Published online May 1, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. 905-911 (doi:10.1542/peds.2006-2040)
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ARTICLE

Aminoglycoside-Based Triple-Antibiotic Therapy Versus Monotherapy for Children With Ruptured Appendicitis

Adam B. Goldin, MD, MPHa, Robert S. Sawin, MD, MSa, Michelle M. Garrison, PhDb, Danielle M. Zerr, MD, MPHc and Dimitri A. Christakis, MD, MPHd

a Departments of Pediatric General and Thoracic Surgery
c Pediatric Infectious Diseases
d Pediatrics, Children's Hospital and Regional Medical Center, Seattle, Washington
b Child Health Institute, University of Washington Medical Center, Seattle, Washington


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. We conducted a retrospective cohort study to compare the use of triple therapy versus monotherapy for children and adolescents with perforated appendicitis and to determine whether there has been a transition to monotherapy within the freestanding children's hospitals that contribute to the Pediatric Health Information System database.

METHODS. We used the Pediatric Health Information System database, which includes billing and discharge data for 32 children's hospitals in the United States, to examine the trend in antibiotic usage and whether the postappendectomy antibiotic regimen was associated with differences in complication-related readmissions, length of stay, or charges in a population of children and adolescents with ruptured appendicitis and discharge dates between March 1, 1999, and September 30, 2004. Pairwise regression analyses were performed to compare the most common monotherapy regimens with the triple therapy.

RESULTS. A total of 8545 patients met the inclusion criteria, of whom 58%, over the entire study period, received the aminoglycoside-based triple antibiotic therapy on postoperative day 1. There was, however, a notable transition over this 6-year period, from 69% to 52% of surgeons using aminoglycoside-based combination therapy. There were no significant differences in the odds of readmission at 30 days except for the group receiving ceftriaxone, which was associated with significantly decreased odds. The subgroup receiving piperacillin/tazobactam monotherapy demonstrated significantly decreased length of stay (–0.90 days) and total hospital charges, and the group receiving cefoxitin demonstrated significantly decreased length of stay (–1.89 days), as well as decreased pharmacy and total hospital charges.

CONCLUSIONS. Single-agent antibiotic therapy in the treatment of perforated appendicitis is being used with increasing frequency, is at least equal in efficacy to the traditional aminoglycoside-based combination therapy, and may offer improvements in terms of length of stay, pharmacy charges, and hospital charges.

Key Words: appendicitis • antibiotics

Abbreviations: PHIS—Pediatric Health Information System • OR—odds ratio • CI—confidence interval • ICD-9—International Classification of Diseases, Ninth Revision • LOS—length of stay • ABT—aminoglycoside-based combination therapy

Approximately 4 appendectomies per 1000 children are performed each year in the United States. Of these cases, 15% to 36% are in the presence of perforation.1–3 Although intravenous antibiotic therapy is a cornerstone of therapy for perforated appendicitis, the optimal regimen of antibiotics for children remains controversial. Although many physicians would argue that "standard therapy" consists of an aminoglycoside, a ß-lactam, and an antibiotic with anaerobe coverage (ie, ampicillin, gentamicin, or metronidazole),4–16 increasing evidence suggests that single-agent antibiotic therapy provides equivalent results, compared with multiagent regimens.17–32 In fact, a meta-analysis reviewed 64 randomized, controlled trials comparing ß-lactam monotherapy with ß-lactam/aminoglycoside combination therapy for patients with sepsis.33 The addition of an aminoglycoside increased the risk for adverse events while leaving fatality rates unchanged. This has led some to conclude that, for sepsis, adding an aminoglycoside to ß-lactams should be discouraged.33,34 Although these studies are not specific to ruptured appendicitis in children, they do call into question the use of aminoglycoside-based combination therapy (ABT). Given the expanding body of evidence suggesting that single-agent, broad-spectrum, antibiotic therapy for children with perforated appendicitis is both safe and effective, we conducted a retrospective cohort study to compare the use of ABT with that of monotherapy for children and adolescents with perforated appendicitis and to determine whether there has been a transition to monotherapy within the freestanding children's hospitals throughout the nation that contribute to the Pediatric Health Information System (PHIS) database. The study end points included hospital readmissions because of early and late complications of perforated appendicitis, as well as the length of stay (LOS) and hospital charges for the initial admission.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Data Source
We used the PHIS database developed by the Child Health Corporation of America, which includes demographic, diagnostic, and charge data for freestanding, noncompeting, children's hospitals. The PHIS includes both diagnoses and procedures coded by using the International Classification of Diseases, Ninth Revision (ICD-9) format. For a subset of participating hospitals, the database also has level II data, which use Clinical Transaction Classification codes to map hospital-specific charge codes at the patient level to categorical variables across all hospitals; because medication use data are available only for this subset, we restricted our analysis to the 32 hospitals that had level II data coded during the study period.

Patients
Our study included pediatric patients (through 18 years of age) with discharge dates between March 1, 1999, and September 30, 2004. We restricted the analysis to patients who had both an ICD-9 diagnosis code for ruptured appendicitis (540.0x or 540.1x) and an ICD-9 procedure code (47.01, 47.09, 47.2x, or 47.99) for appendectomy during the same hospital stay. Unique patient identifiers were used to ensure that each patient was included in the study only once.

Primary Outcomes and Predictors
The primary outcome measure in the analysis was complication-related readmissions. Because of the nature of the data, we were not able to assess complications that might have been diagnosed during the initial admission. Complications were determined by using discharge diagnosis codes, which are associated with the admission as a whole, rather than with any specific date within the stay. Therefore, it was not possible to ascertain whether such conditions arose before or after the appendectomy procedure; clearly, conditions that arose before the appendectomy and the antibiotic protocol could not legitimately be considered complications. Readmissions were categorized as early (postoperative day <31) or late (postoperative day 31–730) and were analyzed separately because of an a priori decision that the mechanisms involved would differ. Complication-related readmissions were defined as those with primary ICD-9 diagnoses of peritonitis, appendicitis or appendiceal abscess, surgical site infection, Clostridium difficile infection, postsurgical complications, intestinal obstruction or adhesion, or abdominal pain. The timing of early and late complications was defined on the basis of previously published intervals for early and late adhesive bowel obstruction.35,36 Secondary outcomes examined were postoperative LOS, pharmacy charges during the hospital stay, and total charges during the hospital stay. For both charge-related outcomes, we used measures of charges that were adjusted by using the Centers for Medicare and Medicaid Services wage/price index for the hospital's location.

Patients were categorized into 1 of 5 groups on the basis of antibiotics administered on postoperative day 1 (Table 1). This day was chosen to ensure that preoperative antibiotics were not captured, thereby maintaining an intent-to-treat perspective, because the surgeons' knowledge of perforated versus nonperforated appendicitis would be definite. The reference group in each analysis was composed of patients receiving ABT and was examined in pairwise comparisons with the 4 most common types of monotherapies used. Patients were not included in a category if on postoperative day 1 they received antibiotics in addition to those specified for the category. Only patients who met the criteria for 1 of the 5 antibiotic groups were included in the analysis. Because ampicillin/sulbactam does not have equivalent antimicrobial coverage, compared with the other antibiotics in the piperacillin/tazobactam category, we decided to perform a subanalysis to determine whether the results for that category differed if patients receiving ampicillin/sulbactam were removed.


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  		TABLE 1 Antibiotic Categories

 
Statistical Analyses
Descriptive characteristics of the population were compared between the groups receiving ABT versus any of the monotherapy regimens, by using {chi}2 tests for dichotomous variables (gender, Medicaid status, laparoscopic procedure, abscess diagnosed, and procedure day) and t tests for continuous variables (age, LOS, and procedure day). In the multivariate analyses, we used logistic regression for the readmission outcomes and linear regression for LOS and charge outcomes. Although the distributions of both charges and LOS were highly skewed, our large sample size made linear regression appropriate.37 All regressions were performed pairwise, comparing each of the monotherapy groups in turn with the ABT group as reference.

We controlled for potential confounders by using a propensity score, which was developed separately for each pairwise comparison by using hierarchical, stepwise, logistic regression. Only covariates that likely would have been known to the providers at initial antibiotic assignment on postoperative day 1 were included in the models to develop the propensity scores. The covariates entered into the stepwise model included demographic variables (gender, age, and Medicaid status), clinical factors ascertainable at antibiotic assignment (chronic comorbid conditions, priority of admission score, abscess diagnosed, procedure performed laparoscopically, and day of hospital stay on which procedure was performed), and hospital stay variables (hospital and admission date). Predicted probability of assignment to the given monotherapy group was used as the propensity score covariate in the analytic regressions.

We also stratified the readmission regressions according to whether an abscess was diagnosed during the initial hospitalization for ruptured appendicitis, because we thought that the effect of the antibiotics could differ across the 2 populations. In addition, a covariate for follow-up time was included in the regressions examining readmissions as an outcome, because fewer months of follow-up data were available for index hospitalizations that occurred later in the study period. The follow-up time variable was modeled as the percentage of time examined for readmission (30 or 720 days, respectively) that could have been captured after each index hospitalization. Finally, all regression analyses were clustered with respect to hospital, to account for the decreased within-hospital variation, as opposed to that between hospitals.

To protect the integrity of the participating hospitals, all results are presented with hospitals deidentified. All analyses were conducted by using Stata 8.0 software (Stata, College Station, TX).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 14616 hospital admissions with a ruptured appendicitis diagnosis and appendectomy procedure coded in the PHIS database, 8545 were unique patients who met all inclusion criteria for the analysis (Fig 1). Of those, 58% received ABT on postoperative day 1. The most common monotherapy was second-generation cephalosporins such as cefoxitin. Regimen selection did vary over time, with 69% of study patients admitted in 1999 receiving the triple therapy, compared with 52% in 2004. Significant increases over this time period in the use of each monotherapy, except for the cefoxitin group, were observed.


Figure 1
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  		FIGURE 1 Study sample. Pip/Tazo indicates piperacillin/tazobactam.

 
Although the only significant difference between groups in the demographic variables was a slightly lower mean age in the triple-therapy group (Table 2), significant differences between groups were observed across every appendectomy-related variable. Patients who received triple therapy were significantly less likely to have had a laparoscopic procedure (27% vs 57%) and were significantly more likely to have had an abscess diagnosed (30% vs 25%) than were those who received a monotherapy regimen. A somewhat longer mean LOS was observed for the triple-therapy group, compared with the monotherapy groups (6.83 vs 5.77 days).


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  		TABLE 2 Description of Study Sample

 
In the pairwise regressions examining readmissions (Table 3), the ceftriaxone group was associated with reduced odds for 30-day readmission, both in the complete sample (odds ratio [OR]: 0.56; 95% confidence interval [CI]: 0.34–0.91) and in the sample without an abscess diagnosis (OR: 0.27; 95% CI: 0.12–0.60), compared with the triple-therapy group. Similarly, the piperacillin/tazobactam group was associated with decreased odds of 2-year readmission in the sample without an abscess diagnosis (OR: 0.36; 95% CI: 0.19–0.67). However, both the meropenem group and the ceftriaxone group seemed to be associated with increased odds for 2-year readmission, with significant findings in the complete sample for meropenem (OR: 3.74; 95% CI: 1.08–12.94). For the ceftriaxone group, the findings were statistically significant in both the complete sample (OR: 2.69; 95% CI: 1.17–6.21) and the sample with an abscess diagnosis (OR: 2.43; 95% CI: 1.24–4.76). No significant changes in the findings were observed when regressions were repeated after removal of the patients receiving ampicillin/sulbactam from the piperacillin/tazobactam group.


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  		TABLE 3 Monotherapy Versus Triple Therapy and Odds of Complication-Related Readmission

 
In the regressions examining antibiotic regimen and postoperative LOS (Table 4), significant decreases were seen in the cefoxitin (–1.89 days; 95% CI: –2.75 to –1.03 days) and piperacillin/tazobactam (–0.90 days; 95% CI: –1.69 to –0.11 days) groups, compared with the triple-therapy group. Cefoxitin was also associated with significantly decreased pharmacy charges (–2187 dollars; 95% CI: –3110 to –1264 dollars), and both cefoxitin and piperacillin/tazobactam were associated with decreased total charges, compared with the triple-therapy group.


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  		TABLE 4 Monotherapy Versus Triple Therapy and Hospital Stay Characteristics

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Appendicitis is the most common indication for urgent abdominal surgery in the pediatric population, and ruptured appendicitis affects a large proportion of those patients. Minimizations of morbidity, costs, hospital LOS, and readmissions remain primary objectives of surgical management. Postappendectomy infection relates to all of these measurable outcomes, and the choice of antibiotic regimens has a major effect on each of these parameters.

The optimal antibiotic regimen for the treatment of ruptured appendicitis, however, has yet to be determined. As outlined above, many recent articles have suggested that monotherapy may be preferable to the traditional multiagent regimen, and the evidence presented herein demonstrates that monotherapy is being used with increasing frequency in the treatment of perforated appendicitis. In addition, our findings support many of the aforementioned studies that do not demonstrate a difference in the effectiveness of ABT, compared with monotherapy, for either early or late readmissions. The differences in our study that were significant were not consistent across early and late readmissions. The findings from our study demonstrated that, although there was little difference in antibiotic regimens in terms of odds of readmission, there were significant differences in terms of postoperative LOS, pharmacy charges, and total hospitalization charges over a 5-year period among 32 freestanding pediatric hospitals throughout the nation. These findings are important in that they support the use of single-agent antibiotic therapy as a safe and more cost-effective alternative to ABT for the treatment of perforated appendicitis.

Our findings demonstrated a transition toward a preference for monotherapy in the 5 years during which we evaluated patients in the PHIS. Whereas the frequency of ABT was 69% during the first year of our study, 52% of patients received monotherapy during the last year. Articles evaluating the treatment of sepsis in adults have demonstrated improved outcomes with monotherapy, compared with ABT,33,34 and others have demonstrated improved outcomes in randomized trials of treatment of perforated appendicitis in children.20–24,26,28–32 Despite existing evidence, however, tremendous variability in practice patterns, including the use of antibiotics, among pediatric surgeons still endures.3 Almost 60% of surgeons base their clinical practice in the management of perforated appendicitis on their individual preferences.38

There are several limitations to our analysis. First, the PHIS is an administrative discharge database that requires data entry by nonmedical staff members; therefore, there is potential for misclassification. The principal diagnoses used, as well as the medications dispensed, however, are likely to have been coded accurately. Moreover, any random misclassification would bias our findings toward the null hypothesis. There is no a priori reason to suspect systematic bias in the coding of complications and antibiotic regimens. Second, the observational nature of this study precludes drawing causal inferences. For example, we do not know whether the LOS for patients who received monotherapy was shorter because of the choice of antibiotics or because surgeons who tend to choose monotherapy also tend to be more aggressive about discharging patients from the hospital. The purpose of an observational study is to identify associations that will allow us to develop well-designed, hypothesis-driven studies. Third, our data set includes only patients treated in the 32 hospitals in the PHIS database. Although this represents a large diverse sample of patients and institutions, the extent to which these findings can be generalized to other community-based institutions is unknown. Fourth, we were not able to address the trend toward the use of interval appendectomy in this study. Because our inclusion criteria required codes for both diagnosis of appendicitis and the procedure of an appendectomy, we did not include patients who were admitted with perforated appendicitis and treated with antibiotics or percutaneous drainage and antibiotics. In addition, the second hospitalization with a diagnosis of appendicitis was excluded; therefore, those patients would not have been included on their return for their operations. Fifth, we did not try to identify the frequency of central line placement and home intravenous antibiotic treatment. This is a common mode of treatment that influences the evaluation of outcomes such as hospital costs and LOS. Sixth, almost 42% of the patients in the database were excluded because they did not meet our inclusion criteria, because of age, because it was a repeat admission with appendicitis, because the patient received care at an institution that did not contribute pharmacy data to the PHIS, or because the patient received an antibiotic that did not fall into one of our predefined regimens. The majority of those patients were excluded on the basis of available data; therefore, we assumed that this would not introduce a significant bias into the analysis. The patients who were excluded because they received additional antibiotics on postoperative day 1 (17% of the population), however, remain more difficult to describe. Those patients were excluded primarily because they could not be assigned accurately to one of our predetermined groups. The patients received unusual combinations of drugs, and there were not enough patients with each of the combinations for analysis as a group. In our study, the least commonly used monotherapy regimen was ceftriaxone; this population represented only 3% of the total population. We elected to concentrate our analysis on the most commonly used regimens, rather than adding more data for <1% of the population. Despite these limitations, our data suggest that single-agent therapy for ruptured appendicitis in children is accepted practice among almost one half of surgeons practicing at children's hospitals contributing to the PHIS database and may be optimal with respect to morbidity, costs, and LOS.


   FOOTNOTES
 
Accepted Jan 8, 2007.

Address correspondence to Adam B. Goldin, MD, MPH, Department of Pediatric General and Thoracic Surgery, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105. E-mail: adam.goldin{at}seattlechildrens.org

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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