CRP and presepsin levels found that PCT in combination with CRP had greater diagnostic accuracy than either PCT or CRP alone, which highlights a potential opportunity for prospective study.¹³ Second, more data are needed on the use of PCT in the ≤ 28-day age group given the increased risk of both IBI and neonatal herpes simplex virus infection (HSV), compared with that in the second month of life. Neonatal HSV poses diagnostic challenges because half of infants will initially present as afebrile,¹⁴ and delays in initiating antiviral treatment dramatically increase the risk of permanent disability or death.¹⁵ There have been no prospective studies evaluating PCT use as part of neonatal HSV evaluations.

In summary, PCT can play an important adjunctive diagnostic role in the evaluation of febrile young infants, especially during the second month of life when outpatient management is more likely to be considered. PCT is superior to other inflammatory markers in identifying IBI, though the optimal cutoffs to maximize sensitivity and specificity are uncertain. Its performance characteristics, both alone and within clinical decision rules, can help clinicians better identify children at low risk for IBI when compared with clinical decision rules without PCT. PCT measurement can help clinicians miss fewer infants with IBI and identify infants for whom safely doing less is an appropriate option, which can ultimately reduce costs and hospitalizations. PCT may be particularly helpful when the clinical history is difficult to assess or when other diagnostic test results are missing or give conflicting results. Centers that use PCT will need to ensure that results are available within a short turnaround time (a few hours) in order to meaningfully affect care. Future studies of PCT in febrile infant evaluations should focus on identifying optimal strategies for incorporating this biomarker into risk assessments that present information to parents in a way that enables them to understand their child’s risk of a serious infection.

The sensitivity of the urinalysis (UA) in young infants has been reported to be in the 75% to 85% range.^1-4 This suboptimal sensitivity has prevented a widespread adoption of the UA as a true screening test for urinary tract infection (UTI). Although infants with a positive urine culture and a negative UA may have asymptomatic bacteriuria (AB) or contamination,^5-7 they are often treated for UTI.

Due to these concerns, the American Academy of Pediatrics (AAP) recommended in their 2011 UTI Practice Guidelines that UA criteria should be incorporated into the definition of UTI.¹ However, these guidelines were intended for the 2-24 month age range, leaving a gap in our understanding of the appropriate management of infants <2 months. It is unknown how UA results influence the current management of UTI in young, febrile infants. Using data from a large, nationally representative quality improvement project surrounding the management of febrile infants, this investigation aimed to examine how frequently infants are treated for UTI despite having normal UAs and to determine whether infant and hospital characteristics are different in infants treated for UTI with a positive UA as compared to those treated for UTI with a negative UA.

Subjects and Setting

This is a secondary analysis of the AAP’s Reducing Excessive Variability in the Infant Sepsis Evaluation (REVISE) project that involved 20,570 well-appearing infants 7-60 days of age evaluated in the emergency department and/or inpatient setting for fever ≥38◦C without a source between September 2015 and November 2017 at 124 community- and university-based hospitals in the United States. Data were collected via chart review and entered into a standardized tool for the project. This project was deemed exempt by the AAP Institutional Review Board. Because all data were de-identified, some sites did not require Institutional Review Board approval while others required data sharing agreements.

Variables and Definitions

A positive UA was defined as having any leukocyte esterase, positive nitrites, or >5 white blood cells (WBCs) per high power field. Treatment for UTI was defined using the question “Did the urine culture grow an organism that was treated as a pathogen with a full course of antibiotics?” Subjects treated for meningitis or bacteremia were excluded in order to focus on uncomplicated UTI. “Abnormal inflammatory markers” were defined as having a WBC count <5,000 or >15,000 cells/mm³, an absolute band count ≥ 1,500 cells/mm³, a band to neutrophil ratio of >0.2, cerebrospinal fluid (CSF) WBC count of >8/mm³, a positive CSF gram stain, or an elevated C-reactive protein or procalcitonin level, as defined by the institutional range. Although technically not an “inflammatory marker,” CSF gram stain was included in this composite variable because in the rare cases that it is positive, the result would likely influence risk stratification and immediate management. Infants’ ages were categorized as either 7-30 days or 31-60 days. Hospital length-of-stay (LOS) was recorded to the nearest hour and infants who were not hospitalized were assigned a LOS of 0 hours. Hospital characteristics were determined through a survey completed by site leads.

Statistics

Proportions were compared using chi-square test. We used multilevel mixed-effects logistic regression to determine associations between patients and hospital characteristics and UA-positivity in subjects treated for UTI. We accounted for the hospital clustering effect with a random effect that did not vary with patient characteristics. We “marginalized” the regression coefficients to reflect the average effect across hospitals.^8,9 We tested the overall importance of the hospital clustering effect on the treatment by comparing our multilevel model to a single-level model without hospital random effects using the likelihood ratio test.

A total of 20,570 infants from 124 hospitals were enrolled in the REVISE project, and 648 (3.2%) were treated for bacteremia and/or meningitis. Of the remaining 19,922 infants, 2,407 (12.1%) were treated for UTI, of whom 2,298 (95.5%) had an initial UA performed. Urine cultures were obtained by catheterization or suprapubic aspirate in 90.3% and “other/unknown” in 9.7% of these 2,298 subjects.

UAs were negative in 337/2,298 (14.7%) treated subjects. UA-negative subjects were more likely to be 7-30 days old (adjusted odds ratio [aOR] 1.3, 95% CI 1.02-1.7) and have upper respiratory symptoms (aOR 1.7, 95% CI 1.3-2.3) and were less likely to have abnormal inflammatory markers (aOR 0.3, 95% CI 0.3-0.4) than UA+ subjects (Table). Even after accounting for the hospital characteristics depicted in the Table, treatment of UA-negative UTI was affected by the hospital (P < .001), and the intraclass correlation coefficient was 6% (95% CI, 3% to 14%). The Figure illustrates substantial site variability in the proportion of infants treated for UTIs that were UA-negative, ranging from 0% to 35% in hospitals with ≥20 UTI cases.

In this large, nationally representative sample of febrile infants 7-60 days of age, we demonstrate that nearly 15% of young febrile infants who are treated for UTIs have normal UAs. This proportion varied considerably among hospitals, suggesting that there are institutional differences in the approach to the UA. Infants treated for UA-negative UTIs were more likely to have respiratory symptoms and less likely to have abnormal inflammatory markers than infants treated for UA-positive UTIs, indicating that these infants are either developing a milder inflammatory response to their underlying illness and/or might not have true UTIs (eg due to AB or contamination).

The AAP recently updated their UTI practice parameter to recommend inclusion of UA results as diagnostic criteria for UTI.¹ However, the fact that these guidelines do not include infants <2 months creates a gap in our understanding of the appropriate diagnostic criteria in this age group, as reflected by the site variability demonstrated in our investigation. The fact that up to 35% of infants treated for UTI at these different sites have normal UAs suggests that many practitioners continue to treat positive urine cultures regardless of UA values.

Several prior studies provide insight into the clinical significance of a positive urine culture in the absence of pyuria. Wettergren et al.^6,7,10 reported growth from suprapubic aspirate in 1.4% of infants who were screened periodically with urine cultures obtained by bag at well-child checks over the course of the first year (with a point prevalence as high as 1.5% in boys aged 0.25 to 1.9 months).¹⁰ These infants were not more likely to have subsequent UTIs⁷ or renal damage⁶ than infants without asymptomatic growth, leading the authors to conclude that this growth likely represented AB. These findings emphasize that the probability of a positive urine culture in any infant, even asymptomatic infants, is not insignificant.

Hoberman et al.¹¹ demonstrated that dimercaptosuccinic acid scans did not reveal signs of pyelonephritis in 14/15 children < 2 years of age with urine cultures growing >50,000 CFU/mL but no pyuria on UA, and concluded that AB was the most likely explanation for this combination of findings. Schroeder et al.⁵ and Tzimenatos et al.¹² examined infants <2-3 months with UTI and bacteremia caused by the same organism (and hence a true infection that cannot be explained by AB or contamination) and demonstrated that the UA sensitivity in this population was 99.5% and 100%, respectively, suggesting that the prior lower estimates of UA sensitivity in UTI in general, may have been biased by inclusion of positive urine cultures that did not represent UTI.

On the other hand, Shaikh et al.¹³ recently demonstrated that the sensitivity of the UA appears to vary by organism, with lower reported sensitivity in non-Escherichia coli organisms, leading the authors to conclude that this variability is evidence of suboptimal UA sensitivity. However, an alternative explanation for their findings is that non-E coli organisms may be more likely to cause AB or contamination.¹⁴ The fact that follow-up suprapubic aspirates on infants with untreated catheterized cultures yielding these organisms are often negative supports this alternative explanation.¹⁵

The median LOS in infants with UA-negative UTI was nearly one day longer than infants not treated for serious bacterial infection. These infants may have also undergone urinary imaging and possibly prophylactic antibiotics, indicating high resource burden created by this subgroup of infants. Expanding AAP UTI guidelines to infants <2 months of age would likely reduce resource utilization, but continued research is needed to assess the safety of this approach. Young infants have immature immune systems and may not develop a timely inflammatory response to UTI, which raises concerns about missing bacterial infections.

Our investigation has several strengths, including the large, nationally representative sample that includes both children’s and non-children’s hospitals. Similar febrile infant investigations of this size have previously been possible only using administrative databases, but our investigation required chart review for all enrolled infants, ensuring that the subjects were febrile, well-appearing, and were treated for UTI. However, our findings are limited in that data were collected primarily as part of a quality improvement initiative, and some of our thresholds for “abnormal” laboratory values might be controversial. For example, urine WBC thresholds differ across studies, and our CSF WBC threshold of >8/mm³ may be somewhat low given prior reports that values slightly above this threshold might be normal in infants under one month of age.¹⁶ The original intent of the inflammatory marker composite variable was to aid in risk stratification, but we were unable to collect granular data for all potentially relevant variables. In planning the REVISE project, we attempted to create straightforward, unambiguous variables to facilitate the anticipated high volume of chart reviews. Although patients categorized as having UTI might not have had true UTIs, by linking the “UTI” variable to practitioner management (rather than UA and microbiologic definitions), our data reflect real-world practice.

Acknowledgments

The authors would like to thank all of the site directors who participated in the REVISE project, and Brittany Jennings, Naji Hattar, Faiza Wasif, and Vanessa Shorte at the American Academy of Pediatrics for their leadership and management.

Disclosures

Dr. Schroeder has received honoraria for grand rounds presentations on the subject of urinary tract infections, and Dr. Biondi has received consulting fees from McKesson Inc. The other authors have no financial relationships to disclose.

The sensitivity of the urinalysis (UA) in young infants has been reported to be in the 75% to 85% range.^1-4 This suboptimal sensitivity has prevented a widespread adoption of the UA as a true screening test for urinary tract infection (UTI). Although infants with a positive urine culture and a negative UA may have asymptomatic bacteriuria (AB) or contamination,^5-7 they are often treated for UTI.

Due to these concerns, the American Academy of Pediatrics (AAP) recommended in their 2011 UTI Practice Guidelines that UA criteria should be incorporated into the definition of UTI.¹ However, these guidelines were intended for the 2-24 month age range, leaving a gap in our understanding of the appropriate management of infants <2 months. It is unknown how UA results influence the current management of UTI in young, febrile infants. Using data from a large, nationally representative quality improvement project surrounding the management of febrile infants, this investigation aimed to examine how frequently infants are treated for UTI despite having normal UAs and to determine whether infant and hospital characteristics are different in infants treated for UTI with a positive UA as compared to those treated for UTI with a negative UA.

Subjects and Setting

This is a secondary analysis of the AAP’s Reducing Excessive Variability in the Infant Sepsis Evaluation (REVISE) project that involved 20,570 well-appearing infants 7-60 days of age evaluated in the emergency department and/or inpatient setting for fever ≥38◦C without a source between September 2015 and November 2017 at 124 community- and university-based hospitals in the United States. Data were collected via chart review and entered into a standardized tool for the project. This project was deemed exempt by the AAP Institutional Review Board. Because all data were de-identified, some sites did not require Institutional Review Board approval while others required data sharing agreements.

Variables and Definitions

A positive UA was defined as having any leukocyte esterase, positive nitrites, or >5 white blood cells (WBCs) per high power field. Treatment for UTI was defined using the question “Did the urine culture grow an organism that was treated as a pathogen with a full course of antibiotics?” Subjects treated for meningitis or bacteremia were excluded in order to focus on uncomplicated UTI. “Abnormal inflammatory markers” were defined as having a WBC count <5,000 or >15,000 cells/mm³, an absolute band count ≥ 1,500 cells/mm³, a band to neutrophil ratio of >0.2, cerebrospinal fluid (CSF) WBC count of >8/mm³, a positive CSF gram stain, or an elevated C-reactive protein or procalcitonin level, as defined by the institutional range. Although technically not an “inflammatory marker,” CSF gram stain was included in this composite variable because in the rare cases that it is positive, the result would likely influence risk stratification and immediate management. Infants’ ages were categorized as either 7-30 days or 31-60 days. Hospital length-of-stay (LOS) was recorded to the nearest hour and infants who were not hospitalized were assigned a LOS of 0 hours. Hospital characteristics were determined through a survey completed by site leads.

Statistics

Proportions were compared using chi-square test. We used multilevel mixed-effects logistic regression to determine associations between patients and hospital characteristics and UA-positivity in subjects treated for UTI. We accounted for the hospital clustering effect with a random effect that did not vary with patient characteristics. We “marginalized” the regression coefficients to reflect the average effect across hospitals.^8,9 We tested the overall importance of the hospital clustering effect on the treatment by comparing our multilevel model to a single-level model without hospital random effects using the likelihood ratio test.

A total of 20,570 infants from 124 hospitals were enrolled in the REVISE project, and 648 (3.2%) were treated for bacteremia and/or meningitis. Of the remaining 19,922 infants, 2,407 (12.1%) were treated for UTI, of whom 2,298 (95.5%) had an initial UA performed. Urine cultures were obtained by catheterization or suprapubic aspirate in 90.3% and “other/unknown” in 9.7% of these 2,298 subjects.

UAs were negative in 337/2,298 (14.7%) treated subjects. UA-negative subjects were more likely to be 7-30 days old (adjusted odds ratio [aOR] 1.3, 95% CI 1.02-1.7) and have upper respiratory symptoms (aOR 1.7, 95% CI 1.3-2.3) and were less likely to have abnormal inflammatory markers (aOR 0.3, 95% CI 0.3-0.4) than UA+ subjects (Table). Even after accounting for the hospital characteristics depicted in the Table, treatment of UA-negative UTI was affected by the hospital (P < .001), and the intraclass correlation coefficient was 6% (95% CI, 3% to 14%). The Figure illustrates substantial site variability in the proportion of infants treated for UTIs that were UA-negative, ranging from 0% to 35% in hospitals with ≥20 UTI cases.

In this large, nationally representative sample of febrile infants 7-60 days of age, we demonstrate that nearly 15% of young febrile infants who are treated for UTIs have normal UAs. This proportion varied considerably among hospitals, suggesting that there are institutional differences in the approach to the UA. Infants treated for UA-negative UTIs were more likely to have respiratory symptoms and less likely to have abnormal inflammatory markers than infants treated for UA-positive UTIs, indicating that these infants are either developing a milder inflammatory response to their underlying illness and/or might not have true UTIs (eg due to AB or contamination).

The AAP recently updated their UTI practice parameter to recommend inclusion of UA results as diagnostic criteria for UTI.¹ However, the fact that these guidelines do not include infants <2 months creates a gap in our understanding of the appropriate diagnostic criteria in this age group, as reflected by the site variability demonstrated in our investigation. The fact that up to 35% of infants treated for UTI at these different sites have normal UAs suggests that many practitioners continue to treat positive urine cultures regardless of UA values.

Several prior studies provide insight into the clinical significance of a positive urine culture in the absence of pyuria. Wettergren et al.^6,7,10 reported growth from suprapubic aspirate in 1.4% of infants who were screened periodically with urine cultures obtained by bag at well-child checks over the course of the first year (with a point prevalence as high as 1.5% in boys aged 0.25 to 1.9 months).¹⁰ These infants were not more likely to have subsequent UTIs⁷ or renal damage⁶ than infants without asymptomatic growth, leading the authors to conclude that this growth likely represented AB. These findings emphasize that the probability of a positive urine culture in any infant, even asymptomatic infants, is not insignificant.

Hoberman et al.¹¹ demonstrated that dimercaptosuccinic acid scans did not reveal signs of pyelonephritis in 14/15 children < 2 years of age with urine cultures growing >50,000 CFU/mL but no pyuria on UA, and concluded that AB was the most likely explanation for this combination of findings. Schroeder et al.⁵ and Tzimenatos et al.¹² examined infants <2-3 months with UTI and bacteremia caused by the same organism (and hence a true infection that cannot be explained by AB or contamination) and demonstrated that the UA sensitivity in this population was 99.5% and 100%, respectively, suggesting that the prior lower estimates of UA sensitivity in UTI in general, may have been biased by inclusion of positive urine cultures that did not represent UTI.

On the other hand, Shaikh et al.¹³ recently demonstrated that the sensitivity of the UA appears to vary by organism, with lower reported sensitivity in non-Escherichia coli organisms, leading the authors to conclude that this variability is evidence of suboptimal UA sensitivity. However, an alternative explanation for their findings is that non-E coli organisms may be more likely to cause AB or contamination.¹⁴ The fact that follow-up suprapubic aspirates on infants with untreated catheterized cultures yielding these organisms are often negative supports this alternative explanation.¹⁵

The median LOS in infants with UA-negative UTI was nearly one day longer than infants not treated for serious bacterial infection. These infants may have also undergone urinary imaging and possibly prophylactic antibiotics, indicating high resource burden created by this subgroup of infants. Expanding AAP UTI guidelines to infants <2 months of age would likely reduce resource utilization, but continued research is needed to assess the safety of this approach. Young infants have immature immune systems and may not develop a timely inflammatory response to UTI, which raises concerns about missing bacterial infections.

Our investigation has several strengths, including the large, nationally representative sample that includes both children’s and non-children’s hospitals. Similar febrile infant investigations of this size have previously been possible only using administrative databases, but our investigation required chart review for all enrolled infants, ensuring that the subjects were febrile, well-appearing, and were treated for UTI. However, our findings are limited in that data were collected primarily as part of a quality improvement initiative, and some of our thresholds for “abnormal” laboratory values might be controversial. For example, urine WBC thresholds differ across studies, and our CSF WBC threshold of >8/mm³ may be somewhat low given prior reports that values slightly above this threshold might be normal in infants under one month of age.¹⁶ The original intent of the inflammatory marker composite variable was to aid in risk stratification, but we were unable to collect granular data for all potentially relevant variables. In planning the REVISE project, we attempted to create straightforward, unambiguous variables to facilitate the anticipated high volume of chart reviews. Although patients categorized as having UTI might not have had true UTIs, by linking the “UTI” variable to practitioner management (rather than UA and microbiologic definitions), our data reflect real-world practice.

Acknowledgments

The authors would like to thank all of the site directors who participated in the REVISE project, and Brittany Jennings, Naji Hattar, Faiza Wasif, and Vanessa Shorte at the American Academy of Pediatrics for their leadership and management.

Disclosures

Dr. Schroeder has received honoraria for grand rounds presentations on the subject of urinary tract infections, and Dr. Biondi has received consulting fees from McKesson Inc. The other authors have no financial relationships to disclose.

The sensitivity of the urinalysis (UA) in young infants has been reported to be in the 75% to 85% range.^1-4 This suboptimal sensitivity has prevented a widespread adoption of the UA as a true screening test for urinary tract infection (UTI). Although infants with a positive urine culture and a negative UA may have asymptomatic bacteriuria (AB) or contamination,^5-7 they are often treated for UTI.

Due to these concerns, the American Academy of Pediatrics (AAP) recommended in their 2011 UTI Practice Guidelines that UA criteria should be incorporated into the definition of UTI.¹ However, these guidelines were intended for the 2-24 month age range, leaving a gap in our understanding of the appropriate management of infants <2 months. It is unknown how UA results influence the current management of UTI in young, febrile infants. Using data from a large, nationally representative quality improvement project surrounding the management of febrile infants, this investigation aimed to examine how frequently infants are treated for UTI despite having normal UAs and to determine whether infant and hospital characteristics are different in infants treated for UTI with a positive UA as compared to those treated for UTI with a negative UA.

Subjects and Setting

This is a secondary analysis of the AAP’s Reducing Excessive Variability in the Infant Sepsis Evaluation (REVISE) project that involved 20,570 well-appearing infants 7-60 days of age evaluated in the emergency department and/or inpatient setting for fever ≥38◦C without a source between September 2015 and November 2017 at 124 community- and university-based hospitals in the United States. Data were collected via chart review and entered into a standardized tool for the project. This project was deemed exempt by the AAP Institutional Review Board. Because all data were de-identified, some sites did not require Institutional Review Board approval while others required data sharing agreements.

Variables and Definitions

A positive UA was defined as having any leukocyte esterase, positive nitrites, or >5 white blood cells (WBCs) per high power field. Treatment for UTI was defined using the question “Did the urine culture grow an organism that was treated as a pathogen with a full course of antibiotics?” Subjects treated for meningitis or bacteremia were excluded in order to focus on uncomplicated UTI. “Abnormal inflammatory markers” were defined as having a WBC count <5,000 or >15,000 cells/mm³, an absolute band count ≥ 1,500 cells/mm³, a band to neutrophil ratio of >0.2, cerebrospinal fluid (CSF) WBC count of >8/mm³, a positive CSF gram stain, or an elevated C-reactive protein or procalcitonin level, as defined by the institutional range. Although technically not an “inflammatory marker,” CSF gram stain was included in this composite variable because in the rare cases that it is positive, the result would likely influence risk stratification and immediate management. Infants’ ages were categorized as either 7-30 days or 31-60 days. Hospital length-of-stay (LOS) was recorded to the nearest hour and infants who were not hospitalized were assigned a LOS of 0 hours. Hospital characteristics were determined through a survey completed by site leads.

Statistics

Proportions were compared using chi-square test. We used multilevel mixed-effects logistic regression to determine associations between patients and hospital characteristics and UA-positivity in subjects treated for UTI. We accounted for the hospital clustering effect with a random effect that did not vary with patient characteristics. We “marginalized” the regression coefficients to reflect the average effect across hospitals.^8,9 We tested the overall importance of the hospital clustering effect on the treatment by comparing our multilevel model to a single-level model without hospital random effects using the likelihood ratio test.

A total of 20,570 infants from 124 hospitals were enrolled in the REVISE project, and 648 (3.2%) were treated for bacteremia and/or meningitis. Of the remaining 19,922 infants, 2,407 (12.1%) were treated for UTI, of whom 2,298 (95.5%) had an initial UA performed. Urine cultures were obtained by catheterization or suprapubic aspirate in 90.3% and “other/unknown” in 9.7% of these 2,298 subjects.

UAs were negative in 337/2,298 (14.7%) treated subjects. UA-negative subjects were more likely to be 7-30 days old (adjusted odds ratio [aOR] 1.3, 95% CI 1.02-1.7) and have upper respiratory symptoms (aOR 1.7, 95% CI 1.3-2.3) and were less likely to have abnormal inflammatory markers (aOR 0.3, 95% CI 0.3-0.4) than UA+ subjects (Table). Even after accounting for the hospital characteristics depicted in the Table, treatment of UA-negative UTI was affected by the hospital (P < .001), and the intraclass correlation coefficient was 6% (95% CI, 3% to 14%). The Figure illustrates substantial site variability in the proportion of infants treated for UTIs that were UA-negative, ranging from 0% to 35% in hospitals with ≥20 UTI cases.

In this large, nationally representative sample of febrile infants 7-60 days of age, we demonstrate that nearly 15% of young febrile infants who are treated for UTIs have normal UAs. This proportion varied considerably among hospitals, suggesting that there are institutional differences in the approach to the UA. Infants treated for UA-negative UTIs were more likely to have respiratory symptoms and less likely to have abnormal inflammatory markers than infants treated for UA-positive UTIs, indicating that these infants are either developing a milder inflammatory response to their underlying illness and/or might not have true UTIs (eg due to AB or contamination).

The AAP recently updated their UTI practice parameter to recommend inclusion of UA results as diagnostic criteria for UTI.¹ However, the fact that these guidelines do not include infants <2 months creates a gap in our understanding of the appropriate diagnostic criteria in this age group, as reflected by the site variability demonstrated in our investigation. The fact that up to 35% of infants treated for UTI at these different sites have normal UAs suggests that many practitioners continue to treat positive urine cultures regardless of UA values.

Several prior studies provide insight into the clinical significance of a positive urine culture in the absence of pyuria. Wettergren et al.^6,7,10 reported growth from suprapubic aspirate in 1.4% of infants who were screened periodically with urine cultures obtained by bag at well-child checks over the course of the first year (with a point prevalence as high as 1.5% in boys aged 0.25 to 1.9 months).¹⁰ These infants were not more likely to have subsequent UTIs⁷ or renal damage⁶ than infants without asymptomatic growth, leading the authors to conclude that this growth likely represented AB. These findings emphasize that the probability of a positive urine culture in any infant, even asymptomatic infants, is not insignificant.

Hoberman et al.¹¹ demonstrated that dimercaptosuccinic acid scans did not reveal signs of pyelonephritis in 14/15 children < 2 years of age with urine cultures growing >50,000 CFU/mL but no pyuria on UA, and concluded that AB was the most likely explanation for this combination of findings. Schroeder et al.⁵ and Tzimenatos et al.¹² examined infants <2-3 months with UTI and bacteremia caused by the same organism (and hence a true infection that cannot be explained by AB or contamination) and demonstrated that the UA sensitivity in this population was 99.5% and 100%, respectively, suggesting that the prior lower estimates of UA sensitivity in UTI in general, may have been biased by inclusion of positive urine cultures that did not represent UTI.

On the other hand, Shaikh et al.¹³ recently demonstrated that the sensitivity of the UA appears to vary by organism, with lower reported sensitivity in non-Escherichia coli organisms, leading the authors to conclude that this variability is evidence of suboptimal UA sensitivity. However, an alternative explanation for their findings is that non-E coli organisms may be more likely to cause AB or contamination.¹⁴ The fact that follow-up suprapubic aspirates on infants with untreated catheterized cultures yielding these organisms are often negative supports this alternative explanation.¹⁵

The median LOS in infants with UA-negative UTI was nearly one day longer than infants not treated for serious bacterial infection. These infants may have also undergone urinary imaging and possibly prophylactic antibiotics, indicating high resource burden created by this subgroup of infants. Expanding AAP UTI guidelines to infants <2 months of age would likely reduce resource utilization, but continued research is needed to assess the safety of this approach. Young infants have immature immune systems and may not develop a timely inflammatory response to UTI, which raises concerns about missing bacterial infections.

Our investigation has several strengths, including the large, nationally representative sample that includes both children’s and non-children’s hospitals. Similar febrile infant investigations of this size have previously been possible only using administrative databases, but our investigation required chart review for all enrolled infants, ensuring that the subjects were febrile, well-appearing, and were treated for UTI. However, our findings are limited in that data were collected primarily as part of a quality improvement initiative, and some of our thresholds for “abnormal” laboratory values might be controversial. For example, urine WBC thresholds differ across studies, and our CSF WBC threshold of >8/mm³ may be somewhat low given prior reports that values slightly above this threshold might be normal in infants under one month of age.¹⁶ The original intent of the inflammatory marker composite variable was to aid in risk stratification, but we were unable to collect granular data for all potentially relevant variables. In planning the REVISE project, we attempted to create straightforward, unambiguous variables to facilitate the anticipated high volume of chart reviews. Although patients categorized as having UTI might not have had true UTIs, by linking the “UTI” variable to practitioner management (rather than UA and microbiologic definitions), our data reflect real-world practice.

Acknowledgments

The authors would like to thank all of the site directors who participated in the REVISE project, and Brittany Jennings, Naji Hattar, Faiza Wasif, and Vanessa Shorte at the American Academy of Pediatrics for their leadership and management.

Disclosures

Dr. Schroeder has received honoraria for grand rounds presentations on the subject of urinary tract infections, and Dr. Biondi has received consulting fees from McKesson Inc. The other authors have no financial relationships to disclose.