Once-Daily Ceftriaxone Plus Metronidazole Versus Ertapenem and/or Cefoxitin for Pediatric Appendicitis

Transcription

1 Journal of the ediatric Infectious Diseases Society Advance Access published December 24, 2015 Original Article Once-Daily Ceftriaxone lus Metronidazole Versus Ertapenem and/or Cefoxitin for ediatric Appendicitis Amanda L. Hurst, 1 Daniel Olson, 2,3 Stig Somme, 2,5 Jason Child, 1 Laura yle, 2 Daksha Ranade, 6 Alexandra Stamatoiu, 4 Timothy Crombleholme, 2,5 and Sarah K. arker 2,3,4 1 Department of harmacy, 2 Department of ediatrics, 3 Division of ediatric Infectious Diseases, 4 Department of Infection Control, 5 Division of General, Thoracic, and Fetal ediatric Surgery, and 6 Division of Clinical Informatics, Children s Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado Corresponding Author: Sarah K. arker, MD, Sections of ediatric Infectious Diseases and Epidemiology, Children s Hospital Colorado, East 16th Avenue Box 055, Aurora, CO sarah.parker@childrenscolorado.org. Received September 17, 2015; accepted November 15, Background. Appendicitis is a common surgical emergency in pediatric patients, and broad-spectrum antibiotic therapy is warranted in their care. A simplified once-daily regimen of ceftriaxone and metronidazole (CTX plus MTZ) is cost effective in perforated patients. The goal of this evaluation is to compare a historic regimen of cefoxitin (CFX) in nonperforated cases and ertapenem (ERT) in perforated and abscessed cases with CTX plus MTZ for all cases in terms of efficacy and cost. Methods. A retrospective review compared outcomes of nonperforated, perforated, and abscessed cases who received the historic regimen or CTX plus MTZ. Length of stay, time to afebrile, time to full feeds, postoperative abscess, and wound infection rates, inpatient readmissions, and antibiotic costs were evaluated. Results. There were a total of 841 cases reviewed (494 nonperforated, 247 perforated, and 100 abscessed). Overall, the CTX plus MTZ group had a shorter time to afebrile ( <.001). Treatment groups did not differ in length of stay. ostoperative abscess rates were similar between groups (4.1% vs 3.3%, not significant). Other postoperative complications were similar between groups. Total antibiotic cost savings were over $ during the study period (from November 2010 to June 2013). Conclusions. Both and CTX plus MTZ result in low abscess and complication rates, suggesting both are effective strategies. Treatment with CTX plus MTZ results in a shorter time to afebrile, while also providing significant antibiotic cost savings. Ceftriaxone plus MTZ is a streamlined, cost-effective regimen in the treatment of nonperforated, perforated, and abscessed appendicitis. Key words. antibiotics; antimicrobial stewardship; appendicitis; pediatric. Appendicitis is the most common surgical emergency in the pediatric population [1 3]. Several pediatric studies suggest that simplified, broad-spectrum perioperative antibiotic regimens are equally effective and less costly than a triple regimen containing an aminoglycoside for appendicitis [3 6]. One such regimen is once-daily ceftriaxone plus metronidazole (CTX plus MTZ), which was evaluated in perforated (but not nonperforated or abscessed) appendicitis [5 9]. Although MTZ is not traditionally administered once daily, its pharmacokinetics, described after its approval in 1960, support infrequent dosing based on high peak levels, low protein binding, long half-life, active metabolite, and post-antibiotic effect [7]. Ertapenem (ERT) as monotherapy is recommended for appendicitis [10] and is likely widely used in pediatric patients cared for at facilities that care for both adult and pediatric patients. However, use of a carbapenem poses issues of increased expense [4] and increased induction of resistance [11]. Because we changed from a historical regimen of ERT (for perforated and abscessed at presentation cases) and cefoxitin ([CFX] for nonperforated cases) to a current regimen of CTX plus MTZ for all appendicitis, we were presented with a unique opportunity to evaluate and compare these regimens for clinical efficacy and cost in a retrospective manner (Figure 1). Both regimens are effective, with similar rates of abscess and other postoperative complications. Journal of the ediatric Infectious Diseases Society pp. 1 9, DOI: /jpids/piv082 The Author ublished by Oxford University ress on behalf of the ediatric Infectious Diseases Society. All rights reserved. For ermissions, please journals.permissions@oup.com.

2 2 Hurst et al Figure 1. Historic and new antibiotic regimens after change in recommended antibiotic(s) in clinical care guideline. Abbreviations: CFX, cefoxitin; CTX, ceftriaxone; ERT, ertapenem; MTZ, metronidazole. For reasons of efficacy, clarity, and cost, once-daily CTX plus MTZ emerged as our regimen of choice. MATERIALS AND METHODS Antimicrobial Regimen Change In order to standardize and outline the most cost-effective treatment of appendicitis at Children s Hospital Colorado (CHCO), the care is dictated by a clinical care guideline. In 2012, the recommended antimicrobial regimen changed from to CTX plus MTZ based on an internal analysis comparing our appendicitis regimen to that of other ediatric Health Information System (HIS) hospitals. This analysis (as part of internal quality improvement; data not published) revealed that no other HIS hospital was using ERT for appendicitis, that our ERT use contributed significantly to patient charges, and finally that many of our patients received both CFX and ERT. This final reason was largely due to diagnostic uncertainty at the time an antibiotic was chosen. With this information and the growing evidence in support of a once-daily regimen [5, 6], the decision was made to transition to CTX plus MTZ for all appendicitis patients regardless of perforation status to minimize alterations in treatment with changes in diagnosis and to decrease costs. This change occurred in July articipants Before evaluation, approval was obtained from the Organizational Research Risk & Quality Improvement Review anel at CHCO after the local investigational review board deemed the project exempt and quality improvement in nature. A retrospective review was conducted to evaluate patients diagnosed with nonperforated appendicitis, perforated appendicitis, and abscessed appendicitis between November 1, 2010 and June 30, 2013 at CHCO. Data were extracted from the electronic medical record, and patients were included in the evaluation whether they (1) received an appendicitis diagnosis based on International Classification of Diseases, Ninth Revision (ICD9) codes (540, 541, 542, 543), (2) underwent a laparoscopic appendectomy, and (3) were treated at the main campus of CHCO according to the newly instituted CTX plus MTZ regimen or historic regimen. Exclusion criteria were applied to achieve a more homogenous cohort for evaluation (Figure 2). All data were collected in the REDCap electronic data capture program hosted at CHCO [12]. Given that the definition of nonperforated, perforated, and abscessed appendicitis was not clearly defined at our institution, we sought to standardize a definition for this review. atients were stratified into the nonperforated, perforated, and abscessed categories after the review of the pathology, operative, and imaging reports. A patient case was deemed perforated only if perforation or rupture was documented in the operative or pathology reports. A patient was deemed abscessed if abscess or phlegmon was documented in the operative note or on imaging. All other patients were deemed to be nonperforated. Data Collection and Outcome Measures The baseline characteristics evaluated among the groups included demographic information (age, weight, gender, race), payor status (Medicaid, private, uninsured), and reported days of symptoms before admission. Antibiotic exposures were also collected by chart review. The antibiotic regimen received before cut time was used to determine which study group a patient would fall into for patients with uncomplicated or nonperforated appendicitis. For patients with complicated appendicitis, including those who were either perforated or abscessed at presentation, the antibiotic regimen that was assigned for study purposes was the regimen that the patient received before cut time and continued on in the immediate postoperative period ( primary regimen received).

3 Once-Daily Regimen for Appendicitis 3 Figure 2. Study sample. Abbreviations: CFX, cefoxitin; CTX, ceftriaxone; ERT, ertapenem; ICU, intensive care unit; MTZ, metronidazole. The primary outcomes evaluated were length of stay (defined in hours) and time to afebrile (defined as the first postoperative day [OD] the patient maintained a temperature less than 38.3 C) [5, 6, 8, 9]. Secondary outcomes evaluated included time to full feeds, postoperative abscess rate, postoperative wound infection rate, inpatient readmissions for complications (abscess formation, Clostridium difficile infection, wound infection, fever, or pain) [3 6], and antibiotic cost. Time to full feeds was defined as the first OD the patient tolerated a full-diet order. ostoperative abscess was defined as presence of an abscess on computed tomography (CT) scan within 30 days postoperatively. ostoperative wound infection was defined by clinical diagnosis in the chart within 30 days postoperatively. A related inpatient readmission was defined as any readmission to an inpatient bed within 30 days deemed related to the appendectomy. atients were classified into only 1 category of readmission. All clinical notes within 30 days postoperatively were reviewed in the electronic medical record to evaluate for postoperative complications and readmissions. Repeat surgical interventions were also recorded for inpatient readmissions due to abscess. Antibiotic regimens prescribed at discharge were also documented, although neither the historic nor newly instituted guidelines dictated outpatient prescribing. To validate the HIS finding that many patients received both CFX and ERT, this was also assessed in the group. The direct pharmacy cost for both antibiotic regimens was calculated for each patient using the lowest contract cost in the year 2013 reported by the CHCO pharmacy department for each antibiotic. The assigned diagnosis (to determine whether to calculate cost for ERT or CFX), length of intravenous antibiotic therapy received, and weight of the patient were used to calculate the total direct pharmacy cost for each regimen (ie, if a patient was deemed perforated and received a total of 5 intravenous days of antibiotics, the cost of ERT for 5 days and CTX and MTZ for 5 days was calculated based on the patient s weight, regardless of which regimen the patient actually received). The difference between the direct pharmacy cost of the

4 4 Hurst et al CTX plus MTZ regimen and the regimen was used to report a per-patient antibiotic cost savings; these were summed and reported as overall cost savings to the pharmacy department for the entire study population. Statistical Analyses The distributions of continuous variables were assessed for normality. If not normally distributed, median values were reported. Descriptive characteristics are reported as median, minimum, maximum, 25th percentile, and 75th percentile, or percentage. Categorical variables were compared between groups using the χ 2 test or Fisher s exact test, continuous variables were compared using the Kruskal Wallis test, and time-to-event outcomes were compared using the log-rank test. values <.05 are identified as statistically significant. All analyses were performed using SAS, version 9.3 (Cary, North Carolina). RESULTS During the study period 991 appendectomies were performed, 841 of which qualified for review. Of the 150 patients excluded, the most common reasons included treatment at an outside site (n = 76) or the receipt of an alternative antibiotic regimen (n = 37) (Figure 2). Of the 841 patients that were reviewed, 418 fell into the CTX plus MTZ group and 423 were in the CFX and/or ERT group; there was significant expansion of the hospital after the transition from the historic regimen (on average 21 cases/month) to the CTX plus MTZ (35 cases/ month). A total of 33% (140 of 423) of patients in the group received both CFX and ERT during their admission. There were no statistically significant differences between the groups in terms of important baseline characteristics including age, gender, weight, race, insurance status, duration of symptoms before admission, and central-line placement (Table 1). When divided by appendicitis category, there were 494 in the no perforation category, 247 in the perforation category, and 100 in the abscessed category (Table 1). There were a few notable differences between study groups at baseline. Among the no perforation category, the CTX plus MTZ group had a slightly longer duration of symptoms before admission by the Kruskal Wallis test than the group ( =.02). Among the abscessed category, the CTX plus MTZ group had a lower median white blood cell count at admission than those in the group (15.5 vs 17.9; =.01) (Table 1). There were no statistically significant differences between antibiotic treatment groups in length of stay among any of the 3 appendicitis categories or when categories were combined (Table 2 and Table 3, respectively). The Table 1. Characteristics of Study Groups Combined Treatment Groups erforation and Abscess erforation No Abscess No erforation No Abscess (N = 423) (N = 418) (N = 52) (N = 48) (N = 116) (N = 131) (N = 255) (N = 239) Characteristic 11.2 ( ) 11.4 ( ) ( ) 8.7 ( ) ( ) 7.5 ( ) ( ) 10.3 ( ).51 Age, median (range), y 41.4 ( ) 41.9 ( ) ( ) 32.9 ( ) ( ) 28.2 ( ) ( ) 37.6 ( ).91 Weight, median (range), kg Male, n (%) 151 (63.2) 151 (59.2) (52) 62 (54) (63) 30 (58) (59.6) 243 (57.5).53 Caucasian, n (%) 152 (63.6) 141 (55.3) (51) 62 (54) (75) 34 (65) (61.0) 237 (56.0).14 Medicaid, n (%) 114 (47.7) 110 (43.1) (56) 65 (56) (40) 31 (60) (49.3) 206 (48.7) ( ) 14.2 ( ) ( ) 16.2 ( ) ( ) 17.9 ( ) ( ) 15.0 ( ).31 WBC on admission, median (range) 1(1 7) 1 (1 8).02 2 (1 7) 2 (1 8).72 3 (1 8) 3 (1 8).31 1 (1 8) 1 (1 8).06 Duration of symptoms before admission, median (range), d 2 (0.8) 2 (0.8) (50) 43 (37) (69) 40 (77) (23.9) 85 (20.1).18 Central line placed, n (%) Abbreviations: CFX, cefoxitin; CTX, ceftriaxone; d, days; ERT, ertapenem; MTZ, metronidazole; n, absolute number; WBC, white blood cells; y, years.

5 Table 2. Outcomes of Antibiotic Regimens, Separated by Disease Category Outcome No erforation, No Abscess (n = 239) (n = 255) erforation, No Abscess (n = 131) (n = 116) erforation and Abscess (n = 48) (n = 52) Length of stay, median (25th percentile, 75th percentile), h 33.3 (25.7, 42.6) 34.9 (25.6, 44.1) (79.8, 146.0) (77.9, 133.7) (113.0, 185.2) (119.4, 183.7).59 Time to full feeds, median (25th 1 (1, 1) 1 (1, 1).71 2 (1, 4) 2 (2, 3).47 3 (2, 5) 3 (3, 5).61 percentile, 75th percentile), d ostoperative abscess within 30 d, 1 (0.4) 6 (2.4) (8) 6 (5).43 6 (13) 2 (4).15 n (%) ostoperative wound infection within 1 (0.4) 2 (0.8) (1) 0 (0) (2) 0 (0) d, n (%) Inpatient readmission within 30 d of 2 (0.8) 10 (3.9).03 7 (5) 3 (3).34 5 (10) 1 (2).10 discharge, n (%) - Abscess, n (%) 1 (0.4) 6 (2.4).12 5 (4) 3 (3).73 2 (4) 1 (2).61 - Abscess requiring repeat surgical 0 (0) 2 (0.8).50 1 (1) 3 (3).20 1 (2) 1 (2) 1.00 intervention, n (%) - Cdiffinfection, n (%) 1 (0.4) 2 (0.8) (0) 0 (0) 1 (2) 0 (0).48 - Wound infection, n (%) 0 (0) 1 (0.4) (0) 0 (0) 0 (0) 0 (0) - Fever, n (%) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) - ain, n (%) 0 (0) 1 (0.4) (2) 0 (0).50 2 (4) 0 (0).23 Length of stay of readmission, median(25th percentile, 75th percentile), h (108.1, 122.8) 58.2 (42.5, 87.0) (38.4, 97.2) (110.0, 205.7) (65.6, 81.0) (284.3, 284.3).14 Abbreviations: C diff, Clostridium difficile; CFX, cefoxitin; CTX, ceftriaxone; d, days; ERT, ertapenem; h, hours; MTZ, metronidazole; n, absolute number; y, years. Once-Daily Regimen for Appendicitis 5

6 6 Hurst et al Table 3. Outcomes of Antibiotic Regimens With Combined Disease Category Combined Treatment Groups Outcome (n = 418) (n = 423) Length of stay, median (25th percentile, 75th percentile), h 48.3 (30.2, 115.8) 48.4 (31.2, 104.1).89 Time to full feeds, median (25th percentile, 75th percentile), d 1 (1, 2) 1 (1, 2).77 ostoperative abscess within 30 d, n (%) 17 (4.1) 14 (3.3).56 ostoperative wound infection within 30 d, n (%) 3 (0.7) 2 (0.5).69 Inpatient readmission within 30 d of discharge, n (%) 14 (3.4) 14 (3.3).98 - Abscess, n (%) 8 (1.9) 10 (2.4).65 - Abscess requiring repeat surgical intervention, n (%) 2 (0.5) 6 (1.4).20 - C diff infection, n (%) 2 (0.5) 2 (0.5) Wound infection, n (%) 0 (0) 1 (0.2) Fever, n (%) 0 (0) 0 (0) - ain, n (%) 4 (1.0) 1 (0.2).22 Length of stay of readmission, median (25th percentile, 75th percentile), h 83.5 (58.2, 97.2) 78.1 (46.5, 117.1).65 Abbreviations: C diff, Clostridium difficile; CFX, cefoxitin; CTX, ceftriaxone; d, days; ERT, ertapenem; h, hours; MTZ, metronidazole; n, absolute number; y, years. CTX plus MTZ group had a significantly shorter time to afebrile compared with the group in each of the separate appendicitis categories and when categories were combined by Cox regression survival analysis, although the median time to afebrile was 1 day in all groups (Figure 3). Because time to afebrile was not normally distributed, median time to afebrile was used for statistical analysis. Figure 3. Survival plots: time to afebrile for all patients (followed by each appendicitis category).

7 Once-Daily Regimen for Appendicitis 7 The 2 antibiotic groups had similar time to full feeds in each appendicitis category and when categories were combined. ostoperative abscess rates were similar between the 2 antibiotic groups when evaluating the combined appendicitis categories, with 4.1% and 3.3% of patients experiencing abscess in the CTX plus MTZ and CFX and/or ERT groups, respectively ( =.56) (Table 3). Rates were also similar when evaluating the appendicitis categories separately (Table 2). In the most historically studied category, perforated without abscess, the overall postoperative abscess rate was 6.5% (16 of 247). In the perforated category, 1 of 5 patients (20%) in the CTX plus MTZ group readmitted due to abscess required repeat surgical intervention, whereas 3 of 3 patients (100%) readmitted due to abscess in the group required repeat surgical intervention ( =.2) (Table 2). Overall, the incidence of postoperative wound infection was low (only 5 patients in the entire population, 0.6%), and there was no difference between treatment groups either among independent appendicitis categories (Table 2) or when categories were combined (Table 3). There were no statistically significant differences in inpatient readmissions for abscess, C difficile infection, wound infection, fever, and pain between treatment groups among independent appendicitis categories in addition to when those categories were combined (Tables 2 and 3, respectively). Overall, the most common reason for an inpatient readmission was abscess: 2.4% in the group, and 1.9% in the CTX plus MTZ group ( =.65) (Table 3). In the no perforation category, the CTX plus MTZ group had lower inpatient readmissions due to any cause in comparison to the historic regimen (0.8% vs 3.9%; =.03) (Table 2). The median length of stay of readmission was 86 hours for perforated patients treated with CTX plus MTZ versus hours for patients treated with ( =.02) (Table 2). Median length of stay of readmission was no different among the Figure 4. rojected annualized antibiotic cost by year. *Annualized antibiotic cost based on available data during study period. other appendicitis categories and when categories were combined (Tables 2 and 3, respectively). When evaluating antibiotics prescribed at discharge, there were no differences between treatment groups when appendicitis categories were combined, nor were there differences in the nonperforated and abscessed categories. In the perforated category, patients in the CFX and/or ERT group more commonly received antibiotics at discharge (58% versus 42%; =.01) and for longer courses (7 days vs 5 days; =.03) compared with those in the CTX plus MTZ group. The regimen was times more costly than the CTX plus MTZ regimen in terms of direct pharmacy acquisition antibiotic cost for the patients included in the study. The total projected pharmacy cost savings if the entire study population was treated with the CTX plus MTZ regimen versus the historic regimen during the 32-month study period was $ The total cost savings for nonperforated patients was $10 871, averaging a cost savings of $22 per patient for the 494 nonperforated patients in the study. The total cost savings for perforated patients was $67 663, averaging a cost savings of $274 per patient for the 247 perforated patients in the study. The total cost savings for abscessed patients was $32 713, averaging a cost savings of $327 per patient for the 100 abscessed patients in the study. The annual total cost savings was $ for 2010 (annualized based on 2 months of data), $ for 2011, $ for 2012, and $ for 2013 (annualized based on 6 months of data) (Figure 4). DISCUSSION Our results demonstrate that once-daily CTX plus MTZ and are both effective regimens for treatment of pediatric appendicitis based on low rates of postoperative complications including abscess. Given comparable efficacy and shorter time to afebrile, CTX plus MTZ offers a less costly, more streamlined option in the treatment of appendicitis. These results support previous studies of once-daily CTX plus MTZ in pediatric perforated appendicitis [5, 6] but extend the regimen to all appendicitis classifications. Due to low abscess rates, most studies, including ours, do not reach statistical significance in regards to postoperative abscess, although it remains of clinical significance to pediatric surgeons. Time to afebrile is used as a surrogate of abscess formation, because longer periods of fever are associated with higher abscess rates [13]. Although differences in postoperative abscess were not detected between groups, time to afebrile was significantly shorter in the CTX plus MTZ group. Overall, postoperative abscess

8 8 Hurst et al was considerably low at 3.7% (31 of 841), and 6.5% (16 of 247) in the perforated but not abscessed group (the most commonly published group); this is lower than a single center s recently reported average of 18% in a perforated but not abscessed population [6]. Our favorable postoperative abscess rates may in part be due to a less strict definition of perforation at our center compared with others [9], which could inflate our denominator. However, it is unlikely this factor is too impactful given our perforation rate (29%, 247 of 841) is on par with other pediatric institutions, although other hospitals may also have similar definition issues [14]. Both regimens are well tolerated, in terms of similar numbers of readmissions for pain (including nausea/ vomiting) and similar time to full feeds between treatment groups, which serve as surrogate markers of tolerability. This evaluation was retrospective in design, which presents inherent limitations. It was done over a 2.5-year time period, in which other factors in care may have changed. In an ideal setting, prospectively classifying patients based on an actual perforation found on review of the appendix would be preferable, as discussed above [9]. In addition, definition of postoperative abscess as presence of abscess on CT scan is confounded by burden of abscess at presentation. It is difficult to discern new abscess formation from residual abscess; thus, an increased use of CT postoperatively over time could bias towards more reports of postoperative abscess. We tried to mitigate this by reporting postoperative abscess requiring repeat surgical intervention, which may serve as a better marker of the complication. Certain outcomes, such as postoperative complications, may be under appreciated because visit documentation may be suboptimal or patients may seek care at other centers [15]. Time to afebrile was also reported as the first OD a patient remained afebrile. Collecting this outcome in hours would have been a more descriptive measure. Although 33% of patients received both CFX and ERT, we performed outcome analyses on each of the primary regimens received (CTX plus MTZ, CFX, ERT, and CFX and ERT), and the results were similar, justifying the grouping of the later 3 groups into 1 (CFX and/or ERT). Our cost evaluation takes into account pharmacy acquisition cost only, and it may underappreciate total cost savings of the simplified regimen. We did not take into consideration the cost savings associated with decreased pharmacy and nursing preparation or administration time and decreased line access with a once-daily regimen (in favor of CTX plus MTZ), and we did not assess total admission costs or charges, because these models are confounded by the 2.5-year period of time. Our results may also not be generalizable to institutions that primarily perform open appendectomies as opposed to the laparoscopic approach, because we excluded these patients to keep a more homogenous cohort. The 10 patients excluded in our study who underwent open procedures were extensively more complex with expansive disease and did not fit the remaining population. When these data and the practicalities of implementation of a regimen are taken into account, the CTX plus MTZ regimen emerged as the best choice for our center. In addition to favorable and/or comparable outcomes in terms of time to afebrile, length of stay, tolerability, and complications, the benefits of the CTX plus MTZ regimen include decreased cost to the pharmacy and streamlining of care; all patients, regardless of category, receive the same regimen. This prevents confusion as to which regimen a patient is to receive and the 33% of cases that received both CFX and ERT in our study population. CONCLUSIONS Overall, both CTX plus MTZ and are effective regimens in pediatric nonperforated, perforated, and abscessed appendicitis, resulting in low rates of postoperative abscess. Ceftriaxone plus MTZ consistently results in shorter times to afebrile in the postoperative period and decreased antibiotic costs compared with, whereas no difference is detected in terms of length of stay, readmission rate, abscess rates, and wound infection rates. The CTX plus MTZ regimen offers a viable, cost-effective, streamlined alternative to other regimens, and this is relevant to centers currently using or considering use of CFX, ERT, or both at their institutions. Although this once-daily regimen is not found within consensus guidelines, our experience in all classifications of appendicitis adds to data in perforated appendicitis, endorsing its future consideration. Acknowledgments We acknowledge the pediatric surgeons and pharmacists at Children s Hospital Colorado, who adopted the new antibiotic regimen uniformly. Disclaimer. S. K.. and A. L. H. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. otential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of otential Conflicts of Interest. References 1. Bennion RS, Baron EJ, Thompson JE Jr, et al. The bacteriology of gangrenous and perforated appendicitis--revisited. Ann Surg 1990; 211: Chiu CJ, Bratu I. The process of treating pediatric appendicitis. Clin ediatr (hila) 2011; 50:803 6.

9 Once-Daily Regimen for Appendicitis 9 3. Lee SL, Islam S, Cassidy LD, et al. Antibiotics and appendicitis in the pediatric population: an American ediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J ediatr Surg 2010; 45: Goldin AB, Sawin RS, Garrison MM, et al. Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis. ediatrics 2007; 119: St eter SD, Little DC, Calkins CM, et al. A simple and more costeffective antibiotic regimen for perforated appendicitis. J ediatr Surg 2006; 41: St eter SD, Tsao K, Spilde TL, et al. Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial. J ediatr Surg 2008; 43: Sprandel KA, Drusano GL, Hecht DW, et al. opulation pharmacokinetic modeling and Monte Carlo simulation of varying doses of intravenous metronidazole. Diagn Microbiol Infect Dis 2006; 55: St eter SD, Aguayo, Fraser JD, et al. Initial laparoscopic appendectomy versus initial nonoperative management and interval appendectomy for perforated appendicitis with abscess: a prospective, randomized trial. J ediatr Surg 2010; 45: St eter SD, Sharp SW, Holcomb GW 3rd, Ostlie DJ. An evidencebased definition for perforated appendicitis derived from a prospective randomized trial. J ediatr Surg 2008; 43: Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010; 50: Furtado GH, erdiz LB, Onita JH, et al. Correlation between rates of carbapenem consumption and the prevalence of carbapenemresistant seudomonas aeruginosa in a tertiary care hospital in Brazil: a 4-year study. Infect Control Hosp Epidemiol 2010; 31: Harris A, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: Fraser JD, Aguayo, Sharp SW, et al. hysiologic predictors of postoperative abscess in children with perforated appendicitis: subset analysis from a prospective randomized trial. Surgery 2010; 147: Newman K, onsky T, Kittle K, et al. Appendicitis 2000: variability in practice, outcomes, and resource utilization at thirty pediatric hospitals. J ediatr Surg 2003; 38: Levy SM, Holzmann-azgal G, Lally K, et al. Quality check of a quality measure: surgical wound classification discrepancies impact risk-stratified surgical site infection rates in pediatric appendicitis. J Am Coll Surg 2013; 217: