Prospective Randomized Evaluation of Antibiotic Regimen Following Appendectomy for Perforated Appendicitis
Condition: Perforated Appendicitis
MeSH terms: Appendicitis
Study type: Observational

Summary: 
      The purpose of this study is to compare traditional triple antibiotic therapy against dual
      single day dosing antibiotic therapy in the management of perforated appendicitis in
      children.
    

Detailed description: 
      Triple antibiotic therapy providing broad spectrum coverage of gram positive, gram negative
      and anaerobic bacteria has long been the standard treatment for perforated appendicitis in
      children. This regimen has traditionally consisted of ampicillin, gentamicin, and
      clindamycin. The dosing regimen for these medications are quite frequent, as follows:
      ampicillin (every 6 hours), gentamicin (every 8 hours), and clindamycin (every 8 hours),
      until there is no evidence for postoperative infection, usually 5 to 7 days. Further,
      gentamicin is an aminoglycoside with known renal and ototoxic side effects. Its therapeutic
      window is small necessitating measurement of serum levels to maintain therapeutic levels and
      avoid toxicity. The contemporary selection of antibiotics includes very few drugs that
      require such monitoring.

      Monotherapy with newer broad-spectrum agents such as piperacillin/tazobactam for
      intraabdominal infections has recently been demonstrated to be equally efficacious as
      traditional triple therapy. Such data calls into question the need for such onerous
      antibiotic regimens which include a nephrotoxic agent (gentamycin). However, the benefits of
      monotherapy are outweighed by the increased expense of the antibiotic, and the ongoing
      cumbersome dosing schedule of 3-4 doses daily. We have recently moved to a dual antibiotic
      regimen (ceftriaxone and metronidazole) which provides excellent antimicrobial coverage and
      can be dosed on a once daily dosing schedule with an identical duration of therapy as for the
      triple antibiotic regimen. This regimen has proven effective in adults with intraabdominal
      infections such as perforated appendicitis. Further, ceftriaxone plus metronidazole has been
      shown equal to the aforementioned monotherapy schedule with piperacillin/tazobactam in
      children with complicated perforated appendicitis. The advantages of dual antibiotic therapy
      with once a day dosing for children with perforated appendicitis are immense, especially if
      the antibiotics are well tolerated, less expensive, and have a simple dosing schedule.
      Additionally, neither drug is nephrotoxic; both have broad therapeutic ranges and therefore
      require no serum level measurements. This translates into less blood draws, less time
      patients need to be receiving infusions, and less utilization of nursing resources. These
      advantages would be expected to culminate in greater nursing and patient satisfaction. The
      purpose of this study is to scientifically compare the traditional triple antibiotic regimen
      to dual antibiotic regimen for children with perforated appendicitis, quantify its
      significance, and report our findings to physicians caring for these children.

      This will be a prospective randomized study involving children who undergo appendectomy for
      perforated appendicitis. All patients will receive antibiotics (ceftriaxone and flagyl)
      preoperatively. The determination of perforation will be made by the surgeon at the time of
      the operation. Perforation will be determined by either identifying a perforation in the
      appendix itself, or by identifying anaerobic odors emanating from the abdominal cavity during
      operation (sniff test). Once perforated appendicitis has been documented, the
      parents/guardians of the patient will be informed of the option to participate in the
      prospective randomized study. Patients whose parents agree and consent to enroll in the study
      will then be randomized to one of 2 groups based on a sequential randomization number created
      by Steve Simon, PhD.

      Based on a power analysis of length of stay, performed by Dr. Simon, 50 patients in each of
      the two arms of the study will provide a power of 82% with an alpha level of 0.05. Dr. Simon
      feels that this level is appropriate for this study.

      The control group will consist of triple antibiotic coverage with ampicillin 50mg/kg every 6
      hours, gentamicin 2.5 mg/kg every 8 hours and clindamycin 10mg/kg every 6 hours, which are
      standard dosing regimens. The experimental group will receive ceftriaxone 50mg/kg once a day
      (maximum dose = 2 grams) and metronidazole 30mg/kg once a day (maximum dose = 1 gram) with
      once a day dosing for both. The length of antibiotic therapy will not differ from our
      standard management and will remain standardized in both arms. All patients will receive a
      minimum of 5 days of therapy (regardless of group randomization). At that time, if they have
      been afebrile for at least 24 hours, a white blood cell (WBC) count will be obtained, and if
      that is within normal limits, the antibiotics will be discontinued. If, after 5 days of
      therapy, the patient remains febrile, therapy will continue without change, unless cultures
      obtained from the febrile response indicate a need for antibiotic coverage change. If a
      change in antibiotic regimen is indicated, the antibiotic profile will be evaluated and the
      most appropriate antibiotic will be instituted. If this occurs, the patient's data will
      continue to be collected in an intention to treat analysis. In cases where there is no
      indication for a change in antibiotic regimen, a WBC count will be drawn once the patient has
      become and remains afebrile for a complete 24 hour period of time. If the WBC is elevated,
      the antibiotic course will continue with WBC counts to be drawn daily until normal values
      return. If leukocytosis or fever persists for 10 days, or if there is clinical indication of
      a postoperative intra-abdominal infection, a CT scan of the abdomen and pelvis will be
      performed to determine if a postoperative abscess has developed. Identification of a
      postoperative abscess will result in percutaneous drainage with culture and sensitivity of
      the abscess fluid. Subsequent antibiotic treatment will be based on the sensitivities
      obtained from the culture of the abscess. In these cases the patients' data will be collected
      and they will be regarded as a failure of antibiotic therapy in the final analysis.

      Parental permission and child assent, if the child is old enough, will be obtained (see
      attached form) and patients will be randomized to the control or experimental group based on
      a randomization number generated by Dr. Steve Simon, PhD. Patient demographics, operative
      approach, time to tolerating full feeds, length of hospitalization, infectious complications,
      medication charges, and hospital charges will be collected for comparison between the groups.
    

Intervention name(s): Ampicillin, gentamicin, clindamycin, flagyl, ceftazidime
Intervention type(s): Drug
Intervention MeSH terms: Clindamycin; Clindamycin palmitate; Clindamycin phosphate; Gentamicins; Ceftazidime; Ampicillin
Observational model: Defined Population
Time perspective: Other
Keywords: appendicitis; perforation