Molgramostim (GM-CSF) Associated with Antibiotic Treatment in Nontraumatic Abdominal Sepsis a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

ORIGINAL ARTICLE Molgramostim (GM-CSF) Associated With Antibiotic Treatment in Nontraumatic Abdominal Sepsis A Randomized, Double-blind, Placebo-Controlled Clinical Trial

He´ctor Orozco, MD; Jorge Arch, MD, PhD; Heriberto Medina-Franco, MD; Juan P. Pantoja, MD; Quintı´n H. Gonza´lez, MD; Mario Vilatoba, MD; Carlos Hinojosa, MD; Florencia Vargas-Vorackova, MD, PhD; Jose´ Sifuentes-Osornio, MD

Hypothesis: The addition of molgramostim (recombi- Main Outcome Measures: Time to improvement, du- nant human granulocyte-macrophage colony-stimu- ration of antibiotic therapy, hospital stay, complica- lating factor) to antibiotic therapy for nontraumatic and tions, mortality, and adverse reactions to drugs. generalized abdominal sepsis is effective and has a significant impact on length of hospitalization, direct medical Results: Median time to improvement was 2 days in group costs, and mortality. 1 and 4 days in group 2 (PϽ.005). Median length of hospitalization was 9 and 13 days, respectively (PϽ.001), and Design: Randomized, double-blind, placebo-con- median duration of antibiotic therapy was 9 and 13 days, trolled clinical trial. respectively (PϽ.001). Numbers of infectious complications in the 2 groups were, respectively, 6 and 16 (P=.02); Setting: Tertiary referral center. of residual abscesses, 3 and 5; and of deaths, 2 and 2. Costs per patient were $12 333 and $16 081 (US dollars), Patients: Fifty-eight patients with abdominal sepsis. respectively. Interventions: Patients were allocated to receive, in ad- Conclusion: Addition of molgramostim to antibiotic dition to ceftriaxone sodium, amikacin sulfate, and metronidazole, molgramostim in a daily dosage of 3 µg/kg for therapy reduces the rate of infectious complications, the 4 days (group 1) or placebo (group 2). Antibiotics were length of hospitalization, and costs in patients with non- administered for at least 5 days and discontinued after clini- traumatic abdominal sepsis. cal improvement had occurred and white blood cell count had been normal for 48 hours. Arch Surg. 2006;141:150-153

ECOMBINANT HUMAN Recent studies in animal models of peri- granulocyte-macrophage tonitis, as well as pilot trials in patients with colony-stimulating factor sepsis, point out that GM-CSF, when used (GM-CSF) is a specific he- as adjuvant therapy, might reduce mortal- matopoietic growth factor ity, disability, and, potentially, health care extensivelyR used for the treatment of neutropenia in patients with cancer after che- See Invited Critique motherapy.1,2 In vitro, GM-CSF stimu- at end of article lates the proliferation and differentiation of hematopoietic precursor cells, as well costs. This randomized, double-blind, pla- as several functional activities of mature cebo-controlled clinical trial was con- granulocytes.1-8 In vivo, it increases cir- ducted to assess the efficacy of one form of culating white blood cells. GM-CSF, molgramostim, added to stan- Treatment with GM-CSF enhances cel- dard antibiotic therapy in patients with gen- Author Affiliations: eralized nontraumatic peritonitis.3,10-14 Departments of Surgery lular functions that are critical in wound (Drs Orozco, Arch, healing, such as neutrophil, monocyte, and Medina-Franco, Pantoja, macrophage activation; endothelial cell mi- METHODS Gonza´lez, Vilatoba, and gration; keratinocyte proliferation; and fi- Hinojosa), Gastroenterology broblast phenotype modulation.4,5,9 As a DESIGN (Dr Vargas-Vorackova), and result, healing time is significantly re- Infectious Diseases Adult patients with generalized peritonitis were (Dr Sifuentes-Osornio), duced, even when contamination or ra- included in this randomized, double-blind, pla- Instituto Nacional de Ciencias diation is present. In addition, GM-CSF has cebo-controlled trial. All underwent surgery and Medicas y Nutricion Salvador been shown to be useful in the treatment were given intravenous antibiotics. During sur- Zubiran, Mexico City, Mexico. of chronic venous leg ulcers.9 gery, they were randomly allocated to receive

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 either molgramostim, 3 µg/kg per day for 4 days (group 1), or an identical-appearing placebo (group 2). Clinical and labora- Table 1. Patients’ Baseline Characteristics tory measurements were carried out without knowledge of the group to which the patient was allocated. The protocol was re- Group 1 Group 2 viewed and approved by the institutional review board, and all Characteristic (n = 28) (n = 30) patients gave written informed consent. Sex, No. M/F 13/17 16/15 Age, mean ± SD, y 43.2 ± 15.9 49.2 ± 16.5 ELIGIBILITY CRITERIA APACHE II score, mean ± SD 7.3 ± 6.3 7.7 ± 6.4 WBC count/µL, mean ± SD 13.5 ± 5.8 14.5 ± 9.1 Patients aged 18 to 80 years, with generalized peritonitis char- Neutrophils, mean ± SD, % 82.6 ± 8.3 80.1 ± 11.5 acterized by septic involvement of 2 or more abdominal quad- Intraoperative diagnosis, No. (%) rants at the time of surgical intervention and with positive peri- Acute appendicitis 16 (57) 12 (40) toneal cultures, were included. Exclusion criteria were terminal Small-bowel perforation* 2 (7) 8 (27) renal, hepatic, or lung failure15,16; positive pregnancy test; cur- Colonic perforation† 5 (18) 2 (7) rent treatment with an immunosuppressive drug17; tuberculo- Gangrenous cholecystitis 3 (11) 2 (7) sis; or leukemia. Perforated peptic ulcer 0 3 (10) Other‡ 2 (7) 3 (10)

INTERVENTION Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation II; WBC, white blood cell. Standard intravenous antibiotic therapy consisting of ceftriax- *Includes ischemic, Meckel diverticulum, and complicated obstruction. one sodium (1 g twice daily), amikacin sulfate (15 mg/kg per †Includes diverticulitis and ulcerative colitis. day), and metronidazole (500 mg 3 times daily) was started at ‡Includes unidentified perforation sites. the time of diagnosis. In patients allergic to ␤-lactams, ofloxa- cin (400 mg twice daily) was administered together with metronidazole. According to the random allocation schedule, mol- 1 from group 2 were excluded because they refused therapy gramostim (3 µg/kg per day) or an identical-appearing placebo after randomization. Baseline demographic characteris- was administered subcutaneously during 4 days beginning in tics, Acute Physiology and Chronic Health Evaluation II the operating room at the time of randomization. Antibiotic treat- score, results of laboratory tests, and intraoperative diag- ment was suspended after a minimum of 5 days of administration, when clinical improvement, normal temperature for at least nosis were statistically comparable in both groups 2 days, and normal white blood cell (WBC) count were ob- (Table 1). Microorganisms isolated from the peritoneal served. Antibiotic treatment was modified according to the an- fluid of patients in groups 1 and 2 were as follows: Esch- timicrobial susceptibility of the microorganisms isolated. erichia coli (16 and 17 patients, respectively), Enterococ- cus species (12 and 9 patients), Streptococcus species (2 MEASUREMENTS and 5 patients), Klebsiella species (4 and 1 patient), Pseu- domonas species (0 and 3 patients), Enterobacter species Clinical data, WBC count, abdominal cultures, and Acute Physi- (0 and 2 patients), Staphylococcus (2 and 0 patients), Clos- ology and Chronic Health Evaluation II scores were obtained on 17,18 tridium species (1 and 0 patients), Bacteroides species (0 admission. Clinical evaluations and WBC count were per- and 1 patient), polymicrobial (9 and 10 patients), and Can- formed on a daily basis during hospital stay and every 2 weeks for up to 2 months after discharge. The following outcomes were dida species (1 and 1 patients). recorded: time to improvement, defined as normalization of body After 24 hours of treatment, WBC count showed a temperature and bowel movements; time with antibiotic therapy, gradual increase in group 1. On day 2, mean WBC count 3 3 defined as duration of antibiotic treatment for abdominal sepsis was 17.8ϫ10 /µL in group 1 and 12.2ϫ10 /µL in group and/or infectious complications; hospital stay, defined as the du- 2(PϽ.001). On day 4, mean values were 20.1ϫ103/µL ration of in-hospital stay related to the episode of abdominal sep- and 10.0ϫ103/µL, respectively (PϽ.001). The WBC val- sis and/or complications; and emergence of infectious and non- ues returned to normal in both groups at the second week infectious complications, mortality, and adverse reactions to drugs. after randomization and remained so up to 8 weeks of For the calculation of direct medical costs, and for international follow-up (Figure). validity, the costs per hospital day, for specific antibiotics, and Median time to clinical recovery and improvement was for molgramostim were derived from the study by Price at al.19 2 days in group 1 and 4 days in group 2 (PϽ.005). Median hospital stay was 9 and 13 days (PϽ.001), and median time STATISTICS with antibiotic therapy was 9 and 13 days (PϽ.001), re- Continuous variables were summarized in terms of mean±SD spectively (Table 2). Because of 2 early deaths in group or median (interval). Nominal and discrete variables were 1, the minimum hospital stay and duration of antibiotic summarized as absolute and relative frequencies. Analysis was therapy were 1 day. performed on an intention-to-treat basis. The 2-tailed t test for Six episodes of infectious complications developed in independent samples was used to compare means, and the group 1 and 16 in group 2 (P=.02). Three patients from Mann-Whitney test was used to compare medians. The Fisher group 1 had residual abscess (presence of a collection of test was used to compare nominal and discrete variables. Ͻ fluid detected by ultrasound or computed tomographic P .05 was considered statistically significant. scan with a positive culture); 2 required reoperation and 1 underwent percutaneous drainage. In group 2, 5 pa- RESULTS tients had residual abscess; 4 required reoperation and 1 underwent percutaneous drainage. Wound infections Sixty-one patients were included in the trial during a 19- were less common in group 1 (3 vs 9 cases), as was pneu- month recruitment period. Two patients from group 1 and monia (0 vs 2 cases).

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 25 Table 2. Clinical Outcomes Group 1 Group 2 Group 1 Group 2 P 20 Outcome (n = 28) (n = 30) Value L µ

/ Ͻ

3 Time to improvement, 2 (1-5) 4 (2-8) .005

10 15 median (range), d × Time with antibiotic therapy, 9 (1-12) 13 (5-21) Ͻ.001 median (range), d 10 Hospital stay, median (range), d 9 (1-12) 13 (5-21) Ͻ.001

WBC Count, Infectious complications, No. (%) 6 (21) 16 (53) .02 5 Surgical wound infection 3 9 Abscess 3 5 Pneumonia 0 2 0 0 20 40 60 Adverse events, No. (%) 5 (18) 7 (23) .75 Ͼ Time, d CT scan–guided drainage, No. (%) 1 (4) 1 (3) .99 Reoperations, No. (%) 2 (7) 4 (13) .67 Deaths, No. (%) 2 (7) 2 (7) Ͼ.99 Figure. Evolution of white blood cell (WBC) counts in both study groups during follow-up. Values are shown as mean and standard deviation. Abbreviation: CT, computed tomography.

Five adverse reactions were observed in group 1, 3 pos- ratinocyte proliferation, and fibroblast modulation, con- sibly related to molgramostim administration (1 case of tributing in this way to the healing process.1,5,8 thrombocytopenia, 1 of generalized rash, and 1 of nau- In 1994, in a rat model of cecal ligation and puncture sea) and 2 apparently not related (1 case of deep vein treated with 20 µg of recombinant murine GM-CSF, Toda thrombosis and 1 of superficial phlebitis). In group 2, 7 et al24 failed to show improvement in 48-hour survival adverse reactions were observed, specifically 1 case of liver but observed some inhibition of early leukocyte seques- and lung failure, 2 cases of pneumonia, 1 eventration, 1 tration in the peritoneal cavity. Later, Gennari et al13 found allergy to ␤-lactams, 1 pulmonary embolism, and 1 epi- a 75% survival rate in a mouse model of cecal ligation sode of encephalopathy. and puncture plus transfusion and burn treated with re- There were 2 deaths in group 1 and 2 in group 2. combinant murine GM-CSF, 100 ng/d for 6 days. This Deaths in group 1 occurred early (within 12 hours after survival was significantly superior to the 30% observed surgery) and were due to sepsis and pulmonary embo- in the placebo-treated animals (PϽ.001) and was attrib- lism. Deaths in group 2 occurred 5 and 7 days after uted to improvement in gut barrier function and better intervention and were due to multiple organ failure and ability to kill bacteria. Austin et al3 conducted a trial in a sepsis. mouse model of trauma, administering GM-CSF or iso- Direct medical costs (in US dollars) in group 1 were tonic sodium chloride solution intraperitoneally for 5 days $9963 for hospitalization, $1170 for antibiotics, and $1200 before performance of cecal ligation and puncture. The for molgramostim, giving a total of $12 333 per patient. group receiving GM-CSF had a better survival rate (40% In group 2, costs were $14 391 for hospitalization and vs 5%; PϽ.05), as well as better macrophage function, $1690 for antibiotics, totaling $16 081 per patient. This less nitric oxide, and reduced bacterial growth indexes. resulted in a savings of $3748 per patient treated with Clinical trials with GM-CSF have been conducted in molgramostim. neutropenic and pediatric patients with sepsis. Bilgin et al25 compared a 7-day administration of GM-CSF, 5 µg/kg COMMENT per day, vs placebo in a randomized trial of 60 neonates with neutropenia and clinical signs of sepsis. Good tol- Our data show that addition of molgramostim to the stan- erance of GM-CSF, no adverse reactions, a statistically dard treatment of patients with abdominal sepsis of non- significant increase in neutrophil count on day 7, and traumatic origin is safe and effective, reducing the rate improved survival (10% vs 30%) were observed, sug- of infectious complications, the duration of antibiotic gesting that GM-CSF is effective in neonatal sepsis with therapy, and the length of hospital stay. To our knowl- neutropenia. edge, this is the first trial to evaluate and demonstrate In a randomized, placebo-controlled trial involving 40 the clinical usefulness of GM-CSF in abdominal sepsis patients with diabetic foot infections, Gough et al9 evalu- in humans. It has been observed experimentally that ated the effect of a different colony-stimulating factor, GM-CF has several effects in peritonitis, such as en- granulocyte colony-stimulating factor, as adjuvant therapy. hancement of hematopoiesis and immune reaction, and They found that this treatment induced statistically sig- it may also play a role in the down-regulation of inflam- nificant differences in terms of earlier eradication of patho- matory mediators that are produced by bone marrow cells gens from infected ulcers (P=.02), quicker resolution of during abdominal sepsis.7,20-22 It is well known that GM- soft tissue infections, shorter hospital stay, shorter dura- CSF enhances many of the granulocyte and monocyte- tion of intravenous antibiotic treatment, and increased neu- macrophage functions,23 such as the generation of su- trophil production. In another study, in neutropenic pa- peroxide anion in response to bacterial peptides, among tients with bacterial and fungal infections, treatment with many others. Also, it has been demonstrated that GM- antibiotics plus GM-CSF resulted in a significantly better CSF induces endothelial proliferation and migration, ke- response rate than antibiotics plus placebo.26

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Results of our study are consistent with those reported 2. Weisbart RH, Gasson JC, Golde DW. Colony-stimulating factors and host defense. 25,27 Ann Intern Med. 1989;110:297-303. by others. Administration of GM-CSF together with an- 3. Austin OM, Redmond HP, Watson WG, Cunney RJ, Grace PA, Bouchier-Hayes tibiotics induces a progressive and significant rise in white D. The beneficial effects of immunostimulation in posttraumatic sepsis. J Surg blood cell count and neutrophils. The observed improve- Res. 1995;59:446-449. ment in clinical outcomes in terms of lower number of in- 4. Engelhard M, Brittinger G. Clinical relevance of granulocyte-macrophage colony- stimulating factor. Semin Oncol. 1994;21:1-4. fectious complications, shorter hospital stay, faster clini- 5. Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. cal improvement, and shorter duration of antibiotic therapy Surgery. 2000;127:117-126. is also consistent with published evidence showing that 6. Oberholzer C, Oberholzer A, Clare-Salzler M, Moldawer LL. Apoptosis in sepsis: a new target for therapeutic exploration. FASEB J. 2001;15:879-892. colony-stimulating factors may be of great help in pa- 7. Presneill JJ, Waring PM, Layton JE, et al. Plasma granulocyte colony-stimulating tients with infectious diseases associated with neutrope- factor and granulocyte-macrophage colony-stimulating factor levels in critical ill- nic and nonneutropenic conditions.28 ness including sepsis and septic shock: relation to disease severity, multiple or- The microorganisms isolated in our patients were com- gan dysfunction, and mortality. Crit Care Med. 2000;28:2344-2354. 8. Williams MA, Withington S, Newland AC, Kelsey SM. Monocyte anergy in septic mon pathogens involved in abdominal sepsis. The low shock is associated with a predilection to apoptosis and is reversed by granulocyte- isolation rate of anaerobes, however, deserves further com- macrophage colony-stimulating factor ex vivo. J Infect Dis. 1998;178:1421-1433. ment. In our environment there is frequently a diffi- 9. Gough A, Clapperton M, Rolando N, Foster AV, Philpott-Howard J, Edmonds ME. Randomized placebo-controlled trial of granulocyte-colony stimulating factor in culty in the handling of abdominal cultures in that samples diabetic foot infection. Lancet. 1997;350:855-859. remain stored in adverse conditions for long periods of 10. Barsig J, Bundschuh DS, Hartung T, Bauhofer A, Sauer A, Wendel A. Control of time, affecting the rate of isolation of anaerobes. fecal peritoneal infection in mice by colony-stimulating factors. J Infect Dis. 1996; Adverse reactions during molgramostim administra- 174:790-799. 11. Davis KA, Fabian TC, Ragsdale DN, Trenthem LL, Croce MA, Proctor KG. Granu- tion were observed in 3 patients. One patient developed locyte colony-stimulating factor and neutrophil-related changes in local host de- a rash that disappeared once molgramostim treatment was fense during recovery from shock and intra-abdominal sepsis. Surgery. 1999; suspended, 1 developed thrombocytopenia, and 1 had 126:305-313. 12. Feterowski C, Weighardt H, Emmanuilidis K, Hartung T, Holzmann B. Immune nausea. This low incidence of adverse reactions agrees protection against septic peritonitis in endotoxin-primed mice is related to re- 27 with the study by Dierdorf et al, who observed 68 pa- duced neutrophil apoptosis. Eur J Immunol. 2001;31:1268-1277. tients with neutropenic pneumonia of fungal or bacte- 13. Gennari R, Alexander JW, Gianotti L, Eaves-Pyles T, Hartmann S. 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