Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Aztreonam versus Colistin-Neomycin for Selective Decontamination of the Digestive Tract in Patients Undergoing Bone Marrow Transplantation: a Randomized Study A. Bosi, R. Fanci, P. Pecile, S. Guidi, R. Saccardi, A.M. Vannucchi, G. Longo, E. Donnini, A. Orsi & P. Rossi-Ferrini To cite this article: A. Bosi, R. Fanci, P. Pecile, S. Guidi, R. Saccardi, A.M. Vannucchi, G. Longo, E. Donnini, A. Orsi & P. Rossi-Ferrini (1992) Aztreonam versus Colistin-Neomycin for Selective Decontamination of the Digestive Tract in Patients Undergoing Bone Marrow Transplantation: a Randomized Study, Journal of Chemotherapy, 4:1, 30-34, DOI: 10.1080/1120009X.1992.11739135 To link to this article: http://dx.doi.org/10.1080/1120009X.1992.11739135
Published online: 15 Jul 2016.
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Citing articles: 1 View citing articles
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Date: 05 August 2017, At: 02:23
Downloaded by [University of Calgary] at 02:23 05 August 2017
Journal of Chemotherapy
Aztreonam versus ColistinNeomycin for Selective Decontamination of the Digestive Tract in Patients Undergoing Bone Marrow Transplantation: a Randomized Study A. BOSI - R. FANCI - P. PECILE * S. GUIDI - R. SACCARDI - A.M. VANNUCCHI G. LONGO - E. DONNINI - A. ORSI * P. ROSSI-FERRINI
Summary ------------------------ --------Aztreonam (Az), a minimally absorbable monobactam antibiotic, was compared to colistin plus neomycin (CN), for intestinal decontamination during Bone Marrow Transplantation (BMT) in a controlled study . Thirty-four consecutive patients were randomized in two groups and evaluated for number of febrile episodes, days of fever, fecal cultures and clinical symptoms related to infections or colonizations. No significant differences were observed suggesting that Az is at least as effective as the CN regimen and may be considered as an alternative approach for intestinal decontamination in BMT patients. Key words: aztreonam, colistin, neomycin, bone marrow transplantation, gut decontamination.
Bone Marrow Transplant Unit, Department of Hematology, University of Florence, * Department of Bacteriology and Virology, Careggi Hospital, 50134 Florence, Italy. Correspondence to: Alberto Basi, MD; BMT Unit, Dept Hematoloty, Careggi Hospital, I-50134 Florence, Italy. © Edizioni Riviste Scientifiche - Firenze
Vol. 4 - n. 1 (30-34) - 1992
INTRODUCTION
The selective elimination of potentially pathogenic bacteria is a technique widely used in patients undergoing bone marrow transplantation (BMT). In fact, the use of aggressive conditioning regimens for BMT increases the occurrence of infections, which are the most frequent complications and the major cause of death after marrow graft 1 • 2 • The microorganisms responsible for these infections frequently originate in the patient's own gastrointestinal tract flora 3 • 4 • Moreover several studies have shown that bacteria within the lumen of the bowel play a role in the development of acute graft-versushost disease (GVHD) H. Therefore, methods for preventing infections in BMT patients have been introduced, with the aim of suppressing potentially pathogenic Gram-negative bacteria and yeasts without modifying the anaerobic intestinal microflora (selective decontamination). In fact, the latter represents a potent mechanism, termed . colonization resistance (CR), for the prevention of colonization of the digestive tract by pontentially pathogenic species. CR should be maintained in order to prevent the acquisition and overgrowth of antibiotic-resistant, potentially pathogenic organisms 7 • 8 • In this setting, aztreonam (Az), a minimally absorbable monobactam antibiotic that is active primarily against aerobic Gram-negative bacilli 9 , represents a useful putative agent as showed in previous studies in healthy volunteers and in neutropenic patients 10 • 11 • After oral administration, less than 1% of the drug is absorbed 12 • This feature, and the distinct spectrum of activity, render Az useful for selective ISSN 1120-009X
AZTREONAM VERSUS COLISTIN-NEOMYCIN FOR SELECTIVE DECONTAMINATION, ETC.
decontamination of the digestive tract in immunocompromised patients. The present study was designed to evaluate the efficacy of Az for the prevention of infections and colonization of the digestive tract by aerobic Gram-negative organisms in marrow graft recipients. Patients treated with colistin plus neomycin (CN) served as controls.
31
evident relationship to blood products infusion. Infections were documented clinically by means of X-rays and microbiological findings . Before antimicrobial decontamination and weekly during the study period surveillance cultures of feces, urine and oral swabs were performed. Weekly, and in case of any febrile episodes, three blood cultures were performed.
Definitions PATIENTS AND METHODS
Downloaded by [University of Calgary] at 02:23 05 August 2017
Study design 34 consecutive patients (pts) undergoing BMT for hematological neoplasms at the BMT Unit of the Careggi Hospital in Florence (Italy), were randomized after informed consent to receive Az (1500 mg per day p.o., in three equally divided doses) or colistin (UCB) (1500 U q6h) plus neomycin (Lagap) (250 mg q6h). For yeast elimination, mepartricine (SPA) (50,000 U q6h) was given in both groups 13 • Both groups were also given nystatin mouth washes (Squibb) 400,000 U q6h. Selective decontamination was started on day - 10 before transplantation and maintained until discharge . Az was kindly provided by Squibb, Rome, Italy.
Bone marrow transplantation All patients were cared for in single rooms with a positive pressure HEPA filtered airflow prior to the conditioning therapy and nourished with sterile food. Decontamination procedures for patients and nursing ward were performed as previously reported 14 • All patients who received allogeneic marrow were treated with a combination of cyclosporin and methotrexate for prophylaxis against acute GVHD 15 • The diagnosis of acute GVHD and the clinical grading of the condition was done according to published criteria 16 •
Clinical and microbiological investigation All pts were examined daily for clinical signs of infection. The axillary body temperature was measured at least 4 times daily. Febrile episodes were defined as an axillary body temperature above 38°C lasting more than 12 h, without
a) Febrile episodes were classified as: - Microbiologically documented with bacteriemia: the infection was clinically symptomatic and microbiologically documented. A bacteriemia was documented as well. - Microbiologically documented without bacteriemia: the infection was clinically symtomatic and microbiologically documented. No bacteriemia was documented. - Clinically documented: clinical signs and symptoms of infection were present, but no microbiological proof was obtained. b) Gut surveillance and classification of infections: - Established fecal colonization: is defined as two or more consecutive isolations of a microorganism in the specimen after the first week of therapy. - Positive stool culture: is defined as the isolation of enteropathogenic organisms in the feces. - Infectious diarrhea : is defined as an emission of unformed stool > 500 ml/die associated with positive stool culture. c) Urinary tract infections (UTI) were defined by the presence of greater than 10 5 bacterial colonies per ml on a catheterized specimen of urine.
Statistical analyses Baseline characteristics of the two groups were compared with the Kruskal Wallis test, Fisher exact test and Pearson chi square. Differences between the two groups in day of fever/days at risk, number of febrile episodes, days with fever, were tested by means of non-parametric statistical techniques (Mann-Whitney U test, one sample chi square test) according to SPSS Pc + program. The chosen level of significance was p 38°C
TABLE
Number Age (mean) Sex (male/female) Diagnosis ANLL ALL NHL HD CML Autologous BMT Allogeneic BMT GvHD prophylaxis (Cya + Mtx) GvHD acute grade I-II grade III-IV
et alii
and days with fever /days at risk could be found between the group Az and CN. The classification of febrile episodes in the two groups is reported in Table 3. No Gram-negative sepsis was observed in both groups . Two patients treated with CN, but none in the Az group, developed urinary tract infections. The results of gut surveillance are reported in Table 4. In both arms, colonization by Gram-negative bacilli was not detected . In one patient treated with Az, an occasional isolation of Campylobacter jejuni, in absence of diarrhea, was observed. No patients experienced infectious diarrhea irrespective of the treatment given. Finally the occurrence and grading of GVHD was similar in the two groups.
1 - Patients' characteristics.
Aztreonam
Colistin+ Neomycin
Total
15 36 (15-58) 12/3
15 30 (10-49) 6/9
30 33 (10-58) 18/12 13 7 3 3
1 11 4 4
7 3 0 2 3 9 6 6
20 10 10
1 0
2 1
3 1
6 4 3
4
Abbreviations used: ANLL, acute non lymphocytic leukemia; ALL, acute lymphocytic leukemia; NHL, non-Hodgkin lymphoma; HD, Hodgkin disease; CML, chronic myelogenous leukemi a; BMT, bone marrow transplantation; GvHD, graft versus host disease; Cya, cyclosporin; Mtx, methotrexate.
TABLE 2 - Analysis of febrile episodes. Colistin+ Neomyci n
Aztreonam
N. Patients N. days at risk N. febrile episodes N . days with fever >38°C Days with fever/at risk
ABMT
BMT
Tot
11 304 18 64 21
4 127 4 11 8.6
15 431 22 75 17.4
ABMT
BMT
Tot
9 234 13 47 20
6 128 7 15 11.7
15 362 20 62 17.1
P value (*)
ns ns ns ns ns
Abbreviations used : ABMT, autologous bone marrow transplantation; BMT, allogeneic bone marrow transplan tation; Tot, total; • N, number; ns, not significant . (*) Mann Whitney test.
33
AZTREONAM VERSUS COLISTIN-NEOMYCIN FOR SELECTIVE DECONTAMINATION, ETC.
3 - Classification of febrile episodes.
TABLE
Aztreonam ABMT
BMT
Tot
ABMT
BMT
Tot
Documented infections * with bacteriemia * without bacteriemia Clinical infections Fever undefined origin
2 (a) 0 1 (e) 15
2 (b) 0 0 2
4 0 17
2 (c) 2 (d) 0 9
0 0 0 7
2 2 0 14
Total
18
5
22
7
20
a = S. viridans, S. epidermidis d = UTI: P. mirabilis, S. faecalis
Downloaded by [University of Calgary] at 02:23 05 August 2017
Colistin+ Neomycin
TABLE
b e
= S. faecalis, = Pneumonia
4 - Analysis of fecal cultures: results. Aztreonam
Colistin+ Neomycin
N. of patients Total fecal cultures
15 82
15 90
Cultures with microbial growth N. of organisms isolated
35 (42.6%) 57
40
N . of colonization
7
6
% of colonization
12.3
15
* Gram + cocci
6
4
1 4
1 2
1 0
0 1
0
0 2 0 0
-
S. avium S. faecalis Staphylococcus coag. neg. S. viridans
* Gram - bacilli *Fungi Positive stool cultures Infectious diarrhea 1
31 (34.4 % )
1
I
0
Campylobacter jejuni.
DISCUSSION
The aim of this prospective randomized study was to assess the efficacy of Az as a selective decontamination regimen in preventing infections during granulocytopenia in BMT recipients, and to compare it to the colistin plus neomycin standard regimen. Aztreonam, a minimally absorbable monobactam antibiotic which is primarily active against Gram-negative bacilli, is a useful putative agent. The features of both a narrow spectrum of antimicrobial activity and virtually absent intestinal absorp-
S. hominis
13
c
= Staphyloccus
coag . neg., S. viridans
tion 12 , make the drug suitable for clinical use in the selective antimicrobial gut decontamination of immunocompromised patients 1 7-1 8 • Volunteer trials have been performed to ascertain suitable dosage regimens for oral use and to monitor both the effects on the intestinal microflora and the obtainable fecal levels of Az 10 • 12 • 19 - 21 • In immunocompromised hosts the efficacy of Az for gut decontamination has been documented both in experimental models 22 and in the clinical setting 11 ' 23 • From this background, we planned a prospective randomized study to evaluate the real efficacy of aztreonam in preventing infections in patients undergoing BMT. The two groups of patients under study were comparable for diseases, methods of BMT, clinical characteristics, and days at risk for infections. No significant differences were observed in the number of febrile episodes, number of days with fever > 38°C, and in the ratio of days with fever/days at risk. Aztreonam was as efficacious as the CN regimen in preventing both gut colonization and septicemia from Gram-negative bacilli arising from the gastrointestinal tract. No patient experienced infectious diarrhea. In one patient treated with Az an asymptomatic infection with positive culture of the stool was observed (Campylobacter jejuni); a negativization was subsequently documented. The use of Az was not associated with any adverse effect and the drug was generally well accepted by the patients as observed by others in both healthy and immunocompromised subjects 10 - 12 • 23 • In conclusion, our randomized study confirms the efficacy of aztreonam in selective intestinal decontamination in immunocompromised hosts as observed by
34
A. BOSI - R. FANCI - P. PECILE - S. GUIDI - R. SACCARDI - A.M. ''ANNUCCHI, et alii
others 11 • 23 in non-randomized studies, and demonstrates the efficacy of the drug in the particular setting of BMT. In this regard the demonstration of a similar incidence of GVHD in the two groups under study is of particular interest. Therefore our data suggest that Az may replace other non-absorbable antibiotics such as colistin and neomycin in selective decontamination regimens used for infection prophylaxis in BMT recipients .
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AcKNOWLEDGEMENT - Supported in part by the Associazione Italiana contro le Leucemie-Firenze. This work is dedicated to Mr. Luigi Tinti, past General Manager of the Cassa di Risparmio di Firenze, for his generous aid to the BMT Unit of Florence. REFERENCES ' Van der Meer JWM, Guiot HFL, van den Brock PJ, van Furth R. Infections in bone marrow transplant recipients. Semin Hematol 1984; 21: 123-140. ' Rogers TR. Prevention of infection in neutropenic bone marrow transplant patients. Antibiot Chemother 1985; 33: 90-113. ' Meyers JD. Infection of bone marrow transplant recipients. Am J Med 1986; 81, Suppl 1 A: 27-38. • Aker SN, Chenney LC. The use of sterile and low microbial diets in ultraisolation environments. J Parenter Enter Nutr 1983; 7: 390-397. ' van Bekkum DW, Knaan S. Role of bacterial microflora in the development of intestinal lesions from graft versus host rection. J Nat! Cancer Inst 1977; 58: 787-789. • Pollard M, Chang CF, Srivastava KK. The role of microflora in development of graft versus host disease. Transplant Proc 1976; 8: 533-536. 7 van der Waajj D, Berghusis-de Vries JM, Lekkerkerkvan der Wees JEC . Colonisation resistance of the digestive tract in conventional and antibiotic-treated mice. J Hyg 1971; 69: 405-11. 1 van der Wajj D. Colonisation resistance of the digestive tract: clinical consequences and implications . J Antimicrob Chemother 1982; 10: 263-70. • Fainstein V, WeaverS, Bodey GP. Comparative in vivo study of SQ 26.776. Antimicrob Agents Chemother 1982; 21 : 294-298. 10 de Vries-Hospers HG, Welling GW, Swabb EA, van der Waajj D . Selective decontamination of the digestive tract
with aztreonam: a study of 10 healthy volunteers . J Infect Dis 1984; 150: 636-642. "Jones PG, Bodey JP, Swabb EA, Rosenbaum B. Effect of aztreonam on throat and stool flora of cancer patients. Antimicrob Agents Chemother 1984; 26: 941-943. " Swabb EA, Sugermann AA, Stern M. Oral bioavailability of the monobactam aztreonam (SQ 26.776) in healthy subjects. Antimicrob Agents Chemother 1983; 23: 548-550. "Van Lint MT, Bacigalupo A, Frassoni F, Podesta M, Soro 0, Grazi G, Marmont A. Ketoconazole versus mepartricin for the prevention of candida infections in the immunocompromised host . Haematologica 1983; 68: 226-232. " Bosi A, Fanci R, Guidi S, Saccardi R, Giambalvo A, Belli A, Canavese MC. Environmental control measures in a new bone marrow transplant unit. Haematologica 1988; 73 (Suppl): 238. " Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Eng! J Med 1986; 314: 729-735. 16 Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG. Bone marrow transplantation. N Eng! J Med 1975; 292: 832-846. "de Vries-Hospers HG, Sleijfer DT, Mulder NH, van der Waaij D, Nieweg HO, van Saene HKF. Bacteriological aspects of selective decontamination of the digestive tract as a method of infection prevention in granulocytopenic patients. Antimicrob Agents Chemother 1981; 19: 813-20. " Guiot HFL, van der Meer JWM, van Furth R. Selective antimicrobial modulation of human microbial flora: infection prevention in patients with decreased host defense mechanism by selective elimination of potentially pathogenic bacteria. J Infect Dis 1981; 143: 644-54. " Sykes RB, Bonner DP, Bush K, Georgopapadakou NH. Aztreonam (SQ 26. 776) a synthetic mono bact am specifically active against aerobic Gram-negative bacteria. Antimicrob Agents Chemother 1982; 21: 85-92. 10 Pielkewicz FG, Remsburg BJ, Fisher SM, Sykes RB. High-pressure liquid chromatographic analysis of aztreonam in sera and urine. Antimcrob Agents Chemother 1983; 23: 852-6. " Ehret W, Probst H, Ruckdeschel G. Determination of aztreonam in faeces of human volunteers: a comparison of reversed-phase high pressure liquid chromatography and bioassay. J Antimicrob Chemother 1987; 19: 541 -549. " Malison WL, Dijkema H, Klasen HJ. Alteration of wound colonisation by selective intestinal decontamination in thermally injured mice. Burns 1990; 16: 166-8. "Sakata H, Kakehashi H, Fujita K, Yoshioka H . Selective decontamination of intestinal flora with oral aztreonam in compromised children. Kansenshogaku-Zasshi 1989; 63: 1165-70.
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Aztreonam versus Colistin-Neomycin for Selective Decontamination of the Digestive Tract in Patients Undergoing Bone Marrow Transplantation: a Randomized Study A. Bosi, R. Fanci, P. Pecile, S. Guidi, R. Saccardi, A.M. Vannucchi, G. Longo, E. Donnini, A. Orsi & P. Rossi-Ferrini To cite this article: A. Bosi, R. Fanci, P. Pecile, S. Guidi, R. Saccardi, A.M. Vannucchi, G. Longo, E. Donnini, A. Orsi & P. Rossi-Ferrini (1992) Aztreonam versus Colistin-Neomycin for Selective Decontamination of the Digestive Tract in Patients Undergoing Bone Marrow Transplantation: a Randomized Study, Journal of Chemotherapy, 4:1, 30-34, DOI: 10.1080/1120009X.1992.11739135 To link to this article: http://dx.doi.org/10.1080/1120009X.1992.11739135
Published online: 15 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yjoc20 Download by: [University of Calgary]
Date: 05 August 2017, At: 02:23
Downloaded by [University of Calgary] at 02:23 05 August 2017
Journal of Chemotherapy
Aztreonam versus ColistinNeomycin for Selective Decontamination of the Digestive Tract in Patients Undergoing Bone Marrow Transplantation: a Randomized Study A. BOSI - R. FANCI - P. PECILE * S. GUIDI - R. SACCARDI - A.M. VANNUCCHI G. LONGO - E. DONNINI - A. ORSI * P. ROSSI-FERRINI
Summary ------------------------ --------Aztreonam (Az), a minimally absorbable monobactam antibiotic, was compared to colistin plus neomycin (CN), for intestinal decontamination during Bone Marrow Transplantation (BMT) in a controlled study . Thirty-four consecutive patients were randomized in two groups and evaluated for number of febrile episodes, days of fever, fecal cultures and clinical symptoms related to infections or colonizations. No significant differences were observed suggesting that Az is at least as effective as the CN regimen and may be considered as an alternative approach for intestinal decontamination in BMT patients. Key words: aztreonam, colistin, neomycin, bone marrow transplantation, gut decontamination.
Bone Marrow Transplant Unit, Department of Hematology, University of Florence, * Department of Bacteriology and Virology, Careggi Hospital, 50134 Florence, Italy. Correspondence to: Alberto Basi, MD; BMT Unit, Dept Hematoloty, Careggi Hospital, I-50134 Florence, Italy. © Edizioni Riviste Scientifiche - Firenze
Vol. 4 - n. 1 (30-34) - 1992
INTRODUCTION
The selective elimination of potentially pathogenic bacteria is a technique widely used in patients undergoing bone marrow transplantation (BMT). In fact, the use of aggressive conditioning regimens for BMT increases the occurrence of infections, which are the most frequent complications and the major cause of death after marrow graft 1 • 2 • The microorganisms responsible for these infections frequently originate in the patient's own gastrointestinal tract flora 3 • 4 • Moreover several studies have shown that bacteria within the lumen of the bowel play a role in the development of acute graft-versushost disease (GVHD) H. Therefore, methods for preventing infections in BMT patients have been introduced, with the aim of suppressing potentially pathogenic Gram-negative bacteria and yeasts without modifying the anaerobic intestinal microflora (selective decontamination). In fact, the latter represents a potent mechanism, termed . colonization resistance (CR), for the prevention of colonization of the digestive tract by pontentially pathogenic species. CR should be maintained in order to prevent the acquisition and overgrowth of antibiotic-resistant, potentially pathogenic organisms 7 • 8 • In this setting, aztreonam (Az), a minimally absorbable monobactam antibiotic that is active primarily against aerobic Gram-negative bacilli 9 , represents a useful putative agent as showed in previous studies in healthy volunteers and in neutropenic patients 10 • 11 • After oral administration, less than 1% of the drug is absorbed 12 • This feature, and the distinct spectrum of activity, render Az useful for selective ISSN 1120-009X
AZTREONAM VERSUS COLISTIN-NEOMYCIN FOR SELECTIVE DECONTAMINATION, ETC.
decontamination of the digestive tract in immunocompromised patients. The present study was designed to evaluate the efficacy of Az for the prevention of infections and colonization of the digestive tract by aerobic Gram-negative organisms in marrow graft recipients. Patients treated with colistin plus neomycin (CN) served as controls.
31
evident relationship to blood products infusion. Infections were documented clinically by means of X-rays and microbiological findings . Before antimicrobial decontamination and weekly during the study period surveillance cultures of feces, urine and oral swabs were performed. Weekly, and in case of any febrile episodes, three blood cultures were performed.
Definitions PATIENTS AND METHODS
Downloaded by [University of Calgary] at 02:23 05 August 2017
Study design 34 consecutive patients (pts) undergoing BMT for hematological neoplasms at the BMT Unit of the Careggi Hospital in Florence (Italy), were randomized after informed consent to receive Az (1500 mg per day p.o., in three equally divided doses) or colistin (UCB) (1500 U q6h) plus neomycin (Lagap) (250 mg q6h). For yeast elimination, mepartricine (SPA) (50,000 U q6h) was given in both groups 13 • Both groups were also given nystatin mouth washes (Squibb) 400,000 U q6h. Selective decontamination was started on day - 10 before transplantation and maintained until discharge . Az was kindly provided by Squibb, Rome, Italy.
Bone marrow transplantation All patients were cared for in single rooms with a positive pressure HEPA filtered airflow prior to the conditioning therapy and nourished with sterile food. Decontamination procedures for patients and nursing ward were performed as previously reported 14 • All patients who received allogeneic marrow were treated with a combination of cyclosporin and methotrexate for prophylaxis against acute GVHD 15 • The diagnosis of acute GVHD and the clinical grading of the condition was done according to published criteria 16 •
Clinical and microbiological investigation All pts were examined daily for clinical signs of infection. The axillary body temperature was measured at least 4 times daily. Febrile episodes were defined as an axillary body temperature above 38°C lasting more than 12 h, without
a) Febrile episodes were classified as: - Microbiologically documented with bacteriemia: the infection was clinically symptomatic and microbiologically documented. A bacteriemia was documented as well. - Microbiologically documented without bacteriemia: the infection was clinically symtomatic and microbiologically documented. No bacteriemia was documented. - Clinically documented: clinical signs and symptoms of infection were present, but no microbiological proof was obtained. b) Gut surveillance and classification of infections: - Established fecal colonization: is defined as two or more consecutive isolations of a microorganism in the specimen after the first week of therapy. - Positive stool culture: is defined as the isolation of enteropathogenic organisms in the feces. - Infectious diarrhea : is defined as an emission of unformed stool > 500 ml/die associated with positive stool culture. c) Urinary tract infections (UTI) were defined by the presence of greater than 10 5 bacterial colonies per ml on a catheterized specimen of urine.
Statistical analyses Baseline characteristics of the two groups were compared with the Kruskal Wallis test, Fisher exact test and Pearson chi square. Differences between the two groups in day of fever/days at risk, number of febrile episodes, days with fever, were tested by means of non-parametric statistical techniques (Mann-Whitney U test, one sample chi square test) according to SPSS Pc + program. The chosen level of significance was p 38°C
TABLE
Number Age (mean) Sex (male/female) Diagnosis ANLL ALL NHL HD CML Autologous BMT Allogeneic BMT GvHD prophylaxis (Cya + Mtx) GvHD acute grade I-II grade III-IV
et alii
and days with fever /days at risk could be found between the group Az and CN. The classification of febrile episodes in the two groups is reported in Table 3. No Gram-negative sepsis was observed in both groups . Two patients treated with CN, but none in the Az group, developed urinary tract infections. The results of gut surveillance are reported in Table 4. In both arms, colonization by Gram-negative bacilli was not detected . In one patient treated with Az, an occasional isolation of Campylobacter jejuni, in absence of diarrhea, was observed. No patients experienced infectious diarrhea irrespective of the treatment given. Finally the occurrence and grading of GVHD was similar in the two groups.
1 - Patients' characteristics.
Aztreonam
Colistin+ Neomycin
Total
15 36 (15-58) 12/3
15 30 (10-49) 6/9
30 33 (10-58) 18/12 13 7 3 3
1 11 4 4
7 3 0 2 3 9 6 6
20 10 10
1 0
2 1
3 1
6 4 3
4
Abbreviations used: ANLL, acute non lymphocytic leukemia; ALL, acute lymphocytic leukemia; NHL, non-Hodgkin lymphoma; HD, Hodgkin disease; CML, chronic myelogenous leukemi a; BMT, bone marrow transplantation; GvHD, graft versus host disease; Cya, cyclosporin; Mtx, methotrexate.
TABLE 2 - Analysis of febrile episodes. Colistin+ Neomyci n
Aztreonam
N. Patients N. days at risk N. febrile episodes N . days with fever >38°C Days with fever/at risk
ABMT
BMT
Tot
11 304 18 64 21
4 127 4 11 8.6
15 431 22 75 17.4
ABMT
BMT
Tot
9 234 13 47 20
6 128 7 15 11.7
15 362 20 62 17.1
P value (*)
ns ns ns ns ns
Abbreviations used : ABMT, autologous bone marrow transplantation; BMT, allogeneic bone marrow transplan tation; Tot, total; • N, number; ns, not significant . (*) Mann Whitney test.
33
AZTREONAM VERSUS COLISTIN-NEOMYCIN FOR SELECTIVE DECONTAMINATION, ETC.
3 - Classification of febrile episodes.
TABLE
Aztreonam ABMT
BMT
Tot
ABMT
BMT
Tot
Documented infections * with bacteriemia * without bacteriemia Clinical infections Fever undefined origin
2 (a) 0 1 (e) 15
2 (b) 0 0 2
4 0 17
2 (c) 2 (d) 0 9
0 0 0 7
2 2 0 14
Total
18
5
22
7
20
a = S. viridans, S. epidermidis d = UTI: P. mirabilis, S. faecalis
Downloaded by [University of Calgary] at 02:23 05 August 2017
Colistin+ Neomycin
TABLE
b e
= S. faecalis, = Pneumonia
4 - Analysis of fecal cultures: results. Aztreonam
Colistin+ Neomycin
N. of patients Total fecal cultures
15 82
15 90
Cultures with microbial growth N. of organisms isolated
35 (42.6%) 57
40
N . of colonization
7
6
% of colonization
12.3
15
* Gram + cocci
6
4
1 4
1 2
1 0
0 1
0
0 2 0 0
-
S. avium S. faecalis Staphylococcus coag. neg. S. viridans
* Gram - bacilli *Fungi Positive stool cultures Infectious diarrhea 1
31 (34.4 % )
1
I
0
Campylobacter jejuni.
DISCUSSION
The aim of this prospective randomized study was to assess the efficacy of Az as a selective decontamination regimen in preventing infections during granulocytopenia in BMT recipients, and to compare it to the colistin plus neomycin standard regimen. Aztreonam, a minimally absorbable monobactam antibiotic which is primarily active against Gram-negative bacilli, is a useful putative agent. The features of both a narrow spectrum of antimicrobial activity and virtually absent intestinal absorp-
S. hominis
13
c
= Staphyloccus
coag . neg., S. viridans
tion 12 , make the drug suitable for clinical use in the selective antimicrobial gut decontamination of immunocompromised patients 1 7-1 8 • Volunteer trials have been performed to ascertain suitable dosage regimens for oral use and to monitor both the effects on the intestinal microflora and the obtainable fecal levels of Az 10 • 12 • 19 - 21 • In immunocompromised hosts the efficacy of Az for gut decontamination has been documented both in experimental models 22 and in the clinical setting 11 ' 23 • From this background, we planned a prospective randomized study to evaluate the real efficacy of aztreonam in preventing infections in patients undergoing BMT. The two groups of patients under study were comparable for diseases, methods of BMT, clinical characteristics, and days at risk for infections. No significant differences were observed in the number of febrile episodes, number of days with fever > 38°C, and in the ratio of days with fever/days at risk. Aztreonam was as efficacious as the CN regimen in preventing both gut colonization and septicemia from Gram-negative bacilli arising from the gastrointestinal tract. No patient experienced infectious diarrhea. In one patient treated with Az an asymptomatic infection with positive culture of the stool was observed (Campylobacter jejuni); a negativization was subsequently documented. The use of Az was not associated with any adverse effect and the drug was generally well accepted by the patients as observed by others in both healthy and immunocompromised subjects 10 - 12 • 23 • In conclusion, our randomized study confirms the efficacy of aztreonam in selective intestinal decontamination in immunocompromised hosts as observed by
34
A. BOSI - R. FANCI - P. PECILE - S. GUIDI - R. SACCARDI - A.M. ''ANNUCCHI, et alii
others 11 • 23 in non-randomized studies, and demonstrates the efficacy of the drug in the particular setting of BMT. In this regard the demonstration of a similar incidence of GVHD in the two groups under study is of particular interest. Therefore our data suggest that Az may replace other non-absorbable antibiotics such as colistin and neomycin in selective decontamination regimens used for infection prophylaxis in BMT recipients .
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AcKNOWLEDGEMENT - Supported in part by the Associazione Italiana contro le Leucemie-Firenze. This work is dedicated to Mr. Luigi Tinti, past General Manager of the Cassa di Risparmio di Firenze, for his generous aid to the BMT Unit of Florence. REFERENCES ' Van der Meer JWM, Guiot HFL, van den Brock PJ, van Furth R. Infections in bone marrow transplant recipients. Semin Hematol 1984; 21: 123-140. ' Rogers TR. Prevention of infection in neutropenic bone marrow transplant patients. Antibiot Chemother 1985; 33: 90-113. ' Meyers JD. Infection of bone marrow transplant recipients. Am J Med 1986; 81, Suppl 1 A: 27-38. • Aker SN, Chenney LC. The use of sterile and low microbial diets in ultraisolation environments. J Parenter Enter Nutr 1983; 7: 390-397. ' van Bekkum DW, Knaan S. Role of bacterial microflora in the development of intestinal lesions from graft versus host rection. J Nat! Cancer Inst 1977; 58: 787-789. • Pollard M, Chang CF, Srivastava KK. The role of microflora in development of graft versus host disease. Transplant Proc 1976; 8: 533-536. 7 van der Waajj D, Berghusis-de Vries JM, Lekkerkerkvan der Wees JEC . Colonisation resistance of the digestive tract in conventional and antibiotic-treated mice. J Hyg 1971; 69: 405-11. 1 van der Wajj D. Colonisation resistance of the digestive tract: clinical consequences and implications . J Antimicrob Chemother 1982; 10: 263-70. • Fainstein V, WeaverS, Bodey GP. Comparative in vivo study of SQ 26.776. Antimicrob Agents Chemother 1982; 21 : 294-298. 10 de Vries-Hospers HG, Welling GW, Swabb EA, van der Waajj D . Selective decontamination of the digestive tract
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