ANTIBIOTIC MANAGEMENT FOR PEDIATRIC APPENDICITIS

An Evidence Review from the Penn Medicine Center for Evidence-based Practice June 2011
Authors: Brian Leas, MS, MA; Craig A. Umscheid, MD, MSCE Keywords: Appendicitis; Pediatric; Antibiotic therapy

EVIDENCE SUMMARY
1. For patients with uncomplicated, non-perforated appendicitis, two recent guidelines recommend pre-operative antibiotic prophylaxis using any regimen that provides sufficient coverage against aerobic, anaerobic and gram-negative pathogens. Duration of post-operative treatment is suggested to be very short, usually not exceeding 24 hours following surgery. One randomized controlled trial (RCT) indicated that shorter duration is as effective as longer treatment, and may be associated with fewer antibiotic-related complications. 2. For patients with perforated or gangrenous appendicitis, two guidelines and two systematic reviews agree that monotherapy and dual-drug treatment regimens are as effective as traditional triple-drug therapy for preventing wound infection. Several head-to head primary studies found few differences between regimens in the risk of infection, abscess, readmission, or extended length of hospitalization. 3. For patients with perforated or gangrenous appendicitis, two guidelines and one systematic review support the use of clinical judgment to determine the optimal post-operative duration of treatment for each patient, rather than a fixed minimum or maximum timeframe. Clinical judgment should be based on signs including fever, white blood cell count, food intake, and resolution of symptoms. The evidence does not indicate additional benefits associated with longer duration of treatment.

Copyright 2011 by the Trustees of the University of Pennsylvania. All rights reserved. No part of this publication may be reproduced without permission in writing from the Trustees of the University of Pennsylvania.

TABLE OF CONTENTS
Background ........................................................................................................................... 3 Methods ................................................................................................................................. 4 Protocol for Systematic Review .......................................................................................... 4 Search Strategy ................................................................................................................. 5 Evidence Review ................................................................................................................... 7 Table 1. Guidelines for Antibiotic Management of Pediatric Appendicitis ........................... 8 Table 2. Systematic Reviews of Antibiotic Management of Pediatric Appendicitis .............. 9 Table 3. Primary Head-to-head Studies of Antibiotic Selection for Pediatric Appendicitis . 10 Table 4. Primary Head-to-head Studies of Antibiotic Duration for Pediatric Appendicitis .. 11 Summary and Conclusions .................................................................................................. 12 References .......................................................................................................................... 13

Antibiotic Management for Pediatric Appendicitis

June 2011

BACKGROUND
Appendicitis is one of the most common causes of hospitalization in children. Most cases of appendicitis are treated surgically, whether or not the appendix is perforated or gangrenous, and the prognosis following treatment is usually excellent for patients who are otherwise in good health. Some patients, however, may develop wound infections, post-operative abscesses, or other complications. Patients are routinely managed preand post-operatively with antibiotics to prevent infection. Children with uncomplicated, non-perforated appendicitis may receive one or more antibiotics from a large selection of available drugs, prior to surgery. Whether these drugs differ substantially in their safety and effectiveness has been a question for debate. Surgeons have also debated the use and duration of antibiotic therapy following surgery. For a patient with a perforated or gangrenous appendix, the traditional gold standard for antimicrobial therapy includes a triple-drug approach, most often incorporating ampicillin, gentamicin, and clindamycin. A substantial body of research has emerged in recent years, however, demonstrating the efficacy of alternative multi-drug or monotherapy regimens in this population. The duration of these regimens also varies widely in practice, with some physicians advocating post-operative use for only 48-72 hours, while others recommend treatment for as long as 14 days. The Childrens Hospital of Philadelphia (CHOP), while developing a clinical treatment pathway for patients with appendicitis, requested the Center for Evidence-based Practice (CEP) to evaluate the clinical evidence addressing 1) the selection of antibiotic therapy and 2) the optimal duration of treatment for children receiving surgical management for acute appendicitis.

Antibiotic Management for Pediatric Appendicitis

June 2011

METHODS
CENTER FOR EVIDENCE-BASED PRACTICE

PROTOCOL FOR SYSTEMATIC REVIEW

SPECIFIC AIM:
To evaluate the effectiveness of antibiotic regimens used during treatment of appendicitis in children.

METHODS:
Study designs: Clinical practice guidelines, systematic reviews, randomized controlled trials, other controlled studies (cohort, pre-post). Inclusion and exclusion criteria: Participants: Children with acute appendicitis, either perforated or non-perforated. Interventions and Comparisons: Monotherapy vs. multi-drug regimens; shorter vs. longer duration of antibiotic therapy. Outcomes: Wound infection; post-operative abscess; length of stay; readmission; adverse events Data collection Databases: National Guideline Clearinghouse; Cochrane Database; Medline; HTA Database. We also explored the websites of several organizations that provide guidance on pediatric care, surgery, and infectious disease, including: the American Academy of Pediatrics (AAP); American Pediatric Surgery Society; Infectious Diseases Society of America (IDSA); and Surgical Infection Society.

Antibiotic Management for Pediatric Appendicitis

June 2011

SEARCH STRATEGY FOR GUIDELINES, SYSTEMATIC REVIEWS AND PRIMARY STUDIES

1. MEDLINE
Search 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Syntax Exp Appendix/ Appendicitis.mp OR exp Appendicitis/ Appendectomy.mp OR exp Appendectomy/ 1 OR 2 OR 3 Exp Infection Control/ OR exp Infection/ OR exp Surgical Wound Infection/ OR Infection.mp. Antibiotic.mp. OR exp Anti-Bacterial Agents/ 5 OR 6 4 AND 7 Pediatric.mp. OR exp Pediatrics/ Exp Child/ Exp Adolescent/ Exp Infant/ 9 OR 10 OR 11 OR 12 8 AND 13 Limit 14 to (English language; humans; clinical trial, all OR clinical trial OR controlled clinical trial OR randomized controlled trial) Results 4681 15945 9175 22623 1014283 507306 1385948 4278 158543 1381292 1412356 843920 2572930 1976 203 Retrieved 15 Included 10

Antibiotic Management for Pediatric Appendicitis

June 2011

2. COCHRANE LIBRARY
Keyword Appendicitis OR Appendectomy Results 82 Retrieved 1 Included 1

3. NATIONAL GUIDELINE CLEARINGHOUSE

Search 1 2 Syntax Appendicitis Appendectomy Results 17 7 Retrieved 2 0 Included 2 0

4. HTA DATABASE
Syntax Appendicitis OR Appendectomy Results 148 Retrieved 0 Included 0

Antibiotic Management for Pediatric Appendicitis

June 2011

EVIDENCE REVIEW
The search strategy identified two recent practice guidelines that address antibiotic management in children with appendicitis. The Surgical Infection Society produced a guideline in 2008 focused specifically on pediatric appendicitis. In 2010, the society also published a broader guideline, jointly with the Infectious Diseases Society of America, providing guidance on treatment of intra-abdominal infections in adults and children. In addition to these guidelines, CEP was provided clinical pathways developed by other pediatric hospitals around the country. Table 1 summarizes these guidelines and pathways. Three systematic reviews were identified that evaluated antibiotic management. Two of these were restricted to studies in children. Lee assessed the evidence for antibiotic selection as well as duration, in patients with and without complications. Snelling was more narrowly focused and evaluated studies of antibiotic duration in cases of perforated or gangrenous appendicitis. Andersen conducted a Cochrane review and included adults as well as children. That review focused on studies comparing multiple regimens to placebo, but did not present head-to-head comparisons. The results of these reviews are shown in Table 2. We also identified six primary studies that were published in the past twenty years, were not included in the systematic reviews, and which directly compared different antibiotic regimens to each other. Four of these studies were randomized controlled trials, and two were retrospective cohort studies. All six studies were limited to patients with perforated, gangrenous, or other complicated appendicitis. The studies used a very heterogeneous selection of regimens for comparison, but most included at least one monotherapy and one or more multi-drug strategies. Results of these studies are summarized in Table 3. Table 4 presents the results of the only two primary studies we found on antibiotic duration that were published in the years since Snellings systematic review. Van Wijck conducted a retrospective cohort study of children with perforated appendicitis, while Mui undertook a randomized controlled trial in children and adults with non-perforated, uncomplicated appendicitis.

Antibiotic Management for Pediatric Appendicitis

June 2011

Table 1: Guidelines for Antibiotic Management of Pediatric Appendicitis

Non-perforated Appendix Author, Year Antibiotic Selection Antibiotic Duration
Any single agent, or combination of agents, that provides adequate gramnegative and anaerobic coverage (e.g., cefoxitin; ampicillin-sulbactam)

Perforated Appendix Antibiotic Selection

First choice: monotherapy, because it is more costeffective and equally efficacious compared with multi-drug treatment Second choice: any other regimen that provides adequate gram-negative and anaerobic coverage All broad spectrum regimens can be used: o aminoglycoside-based triple therapy o carbapenem o beta-lactam/betalactamase inhibitor combination o cephalosporin plus metronidazole

Interval Appendectomy Antibiotic Selection Antibiotic Duration

Continue IV until patient is afebrile, normal WBC, resolution of symptoms Insufficient evidence regarding oral therapy following IV treatment

Antibiotic Duration

Surgical Infection Society, 2008

No recommendation

Continue IV until patient is afebrile, normal WBC, resolution of symptoms Oral therapy following IV treatment not necessary

Any single agent, or combination of agents, that provides adequate gramnegative and anaerobic coverage

Infectious Diseases Society of America/ Surgical Infection Society, 2010

Narrow spectrum regimen active against aerobic, facultative, and obligate anaerobes

Discontinue within 24 hours

4-7 days; use clinical signs of infection (e.g., fever, white blood cell count, symptoms) to discontinue therapy

No recommendation

Childrens Hospital of Pittsburgh of UPMC, 2010*

Cefoxitin

Pre-op 1 dose post-op (8 hours after preop dose)

Ertapenem

10-14 days pre-op 4 days post-op or until discharge Oral antibiotics after discharge at physician discretion

Ertapenem

10-14 days

Childrens Hospital of Orange County, 2009*

Cefoxitin

Pre-op 1 dose post-op ( 6 hours after previous dose) (optional)

Ampicillin + gentamicin + metronidazole

Not described

Ampicillin + gentamicin + metronidazole Adjust based on culture results Change to single agent at discharge

Not described

Arkansas Childrens Hospital, 1995*

Unasyn

Discontinue after rd 3 dose

Ampicillin + gentamicin + clindamycin

Discontinue when afebrile, normal WBC, tolerating diet; change to oral bactrim; discontinue all at 4 days

No recommendation

*Clinical treatment pathways provided by Childrens Hospital of Philadelphia

Antibiotic Management for Pediatric Appendicitis

June 2011

Table 2: Systematic Reviews of Antibiotic Management of Pediatric Appendicitis

Author, Year Population Literature reviewed Comparisons Conclusion
Non-perforated o High quality evidence: pre-operative broad-spectrum antibiotics o No evidence favoring one regimen over another o No evidence supporting post-operative dose Perforated o Moderate quality evidence: broad-spectrum single or dual-agent antibiotics o Moderate quality evidence: use of clinical criteria (fever, pain, WBC, bowel function) to determine duration o Moderate quality evidence: if intravenous antibiotics less than 5 days, oral antibiotics should be used to achieve total duration of 7 days Non-operative o Low quality evidence: broad-spectrum single or dual-agent antibiotics o Low quality evidence: use of clinical criteria to determine duration Wound Infection Antibiotic Regimen Children only Post-op 1 agent, multi-dose Andersen, 2005 (Cochrane Review) Children and Adults 45 controlled studies (37 randomized) 9,576 patients Antibiotics VS placebo Children and Adults Pre-op 1 agent Pre-op multi-agent Post-op 1 agent, 1 dose Post-op 1 agent, multi-dose Post-op multi-agent, multi-dose Antibiotic duration for perforated or gangrenous appendix 0.34 (0.25-0.45) 0.14 (0.05-0.39) 0.16 (0.07-0.36) 0.46 (0.35-0.60) 0.18 (0.11-0.27) 0.37 (0.25-0.54) 0.16 (0.04-0.59) NR 0.46 (0.30-0.70) 0.20 (0.11-0.35) 0.29 (0.18-0.47) NR NR 0.47 (0.24-0.90) 0.08 (0.03-0.22) 0.34 (0.05-2.45) NR 0.12 (0.02-0.89) 0.14 (0.01-1.30) 0.38 (0.05-2.72) 0.34 (0.05-2.45) NR NR 0.15 (0-7.38) 0.15 (0.01-2.38) NR NR NR NR NR 0.52 (0.29-0.93) 0.85 (0.26-2.80) 0.16 (0.06-0.44) 0.29 (0.10-0.83) 0.14 (0.02-0.98) 0.78 (0.11-5.70)
(odds ratio, 95% confidence interval)

Lee, 2010

Children

126 studies

Selection of antibiotics Duration of antibiotics Perforated and non-perforated

Post-operative Abscess
(odds ratio, 95% confidence interval)

All appendicitis

Simple

Complicated*

All appendicitis

Simple

Complicated*

Snelling, 2004

Children

28 studies 2,284 patients

Antibiotic regimens of 3 or fewer days do not appear to be associated with higher infection rates than regimens of more than 3 days

*Complicated appendicitis includes non-perforated gangrenous, or perforated appendix. Note: Shaded cells are statistically significant. NR = Not reported

Antibiotic Management for Pediatric Appendicitis

June 2011

Table 3: Primary Head-to-head Studies of Antibiotic Selection for Pediatric Appendicitis

Author, Year Population Research Design Outcomes Comparison
Wound Infection Abscess Mean LOS Readmission Other Time to regular diet (days) o Triple: 3.25 o Dual: 3.2 (p=0.82) Mean operating time (minutes) o Triple: 48 o Dual: 41 (p=0.09) Infection cure rate 100% in both groups Infection cure rate o Dual: 93.5% o Mono: 93.5% (p=0.50) Time to regular diet (days) o Triple (a): 3.3 o Triple (b): 3.5 o Dual: 2.9 o Mono: 3.0

St. Peter, 2008

Perforated N = 100

RCT

Triple: Ampicillin + gentamicin + clindamycin VS Dual: Ceftriaxone + metronidazole

2% 0 (p=0.99)

16% 20% (p=0.60)

6.3 days 6.5 days (p=0.85) NR

Maltezou, 2001

Perforated or gangrenous N = 56 Complicated or advanced N = 361

RCT

Dual: Cefotaxime + metronidazole VS Mono: Piperacillin/tazobactam Dual: Cefotaxime + metronidazole VS Mono: Piperacillin/tazobactam Triple: Penicillin + tobramycin + clindamycin VS Triple: Penicillin + tobramycin + ornidazole VS Dual: Ceftriaxone + ornidazole VS Mono: Piperacillin Triple: (Ampicillin or vancomycin) + (amikacin or gentamicin or kanamycin or tobramycin) + (clindamycin or metronidazole) VS Mono (a): Piperacillin/tazobactam or ticarcillin/clavulanate or ampicillin/sulbactam VS Mono (b): Meropenem or imipenem VS Mono (c): Cefoxitin or cefotetan or cefprozil or cefuroxime VS Mono (d): Ceftriaxone or ceftazidime or cefotaxime or cefepime

NR

NR

NR

NR

4.1% 0.7% (p=0.01) 4% 4% 4% 8%

2.6% 2.2% (p NR) 0 4% 0 0

Adam, 2001

RCT

Mono less than dual (p=0.01) 7.4 days 7.9 days 7.2 days 6.8 days Comparison case

1.5% 6.0% (p=0.03)

Ciftci, 1997

Perforated N = 200

RCT

NR

Comparison case

Goldin, 2007

Perforated N = 8,545

Retrospective cohort, adjusted for gender, age, Medicaid status, comorbidity

-0.90 days NR NR

OR: 1.17 (0.61 2.22, p=0.63) OR: 0.82 (0.53 1.26, p=0.36) OR: 1.22 (0.79 1.89, p=0.37) OR: 0.56 (0.34 0.91, p=0.02) NR

-1.09 days

-1.89 days

-1.15 days

Antibiotic Management for Pediatric Appendicitis

June 2011

10

Nadler, 2003

Perforated N = 94

Retrospective cohort; unadjusted but no differences observed in gender, age, length of stay, white blood cell count, or duration of symptoms

Triple: Ampicillin + gentamicin + (clindamycin or metronidazole) VS Mono: Piperacillin/tazobactam

4.7%

11.6%

6 days

2.0%

3.9%

6 days

NR

All complications o Triple: 32% o Mono: 8% (p=0.002) Antibiotic related complications o Triple: 23% o Mono: 8% (p=0.04)

Note: Shaded cells are statistically significant. NR = Not reported

Table 4: Primary Head-to-head Studies of Antibiotic Duration for Pediatric Appendicitis

Author, Year Population Research Design Comparison Outcomes
Wound infection o 1 dose: 6.5% o 3 dose: 6.4% o 5 day: 3.6% (p=0.5) Nonperforated N = 269 Children and adults 1 dose pre-op VS 3 doses VS 5 days (Cefuroxime + metronidazole) Antibiotic related complications o 1 dose: 0 o 3 dose: 1 patient o 5 day: 4 patients (p=0.05) Length of stay o 1 dose: 4.3 days (SD=1.3) o 3 dose: 4.6 days (SD=1.2) o 5 day: 4.8 days (SD=2.3) (p=0.13) (p values are 5 day vs 1 dose) Van Wijck, 2010 Retrospective cohort, adjusted for age, gender 5 days post-op amoxicillin clavulanate VS 5 days amoxicillin clavulanate + gentamicin, followed by testing of CRP; amoxicillin/ clavulanate continued until CRP <20 mg/l (median length of therapy: 7 days; maximum: 32 days) Abscess formation o Shorter duration: 19% o Longer duration: 20% (p=0.95)

Mui, 2005

RCT

Perforated N = 149

Antibiotic Management for Pediatric Appendicitis

June 2011

11

SUMMARY AND CONCLUSIONS

The guidelines, reviews, and primary studies provide a diverse evidence base addressing antibiotic management for pediatric appendicitis. For patients with uncomplicated, non-perforated appendicitis, the guidelines recommend any regimen that provides sufficient coverage against aerobic, anaerobic and gram-negative pathogens. Two of the hospital pathways identify cefoxitin as their preferred agent, but the guidelines do not endorse any specific therapy. Duration of post-operative treatment is suggested to be very short, ranging from a single optional dose to no more than 24 hours following surgery. One RCT found that neither three post-operative doses nor a five day duration of treatment significantly reduced infection rates or length of stay. Antibiotic-related complications, though, did increase with five days of post-operative therapy. In children with perforated appendicitis, the most recent guideline gives maximum discretion to the physician to select any broad spectrum regimen, including single, dual, or triple-drug therapies. The earlier guideline from the Surgical Infection Society notes that monotherapy may be the most cost-effective regimen, and thus preferable; but they endorse any regimen with sufficient gram-negative and anaerobic coverage. Two of the hospital pathways use triple-drug therapies, while one prefers ertapenem. A recent systematic review found moderate quality evidence indicating that single or dual-drug regimens are as effective as triple-drug therapy. The Cochrane review found that any drug or combination of treatments reduced infection rates significantly when compared with placebo. Multi-drug regimens appeared to reduce the risk of infection even more than monotherapy, but no head-to-head analyses were conducted. Six head-to-head studies of different regimens found very few differences between treatment strategies. One study that compared monotherapy with dual-drug therapy reported a significant reduction in wound infection rates and a shorter length of stay for patients on monotherapy, while the other studies found no differences or did not report significance. This study, however, also found that monotherapy was associated with higher readmission rates; only one other study examined readmissions and found the opposite association, with one type of monotherapy leading to fewer readmissions than triple-drug therapy. Both guidelines recommend that inpatient therapy end when the patient demonstrates signs of recovery, such as resolution of symptoms, normal white blood cell count, regular food intake, and lack of fever; one guideline indicates that duration should usually last between four and seven days. This approach is reflected in the most recent systematic review, which found moderate quality evidence favoring use of clinical criteria to determine duration, as opposed to setting a mandatory minimum or maximum timeline; this review also found evidence supporting a total duration of around seven days. Conversely, Snellings review found that providing antibiotics for three or fewer days did not appear to increase the risk of infection compared with longer lasting regimens. The one primary study that examined duration in cases of perforated appendicitis found no difference in abscess formation rates between shorter and longer regimens, but wound infection rates were not reported. In conclusion, current guidelines and the best available evidence suggests that monotherapy and dual-drug therapy are as effective as triple-drug therapy for treating children with appendicitis, but the evidence does not support the value of any specific regimen over another. Optimal postoperative duration of treatment for cases of perforated appendicitis should be guided by clinical judgment, and the evidence does not indicate additional benefits associated with longer duration of treatment.

Antibiotic Management for Pediatric Appendicitis

June 2011

12

REFERENCES
Adam D, Linglof T, Floret D, Kirsch T. Piperacillin/tazobactam versus cefotaxime plus metronidazole for the treatment of severe intra-abdominal infections in hospitalized pediatric patients. Curr Ther Res Clin Exp. 2001;62:488-502. Andersen BR, Kallehave FL, Andersen HK. Antibiotics versus placebo for prevention of postoperative infection after appendicectomy. Cochrane Database Sys Rev. 2005;3:CD001439. Ciftci AO, Tanyel C, Buyukpamukcu N, Hicsonmez A. Comparative trial of four antibiotic combinations for perforated appendicitis in children. Eur J Surg. 1997;163:591-596. Goldin AB, Sawin RS, Garrison MM, Zerr DM, Christakis DA. Aminoglycaside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis. Pediatrics. 2007;119:905-911. Lee SL, Islam S, Cassidy LD, Adullah F, Arca MJ. Antibiotics and appendicitis in the pediatric population: an American pediatric surgical association outcomes and clinical trials committee systematic review. J Pediatr Surg. 2010;45:2181-2185. Maltezou HC, Nikolaidis P, Lebesii E, Dimitriou L, Androulakaki E, Kafetzis DA. Piperacillin/tazobactam versus cefotaxime plus metronidazole for treatment of children with intra-abdominal infections requiring surgery. Eur J Clin Microbiol Infect Dis. 2001;20:643-646. Mui LM, Ng CSH, Wong SKH et al. Optimum duration of prophylactic antibiotics in acute non-perforated appendicitis. ANZ J Surg. 2005;75:425428. Nadler EP and Gaines BA, for the Surgical Infection Society. The surgical infection society guidelines on antimicrobial therapy for children with appendicitis. Surg Infect. 2008;9:75-83. Nadler EP, Reblock KK, Ford HR, Gaines BA. Monotherapy versus multi-drug therapy for the treatment of perforated appendicitis in children. Surg Infect. 2003;4:327-333. Snelling CMH, Poenaru D, Drover JW. Minimum postoperative antibiotic duration in advanced appendicitis in children: a review. Pediatr Surg Int. 2004;20:838-845. Solomkin JS, Mazuski JE, Bradley JS et al, for the Infectious Diseases Society of America and Surgical Infection Society. Diagnosis and management of complication intra-abdominal infection in adults and children: guidelines by the surgical infection society and the infectious diseases society of America. Clin Infect Dis. 2010;50:133-164. St. Peter 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 Pediatr Surg. 2008;43:981-985. Van Wijck K, de Jong JR, van Heurn LWE, van der Zee DC. Prolonged antibiotic treatment does not prevent intra-abdominal abscesses in perforated appendicitis. World J Surg. 2010;34:3049-3053.

Antibiotic Management for Pediatric Appendicitis

June 2011

13