Continuous Sulfa Prophylaxis for Urinary Tract Infection

In Renal Transplant Recipients

Charles Peters, MD, Minneapolis, Minnesota

Phillip Peterson, MD, Minneapolis, Minnesota

Patrick Marabella, MD, Minneapolis, Minnesota

Richard L. Simmons, MD, Minneapolis, Minnesota

John S. Najarian, MD, Minneapolis, Minnesota

Infecti.on is cited as one of the most common post- operative complications of renal transplantation with the urinary tract being most frequently involved [I]. This complication may lead to bacteremia and pos- sibly an increased rate of rejection [2], both of which may contribute to decreased graft survival. Efforts to reduce this potential morbidity include meticulous attention to surgical detail during the operative procedure and careful postoperative wound man- agement. A role for prophylactic antibiotics also warrants consideration, because a recent report has suggested that postoperative coverage for at least 4 months significantly lowers the incidence of urinary tract infections [3].

Since the early 19709, all renal transplant patients at the University of Minnesota have been maintained with continuous sulfa antibiotic prophylaxis. Allergy or intolerance to sulfas resulted in the administration of an alternative agent for continuous prophylaxis. The intended rationale was to lower the incidence of urinary tract infection. In the mid 197Os, it was ob- served that the renal transplant population was ex- periencing a very low infection rate with Pneumo- cystis carinii, Nocardia, Listeria monocytogenes, and Toxoplasma gondii. This observation coincided with the appearance of randomized studies that docu- mented the effectiveness of combination trimetho- prim and sulfamethoxazole as effective prophylaxis against urinary tract infection in high-risk women [4], as well as against pneumocystosis [5] and gram- negative sepsis [6] in immunocompromised patients. Given these reports, in May 1979 the University of

From the w of Surgery and Medicine, The Uniiersity of Minnesota, Minneapolis, Minnesota.

Requests for reprints should ba addressed to John S. Najarian, MD, De- partment of Surgery, University of Minnesota, 516 Delaware Street SE, Minneapolis, Minnesota 55455.

Minnesota Transplant Service changed its prophy- lactic regimen from sulfisoxazole to trimethoprim- sulfamethoxazole, a protocol that has continued. This antibiotic combination, which blocks two different steps during bacterial folate metabolism, was adopted to provide potentially improved protection against urinary tract infection. Because of the per- ceived benefits of continuous sulfa prophylaxis, a placebo-controlled randomized study was not un- dertaken. The object of the present study and report was to retrospectively investigate the incidence of positive urine cultures which lead to treatment among outpatients, and to see if the two sulfa agents used could be distinguished in terms of effectiveness or associated complications.

Material and Methods

Protocol: Antibiotics. Once the peritransplant ileus resolved, all patients were given antibiotic prophylaxis. For recipients before May 1979 with no previous history of sulfa intolerance, therapy with 1 g four times a day of sulfisox- azole was begun, being reduced to 1 g twice a day after 1 year (or after 2 years if the recipient was diabetic). Starting in May 1979, the posttransplant antibiotic regimen was trimethoprim-sulfamethoxazole, maintained at 1 tab (trimethoprim 80 mg, sulfamethoxozole 400 mg) twice a day. After mid 1979, 16 patients who had been receiving sulfisoxazole were changed to the trimethoprim-sulfa- methoxazole regimen. The dose of sulfa was reduced or there was a change to another antibiotic if the recipient experienced a persistent elevation in serum creatinine (above 3 mg/lOO ml), an elevation in liver function test values, or unexplained hyperkalemia. If the patient had a history of pretransplant or posttransplant intolerance to sulfas, an alternative antibiotic was substituted, such as cephalexin, nitrofurantoin, or tetracycline.

Zmmunosuppressants. Peritransplant immunosup- pressant regimens have been previously described [ 71. Most of the outpatients were maintained with azathioprine and

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TABLE I Changes in Antibiotic Regimens During Two TABLE II Dosage Alterations During Two Prophylactic Prophylactic Antibiotic Study Periods Antibiotic Study Periods

SSZ TMP-SMZ Total SSZ TMP-SMZ Total

Patients originally given sulfas 126 126 252

Patients withdrawn from sulfas 7 5 12 Reason

Allergy 3 3 6 Elevated liver function test values 0 2 Elevated creatinine level 3 0 E Other complications 1 0 1

Patients changed to another sulfa 16 4 22 Reason

Allergy 1 1 2 Other complications 1 3 4 Routine change 16 0 16

Patients continuing original sulfa 101 117 216 regimen

SMZ = sulfamethoxazole; SSZ = sulfisoxazole; TMP-SMZ = trimethoprim-sulfamethoxazole.

prednisone; 10 of them also received total lymphoid irra- diation because of a previous transplant having been lost to early rejection [B]. One patient received cyclophos- phamide initially because of alleged ptetransplant aza- thioprine intolerance, and other patients later required a change to cyclophosphamide after transplantation. During the time periods being studied, only six patients began receiving the recently introduced agent, cyclosporine. Doses of immunosuppressant were adjusted to keep the total white blood cell count greater than 5,000 cells/mm3. If the white blood cell count neared or fell below 3,000 cells/mms, the agent was stopped until a rebound in the white blood cell count allowed resumption of immuno- suppression.

Infection: This study records the incidence of urine cultures displaying more than lo5 organisms/mm3 (bac- teriuria) that required outpatient treatment using con- ventional antibiotics, selected usually on the basis of ap- propriate sensitivities. Such cultures were obtained rou- tinely during an outpatient clinic visit at 3 months and at yearly intervals after transplantation. Otherwise, cultures were obtained during evaluation of febrile episodes or other suspected illnesses, with the workup being performed by physicians at the University of Minnesota or by the pa- tient’s local physician.

Patient population: Two patient populations were studied according to whether the sulfa originally begun was sulfisoxazole or trimethoprim-sulfamethoxazole. During the 13 months before May 1979,162 recipients underwent renal transplantation and began receiving sulfisoxazole. This cohort was followed for the next 12 months (through April 1980). A second group of 148 recipients who received renal transplants during a 13 month period after May 1979 began receiving trimethoprim-sulfamethoxazole prophy- laxis and were also followed for a 12 month period (through June 1981). A 12 to 25 month follow-up period was there- fore available for two groups of patients maintained with continuous sulfa prophylaxis.

Certain patients were excluded from the study. Among those not studied were 19 pediatric patients who under- went transplantation at age 12 years or younger, 15 patients whose grafts were not functioning at the time of discharge after renal transplantation, 11 recipients who could not

Patients completing course with original 101 117 216 sulfa

Temporary change to nonsulfa antibiotic 3 6 9 Reason

Elevated creatinlne level 0 1 1 Elevated liver function test values 1 0 1 Elevated potassium level 0 2 2 Other complications 2 3 5

Dosage reduced 50 6 56 Reason

Elevated creatinine level 0 5 5 Elevated liver function test values 0 1 Routine change 50 0 5:

Stable dosaae 46 105 153

SMZ = sulfamethoxazole; SSZ = sulfisoxazole; TMP-SMZ = trimethoprim-sulfamethoxazole.

begin sulfa prophylaxis because of allergy, and 13 patients whose outpatient course was incompletely documented or characterized by frequent urinary tract manipulation in- volving catheters. The total number of patients available for study, therefore, was 126 for each group.

Results

Antibiotic changes: Of the 252 recipients who began receiving sulfas, 5 percent were changed to nonsulfa agents (Table I) because of either an allergy (usually a rash, in 2 percent), or some other compli- cation (persistent elevation in liver function test values or creatinine). Some patients underwent change to an alternative sulfa (6 percent of sulfisox- azole patients had a routine change to trimetho- prim-sulfamethoxazole).

Two hundred eighteen recipients continued re- ceiving the original sulfa during the follow-up peri- ods. A temporary change to a nonsulfa agent was made in 4 percent (because of transient biochemical changes, as noted in Table II). The dosage was re- duced in 4 percent of the patients receiving tri- methoprim-sulfamethoxazole because of extremely elevated creatinine levels. Fifty percent of the pa- tients receiving sulfisoxazole had grafts functioning long enough to undergo the routine dose reduction already mentioned. Ninety-three percent of the pa- tients remained free of any complications requiring departure from the routine dosage schedule.

Bacteriuria: Of the 126 patients who originally received sulfisoxazole and were followed for an av- erage of 15.7 f 0.7 months (mean f standard error of the mean), 7.9 percent (7 women and 3 men) dis- played bacteriuria that was treated with conventional antibiotics, usually for 14 days. Only two patients reported urinary tract symptoms, and recurrence developed in one woman as a result of an incom- pletely eradicated initial organism. The postitive cultures occurred an average of 8.8 f 1.6 months after

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Urinary Tract Infections

TABLE III Characteristics of Renal Transplant Patients Receiving Sulfa Prophylaxis

Average Cadaver HLA-A and -B Diabetes

study Follow-Up Donors Mismatch Mellitus Splenectomy Nephrectomy Age (yr)

Period Bacteriuria n (mo) (“/) (n) (“/) (“/) (%) at TP

ssz 116 15.1 41.4 1.3 45.7 54.8 34.2 34.2

f0.6’ fO.l fl + 10 21.7 30.0 1.2 40 77.8 22.2 40.9

fl f0.3 f3.5 TMP-SMZ - 121 16.9 40.5 1.2 38.8 69.4 38.5 32.1

f0.5 fO.l f0.9 + 5 17.2 60.0 1.4 20.2 80 40 38.2

f0.9 f0.5 f3.2

l Mean f standard error of the mean. SSZ = sulfisoxazole; TMP-SMZ = trimethoprim-sulfamethoxazole; TP = transplant; -I- = present: - = absent.

transplantation. During the follow-up period, the actual graft survival was 76 percent.

Of the 126 patients who originally received tri- methoprim-sulfamethoxazole and were followed for an average of 16.9 f 0.5 months, 4 percent (5 women) displayed bacteriuria which required conventional antibiotics. All were asymptomatic, and one patient experienced four recurrences. The infections oc- curred 9.1 f 1.5 months after transplantation. During the 12 to 25 month follow-up period, the actual graft survival was 82 percent.

Among the recipients in both antibiotic groups, patients in whom bacteriuria developed were slightly older and had a higher incidence of splenectomy than those patients who were free of infection. These dif- ferences (Table III), however, were not significantly different, nor were the differences in donor source (cadaver versus living related), HLA-A and -B anti- gen mismatch, associated diabetes mellitus, or pre- vious nephrectomy.

The organisms which caused bacteriuria are indi- cated in Table IV. Of the identified pathogens, gram-negative bacteria occurred in 50 percent of the cultures from the sulfisoxazole group, and in only 13 percent of the cultures from the trimethoprim-sul- famethoxazole group (difference was not signifi- cant).

Immunosuppressant changes: Change in the immunosuppressant from azathioprine to cyclo- phosphamide was required in 2 percent of the pa-

tients during the sulfisoxazole period, and in 4 per- cent during the trimethoprim-sulfamethoxazole period. In three fourths of these instances, the reason was persistent elevations in liver function test values.

Temporary withholding of azathioprine was re- quired in two situations. When leukopenia developed in the peritransplant period, azathioprine was dis- continued by the time of initial discharge in 9 percent of the patients receiving sulfisoxazole and in 13 percent of those receiving trimethoprim-sulfa- methoxazole. With no change in antibiotic dosage, leukopenia remitted which allowed the resumption of azathioprine prophylaxis an average of 3.7 f 0.4 and 2.9 f 0.4 weeks posttransplant for the sulfisox- azole and trimethoprim-sulfamethoxazole groups, respectively. Total lymphoid irradiation was not used in nine patients who were receiving trimethoprim- sulfamethoxazole. Azathioprine was similarly dis- continued at discharge in 22 percent of the patients who underwent total lymphoid irradiation and was resumed 5.5 f 1.1 weeks after discharge. The other situation that required the withholding of immuno- suppressants arose later in the posttransplant period when leukopenia supervened. Of the patients re- ceiving sulfisoxazole, 25 percent encountered leu- kopenia. It first occurred an average of 2.8 f 0.8 months after transplantation (average of 1.5 episodes per patient) and lasted an average of 13.5 f 2.2 days. For patients receiving trimethoprim-sulfamethox-

TABLE IV Bacteriuria in Renal Transplant Patients Receiving Sulfa Prophylaxis

Staphylococcus Coagulase-

Negative Unspecified a-streptococcus Corynebacterium E. coli Unknown

ssz Women 1 2 0 0 3(4)’ 1 Men 0 0 2 0 1 0

TMP-SMZ Women only 2(5)+ 1+ 0 1 1 1

l One patient had two episodes of bacteriuria which lead to four infections in three patients. + One patient had four episodes of bacteriuria with coagulase-negative staphylococcus and one episode with unspecified staphylo-

coccus. SSZ = sulfisoxazole; TMP-SMZ = trimethoprim-sulfamethoxazole.

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azole, 14 percent required temporary discontinuance of azathioprine because of leukopenia which first occurred an average of 4.8 f 1.2 months after trans- plantation, (average of 1.3 episodes per patient) and lasted an average of 7.2 f 1.8 days. For the nine pa- tients who underwent total lymphoid irradiation, 56 percent required temporary cessation of azathioprine for leukopenia which first occurred an average of 2 f 0.4 months after transplantation (average of 2.2 episodes per patient) and lasted 28.7 f 9.8 days per episode. The withholding of immunosuppressive agents because of leukopenia was not required for any of the six patients receiving cyclosporine plus trimethoprim-sulfamethoxazole. Temporary dis- continuance of cyclophosphamide, however, was required for three of four patients receiving sulfi- soxazole, due to leukopenia which was first encoun- tered an average of 11.3 f 3.6 months after trans- plantation, with an average of 1.3 episodes per re- cipient. Each episode lasted an average of 8.8 f 3.5 days.

Comments

This retrospective study documents that in a standardized protocol using continuous antibiotic prophylaxis after renal transplantation, a low inci- dence of bacteriuria occurs, with minimal compli- cations attributable to antibiotic exposure. Of 252 recipients followed over a 12 to 25 month period after transplantation, bacteriuria occurred in 6 percent and cleared with conventional antibiotics adminis- tered on an outpatient basis. Trimethoprim-sulfa- methoxazole may be preferable to sulfisoxazole be- cause of the former’s lower infection rate (4 percent versus 7.9 percent, respectively). The combination agent is inexpensive, easy to administer twice a day and, in comparison to sulfisoxazole, appears to result in fewer gram-negative organisms on culture speci- mens. During the same 12 to 25 month time period, two patients receiving sulfisoxazole and trimetho- prim-sulfamethoxazole were readmitted for other reasons and also demonstrated bacteriuria on ad- mission which required parenteral antibiotic therapy (Pseudomonas aeruginosa in one patient and Esch- erichia coli plus enterococcus in the other). Another patient receiving sulfisoxazole with asymptomatic P. aeruginosa bacteriuria was specifically admitted for parenteral therapy. The addition of these three patients to those already mentioned lead to an overall incidence of urinary infection of 7.1 percent. For those patients who continued to receive sulfa pro- phylaxis, there were no instances of hospitaliza- tion for treatment of pneumocystosis, listeriosis, nocardiosis, toxoplasmosis, or legionnaires’ disease PI.

When comparing our figures for bacteriuria with those reported in the literature, it is important to note that in our study, treatment was based on the result of a single culture (with a single organism

predominating). Other studies have required a repeat culture displaying the same organism for documen- tation of a urinary tract infection [1,3]. Typical uri- nary tract symptoms or pyuria have usually not been considered necessary for documentation, since these are present in only a minority of immunosuppressed patients with urinary infection [I]. Furthermore, attention must be directed to the time frame over which bacteriuria is being sought, since longer peri- ods will understandably be associated with higher rates of infection [IO].

Complications from antibiotic prophylaxis were few and were easily managed. Symptoms suggestive of sulfa allergy were reported in 2.6 percent of pa- tients before use of an alternative agent was required, whereas posttransplant intolerance (usually a rash) developed in 2.4 percent of patients and resolved when a nonsulfa agent was substituted. Interstitial nephritis suggesting sulfa hypersensitivity [II] was not observed in any patient maintained with sulfa prophylaxis. Metabolic complications (increase in creatinine level or liver function test values) occurred in 2.6 percent of the patients, and resulted in a change to a nonsulfa agent. It was not documented that any metabolic deterioration was directly at- tributable to sulfa toxicity necessitating withdrawal from a sulfa agent. The need to change from azathi- oprine to cyclophosphamide occurred in only 3.1 percent of patients (sulfisoxazole patients 2 percent, trimethoprim-sulfamethoxazole 4 percent), usually reflecting hepatitis and, only infrequently, leuko- penia. Temporary withholding of azathioprine sec- ondary to leukopenia was more commonly required, occurring at discharge in 11 percent of patients and at some other time during the outpatient course in 20 percent. The incidence of such azathioprine-re- lated marrow suppression was similar in the sulfi- soxazole and trimethoprim-sulfamethoxazole groups. Previous administration of total lymphoid irradiation more than doubles this temporary need to discon- tinue azathioprine because of the documented effects of total lymphoid irradiation on marrow suppression. With the low doses of trimethoprim-sulfamethoxa- zole used in this study and others [3], plus the dis- continuance of sulfas in patients with high creatinine levels, the neutropenia and thrombocytopenia re- ported in a recent study [12] were not observed in our patient population.

Continuous sulfa prophylaxis in renal transplant patients has been found to be both safe and effective in minimizing the incidence of urinary tract infection as well as other opportunistic infections known to be treatable by sulfa agents. Significant renal or marrow toxicity from sulfas has not been encountered in patients maintained with azathioprine. As cyclos- porine is being increasingly used as an alternative to azathioprine, the sulfa prophylactic protocol is being continued. Documentation of its safety and effec- tiveness in this setting remains to be investigated.

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Urinary Tract Infections

Summary

During a 12 to 25 month follow-up period, 252 renal transplant recipients maintained with contin- uous sulfa prophylaxis were observed for evidence of bacteriuria. Although symptoms were rare, positive cultures were obtained in 6 percent of the patients who responded to conventional antibiotic outpatient therapy. Compared with sulfisoxazole, trimetho- prim-sulfamethoxazole led to slightly fewer infec- tions, especially with gram-negative organisms. Toxicity from sulfa was minimal, and occasional leukopenia reversed by temporarily withholding azathioprine. Continuous sulfa prophylaxis in renal transplant patients is therefore safe and effective in minimizing the incidence of urinary tract infection, as well as other opportunistic infections known to be treatable by sulfa agents.

References

1. Ramsey DE, Finch WT, Birch AG. Urinary tract infections in renal transplant recipients. Arch Surg 1979; 114: 1022-5.

2. Simmons RL, Weil R, Tallent MB, et al. Do mild infections trigger the rejection on renal allografts? Transplant Proc 1970;2: 419-23.

3. Tolfoff-Rubin NE, Cosimi AB, Russell PS, et al. A controlled study of trimethoprim/sulfamethoxazole prophylaxis of urinary tract infection in renal transplant patients. Rev Infect

Dis 1982;4:814-8. 4. Harding GKM, Buckwold FJ, Marrie TJ, et al. Prophylaxis of

recurrent urinary tract infection in female patients: efficacy of low-dose, thrice-weekly therapy with trimethoprim-sul- famethoxazole. JAMA 1979:242:.1975-7.

5. Huahes WT. Kuhn S. Chaudharv S. et al. Successful chemo- prophylaxis for pneumocystis carinii pneumonitis. N Engl J Med 1977;297:1419-26.

6. Gewurth MJ, Brunton JL, Lank BA. et al. A prospective con- trolled investigation of prophylactic trimethoprimlsulfa- methoxazole in hospitalized granulocytopenic patients. Am J Med 1979;66:248-56.

7. Simmons RL, Kjellstrand CM, Najarian JS. Kidney transplan- tation: technique, complications, and results. In: Najarian JS, Simmons RL, eds. Transplantation. Philadelphia: Lea and Febiger, 1972:445-95.

8. Najarian JS, Ferguson RM, Sutherland DER, et al. Fractionated total lymphoid irradiation as preoperative immunosuppres- sion in high risk renal transplantation: clinical and immuno- logical studies. Ann Surg 1982;196:442-52.

9. Peterson PK, Ferguson RM, Fryd DS, et al. Infectious diseases in hospitalized renal transplant recipients: a prospective study of a complex and evolvina oroblem. Medicine 1982; 61:360-72.

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10. Griffin PJA, Salaman JR. Urinary tract infections after renal transplantation: do thev matter? Br Med J 1979; I:7 10-I.

1 I. Smith EJ, Light JA. Filo RS, et al. Interstitial nephritis caused by trimethoprim-sulfamethoxazole in renal transplant re- cipients. JAMA 1980;244:360-1.

12. Bradley PP, Warden GD, Maxwell JG, et al. Neutropenia and thrombocytopenia in renal allograft recipients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1980;93: 560-2.

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