Intraperitoneal administration of fosfomycin, metronidazole, and granulocyte-macrophage colony-stimulating factor in patients undergoing appendectomy is safe: a phase II clinical trial

Siv Fonnes, Barbara Juliane Holzknecht, Magnus Arpi, Jacob Rosenberg, Siv Fonnes, Barbara Juliane Holzknecht, Magnus Arpi, Jacob Rosenberg

Abstract

We aimed to investigate the safety of intraperitoneal administration of the combination of fosfomycin, metronidazole, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients undergoing appendectomy. We conducted a prospective phase II clinical trial in 14 otherwise healthy men suffering from uncomplicated appendicitis. After appendectomy, the trial treatment was administered intraperitoneally and left in the abdominal cavity. Trial treatment consisted of 4 g fosfomycin, 1 g metronidazole, and 50 µg rhGM-CSF in a total volume of 500 ml. Safety was evaluated through white blood cell count where a toxic effect was predefined. We evaluated harms and adverse events, repeated biochemical markers, vital signs, and length of stay. White blood cell count did not drop below the toxic range. The recorded harms were dizziness, discomfort when breathing deeply, no flatus, and bloating. Adverse events included three patients with diarrhoea after discharge and one patient with a hypotensive episode. No serious adverse events or infectious complications occurred. Intraperitoneal administration of fosfomycin, metronidazole, and rhGM-CSF was safe in otherwise healthy men undergoing laparoscopic appendectomy. There were some possible harms and adverse events but we were unable to assess if they were related to anaesthesia, surgery, or the trial treatment.

Conflict of interest statement

This study was funded by a grant from Reponex Pharmaceuticals ApS to the Department of Surgery, Herlev Hospital covering study expenses. The company did not have any influence on the study design, study conduct, or writing of the manuscript. Repomol was a gift from Reponex Pharmaceuticals ApS.

Figures

Figure 1
Figure 1
Flowchart of the screened, enrolled, and included patients in the trial.
Figure 2
Figure 2
The primary outcome, white blood cell count, at admission and four hours postoperatively (after trial treatment) in 109/l. The toxic limit bellow 3.5 × 109/l is marked with a dashed line. p: p-value, Wilcoxon sign-rank test.
Figure 3
Figure 3
Overview of the trial course of the participants enrolled and included in the trial and the time points for measurement of outcomes. Follow-up consisted of a telephone interview. Vital signs during surgery and anaesthesia were measured prior to and five, ten, and 15 minutes after trial treatment.

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