Restrictive antibiotherapy after renal transplantation SERGE LANGLOIS,* MD; JEAN-CLAUDE PECH.RE,t MD; JEAN-GUY LACHANCE,j MD
Forty-two patients were followed up after 44 renal transplantations in an effort to evaluate possible benefits from the following protocol: systematic microbiologic and clinical surveillance, early and aggressive research for the cause of suspected infections, refusal to use prophylactic antibiotherapy, and selection of treatment according to the established cause of the infection. During 18 030 days of follow-up 124 infections were recorded, of which 110 were bacterial, 11 viral and 3 protozoal. Eighty originated in the urinary tract, 17 in skin wounds and 10 in the lower respiratory tract. Septicemia occurred three times, and one death due to infection was recorded. In the treatment of bacterial infections patients received antibiotics for 2486 days. Ampicillin (given for 816 days) and "minor" drugs such as sulfonamides and urinary antiseptics (given for 1036 days) were used 74.50/0 of the time, whereas gentamicin was used only 2.60/o of the time (64 days). Combined antibacterial therapy was needed 1.20/0 of the time (29 days). A restrictive policy regarding antibiotherapy seems to be beneficial to renal transplant recipients. Ouarante-deux patients ont ete observes apres 44 transplantations renales afin d'evaluer les benefices possibles d'un protocole qui comportait une surveillance microbiologique et clinique systematique, une recherche sans retard et eventuellement aggressive de Ia cause des infections suspectees, le refus de toute antibiotherapie prophylactique et un ajustement selon l'etiologie des infections declarees. Pendant 18 030 jours d'observation 124 infections ont ete relevees, dont 110 de nature bacterienne, 11 virale et 3 parasitaire. Quatre-vingt ont pris naissance dans les voies urinaires, 17 etaient des infections de plaie et 10 ont touche l'appareil bronchopulmonaire. Septicemies sont survenues trois fois, et un deces par infection a ete enregistre. *Resident in nephrology, H6tel-Dieu de Qu6bec tChairman, department of microbiology, Laval University, and head, infectious diseases unit, H6tel-Dieu de Quebec tHead, renal transplant unit, H6tel-Dieu de Quebec Reprint requests to: Dr Jean-Claude Pech.re, H6tel-Dieu de Quebec, 11 C6te du Palais, Quebec, PQ GiR 2J6
Comme traitement des infections bacteriennes les patients ont re.u des antibiotiques pendant 2486 jours. L'ampicilline (donne pendant 816 jours) et de medicaments "mineurs" tels les sulfonamides et les antiseptiques urinaires (donnes pendant 1036 jours) furent utilis6s 74.50/0 du temps, alors que Ia gentamicine ne fut utilis6 que 2.60/o du temps (pendant 64 jours). Des associations d'antibiotiques furent necessaires I .20/o du temps (pendant 29 jours). Une politique restrictive concernant l'antibiotherapie semble profitable aux greffes du rein. Infection remains the main threat to
recipients of renal grafts. Attending physicians feel uneasy about the risk and are tempted to use antimicrobial agents widely. In many centres antibiotics are administered at the slightest suspicion of infection, even when the diagnosis is not clear, and preference is often given to a combination of bactericidal broad-spectrum drugs such as cephalosporins and aminoglycosides. This paper describes a study in which management of infection was subjected to the following guidelines: (a) vigorous efforts had to be made for early recognition of infections and their responsible pathogenic microorganisms; (b) indications for the use of antimicrobial agents were restricted to identified infections (prophylactic use was not permitted); (c) in the choosing of treatment the most elective drugs had to be selected first; and (d) the combined use of antibiotics was limited to polymicrobial or life-threatening infections when results of cultures were not yet available. Patients and methods From November 1972 to December 1975, 44 renal homotransplantations were performed in 42 patients (29 men and 13 women) at H6telDieu de Quebec. Patients were divided into two groups according to graft origin: the 34 patients in group A, aged 19 to 54 years (median 36
426 CMA JOURNAL/FEBRUARY 17, 1979/VOL. 120
years), received 36 cadaver grafts; and the 8 patients in group B, aged 25 to 44 years (median 35 years), each received a kidney from a living relative. Determination of HLA transplantation antigens in both donors and recipients yielded in group A a twoantigen match in 14 patients, a oneantigen match in 14 and no match in 7 (one donor was not HLA-typed). In group B seven patients were HLAidentical, and negative results were obtained in mixed lymphocyte culture; the remaining patient shared three antigens with his donor, and positive results were obtained in mixed lymphocyte culture. The basic immunosuppressive therapy included prednisone at a starting daily dose of 1.0 mg/kg in group A and 0.5 mg/kg in group B. The daily dose was tapered to 0.25 mg/kg within 2 months. Azathioprine, 1.5 to 3.0 mg/kg daily, according to the leukocyte count, was administered to both groups. For a rejection crisis the daily dose of prednisone was increased to 2.0 to 3.0 mg/kg for 5 days, then decreased rapidly to the pretreatment level. One to four 1 -g intravenous boluses of methylprednisolone were also given in a 2-day schedule. No more than two rejection episodes were treated in the first 3 months after transplantation. No patient in the study received antilymphocyte globulin, and two underwent splenectomy before grafting. Urinary tract infection was defined as the growth of at least 100 000 colonies/mL of the same organism from two or more urine specimens collected 24 hours apart, with or without symptoms. Relapse was considered to have occurred when the same organism grew 8 or more days after successful treatment, as defined by sterility of the urine. Graft pyelonephritis was suspected in patients with urinary tract infec-
Differences in results between don when three of the five following criteria were met: fever, positive blood groups and between intervals were culture with the organism found in evaluated by the chi-square method.2 the urine, deterioration of renal function without graft rejection, swelling Results Of the 42 patients 2 died. The of the graft without rejection, and an intravenous pyelogram suggestive of first, in group B, died on the 714th infection. Septicemia was defined as postoperative day of staphylococcal sustained bacteremia (i.e., growing septicemia originating from a urinary of the same organism in two blood tract infection; he had also had chronic active hepatitis with hepatitis cultures 24 hours apart). In all recipients preoperative pul- B surface antigenemia. The second, monary roentgenograms were made in group A, died of an iliac artery and cultures were done of urine, rupture on the 67th postoperative blood, and swabs of anterior nares, day, 5 days after graft removal; no throat, anus and any apparently in- local infection was detectable. Twelve fected skin lesion. Pulmonary roent- grafted kidneys had to be removed genograms were made and urine during the study because of rejection. cultures done daily for the first week after transplantation and three times a week thereafter for the rest of the 8 7 6 100hospital stay (usually 3 to 4 weeks); 90when intravenous and bladder catheters were drawn out, the tips were GRAFTS 80- 36 cultured. Suspected infection led to SURVIVAL 27 7021 14 (%) appropriate sampling. Susceptibility 60of bacteria to antibiotics was determined by the Kirby-Bauer method.1 50Infections were treated only when clearly diagnosed clinically or microbiologically or both. In some cases antibiotics were administered before I I culture results were available, on the 3 6 12 18 basis of the clinical evaluation and the results of direct microscopic examination of smears. Medication was FIG. 1-Graft survival in 42 patients chosen according to the usual criteria, patients with 36 cadaver grafts; group including the determined or predicted a living relative. Numbers over points susceptibility of the pathogen. As far kidneys at beginning of intervaL as possible, drugs with a narrow antibacterial spectrum were chosen and combined therapy was avoided. The preventive use of antimicrobial agents was limited to irrigation, with bacitracin. of the bladder preoperatively and of the surgical wound before closure, and to the gargling and swallowing of nystatin, 500 000 units three times a day. For each transplantation the observation period extended from the day of grafting until the removal of the transplanted kidney, the patient's death or Mar. 31, 1976, whichever was first. This period was further divided into two intervals: interval 1, from day 1 to day 90 after transplantation, and interval 2, from day 91 to the last day. 430 CMA JOURNAL/FEBRUARY 17, 1979/VOL. 120
A 13th kidney was lost in the patient who died of septicemia. The mean graft survival rate was 64.8% for group A after 36 months and 75% for group B after 42 months (Fig. 1). On Mar. 31, 1976, 31 patients had functioning allografts and 9 were again receiving long-term hemodialysis. We recorded 124 infections; 110 were bacterial, 11 viral and 3 protozoal (Table I). No systemic fungal infection was observed, and five patients remained free of infection. After statistical analysis bacterial infections appeared to be significantly more frequent in interval 1 than in interval 2 (P < 0.001) and in group
5
3
3
10
5
1
24
30
36
2
I
42
TIME (months)
with renal transplants. Group A = 34 B = 8 patients with 1 graft each from of curves represent numbers of grafted
A than in group B (P
Forty-two patients were followed up after 44 renal transplantations in an effort to evaluate possible benefits from the following protocol: systematic microbiologic and clinical surveillance, early and aggressive research for the cause of suspected infections, refusal to use prophylactic antibiotherapy, and selection of treatment according to the established cause of the infection. During 18 030 days of follow-up 124 infections were recorded, of which 110 were bacterial, 11 viral and 3 protozoal. Eighty originated in the urinary tract, 17 in skin wounds and 10 in the lower respiratory tract. Septicemia occurred three times, and one death due to infection was recorded. In the treatment of bacterial infections patients received antibiotics for 2486 days. Ampicillin (given for 816 days) and "minor" drugs such as sulfonamides and urinary antiseptics (given for 1036 days) were used 74.50/0 of the time, whereas gentamicin was used only 2.60/o of the time (64 days). Combined antibacterial therapy was needed 1.20/0 of the time (29 days). A restrictive policy regarding antibiotherapy seems to be beneficial to renal transplant recipients. Ouarante-deux patients ont ete observes apres 44 transplantations renales afin d'evaluer les benefices possibles d'un protocole qui comportait une surveillance microbiologique et clinique systematique, une recherche sans retard et eventuellement aggressive de Ia cause des infections suspectees, le refus de toute antibiotherapie prophylactique et un ajustement selon l'etiologie des infections declarees. Pendant 18 030 jours d'observation 124 infections ont ete relevees, dont 110 de nature bacterienne, 11 virale et 3 parasitaire. Quatre-vingt ont pris naissance dans les voies urinaires, 17 etaient des infections de plaie et 10 ont touche l'appareil bronchopulmonaire. Septicemies sont survenues trois fois, et un deces par infection a ete enregistre. *Resident in nephrology, H6tel-Dieu de Qu6bec tChairman, department of microbiology, Laval University, and head, infectious diseases unit, H6tel-Dieu de Quebec tHead, renal transplant unit, H6tel-Dieu de Quebec Reprint requests to: Dr Jean-Claude Pech.re, H6tel-Dieu de Quebec, 11 C6te du Palais, Quebec, PQ GiR 2J6
Comme traitement des infections bacteriennes les patients ont re.u des antibiotiques pendant 2486 jours. L'ampicilline (donne pendant 816 jours) et de medicaments "mineurs" tels les sulfonamides et les antiseptiques urinaires (donnes pendant 1036 jours) furent utilis6s 74.50/0 du temps, alors que Ia gentamicine ne fut utilis6 que 2.60/o du temps (pendant 64 jours). Des associations d'antibiotiques furent necessaires I .20/o du temps (pendant 29 jours). Une politique restrictive concernant l'antibiotherapie semble profitable aux greffes du rein. Infection remains the main threat to
recipients of renal grafts. Attending physicians feel uneasy about the risk and are tempted to use antimicrobial agents widely. In many centres antibiotics are administered at the slightest suspicion of infection, even when the diagnosis is not clear, and preference is often given to a combination of bactericidal broad-spectrum drugs such as cephalosporins and aminoglycosides. This paper describes a study in which management of infection was subjected to the following guidelines: (a) vigorous efforts had to be made for early recognition of infections and their responsible pathogenic microorganisms; (b) indications for the use of antimicrobial agents were restricted to identified infections (prophylactic use was not permitted); (c) in the choosing of treatment the most elective drugs had to be selected first; and (d) the combined use of antibiotics was limited to polymicrobial or life-threatening infections when results of cultures were not yet available. Patients and methods From November 1972 to December 1975, 44 renal homotransplantations were performed in 42 patients (29 men and 13 women) at H6telDieu de Quebec. Patients were divided into two groups according to graft origin: the 34 patients in group A, aged 19 to 54 years (median 36
426 CMA JOURNAL/FEBRUARY 17, 1979/VOL. 120
years), received 36 cadaver grafts; and the 8 patients in group B, aged 25 to 44 years (median 35 years), each received a kidney from a living relative. Determination of HLA transplantation antigens in both donors and recipients yielded in group A a twoantigen match in 14 patients, a oneantigen match in 14 and no match in 7 (one donor was not HLA-typed). In group B seven patients were HLAidentical, and negative results were obtained in mixed lymphocyte culture; the remaining patient shared three antigens with his donor, and positive results were obtained in mixed lymphocyte culture. The basic immunosuppressive therapy included prednisone at a starting daily dose of 1.0 mg/kg in group A and 0.5 mg/kg in group B. The daily dose was tapered to 0.25 mg/kg within 2 months. Azathioprine, 1.5 to 3.0 mg/kg daily, according to the leukocyte count, was administered to both groups. For a rejection crisis the daily dose of prednisone was increased to 2.0 to 3.0 mg/kg for 5 days, then decreased rapidly to the pretreatment level. One to four 1 -g intravenous boluses of methylprednisolone were also given in a 2-day schedule. No more than two rejection episodes were treated in the first 3 months after transplantation. No patient in the study received antilymphocyte globulin, and two underwent splenectomy before grafting. Urinary tract infection was defined as the growth of at least 100 000 colonies/mL of the same organism from two or more urine specimens collected 24 hours apart, with or without symptoms. Relapse was considered to have occurred when the same organism grew 8 or more days after successful treatment, as defined by sterility of the urine. Graft pyelonephritis was suspected in patients with urinary tract infec-
Differences in results between don when three of the five following criteria were met: fever, positive blood groups and between intervals were culture with the organism found in evaluated by the chi-square method.2 the urine, deterioration of renal function without graft rejection, swelling Results Of the 42 patients 2 died. The of the graft without rejection, and an intravenous pyelogram suggestive of first, in group B, died on the 714th infection. Septicemia was defined as postoperative day of staphylococcal sustained bacteremia (i.e., growing septicemia originating from a urinary of the same organism in two blood tract infection; he had also had chronic active hepatitis with hepatitis cultures 24 hours apart). In all recipients preoperative pul- B surface antigenemia. The second, monary roentgenograms were made in group A, died of an iliac artery and cultures were done of urine, rupture on the 67th postoperative blood, and swabs of anterior nares, day, 5 days after graft removal; no throat, anus and any apparently in- local infection was detectable. Twelve fected skin lesion. Pulmonary roent- grafted kidneys had to be removed genograms were made and urine during the study because of rejection. cultures done daily for the first week after transplantation and three times a week thereafter for the rest of the 8 7 6 100hospital stay (usually 3 to 4 weeks); 90when intravenous and bladder catheters were drawn out, the tips were GRAFTS 80- 36 cultured. Suspected infection led to SURVIVAL 27 7021 14 (%) appropriate sampling. Susceptibility 60of bacteria to antibiotics was determined by the Kirby-Bauer method.1 50Infections were treated only when clearly diagnosed clinically or microbiologically or both. In some cases antibiotics were administered before I I culture results were available, on the 3 6 12 18 basis of the clinical evaluation and the results of direct microscopic examination of smears. Medication was FIG. 1-Graft survival in 42 patients chosen according to the usual criteria, patients with 36 cadaver grafts; group including the determined or predicted a living relative. Numbers over points susceptibility of the pathogen. As far kidneys at beginning of intervaL as possible, drugs with a narrow antibacterial spectrum were chosen and combined therapy was avoided. The preventive use of antimicrobial agents was limited to irrigation, with bacitracin. of the bladder preoperatively and of the surgical wound before closure, and to the gargling and swallowing of nystatin, 500 000 units three times a day. For each transplantation the observation period extended from the day of grafting until the removal of the transplanted kidney, the patient's death or Mar. 31, 1976, whichever was first. This period was further divided into two intervals: interval 1, from day 1 to day 90 after transplantation, and interval 2, from day 91 to the last day. 430 CMA JOURNAL/FEBRUARY 17, 1979/VOL. 120
A 13th kidney was lost in the patient who died of septicemia. The mean graft survival rate was 64.8% for group A after 36 months and 75% for group B after 42 months (Fig. 1). On Mar. 31, 1976, 31 patients had functioning allografts and 9 were again receiving long-term hemodialysis. We recorded 124 infections; 110 were bacterial, 11 viral and 3 protozoal (Table I). No systemic fungal infection was observed, and five patients remained free of infection. After statistical analysis bacterial infections appeared to be significantly more frequent in interval 1 than in interval 2 (P < 0.001) and in group
5
3
3
10
5
1
24
30
36
2
I
42
TIME (months)
with renal transplants. Group A = 34 B = 8 patients with 1 graft each from of curves represent numbers of grafted
A than in group B (P
