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Diagnosis and Treatment of Infection in Cardiac Transplant Patients
Organ Transplantation
0039-6109/86 $0.00
+ .20
Diagnosis and Treatment of Infection in Cardiac Transplant Patients
Layne O. Gentry, M.D.,* and Barry]. Zeluff, M.D.t
Infections continue to be the most common cause of death after cardiac transplantation and account for more than half the deaths in the first 90 days after transplantation. 4 Although the incidence of infection is somewhat lower after the first 90 days have passed, the incidence of all infection continues to be related to the level of immunosuppression and is definitely increased following attempts to suppress acute organ rejection episodes. There is uniform agreement, however, that the overall incidence of infection has decreased with the introduction of cyclosporine as the major component of immunosuppressive therapy used following transplantation. An important additional factor in the overall reduction of infectious complications and death can be attributed to the cumulative experience that has been collected with all infections in the various types of transplantation patients. During the past decade, recognizable clinical patterns of infections occurring both early and late after renal, bone marrow, and cardiac transplantation have been published, and newer and more potent antimicrobial agents have become available, including broad-spectrum antibacterials, antivirals, and antifungals. ., The addition of sophisticated diagnostic equipment, such as the CT scanner and certain nuclear imaging techniques, has also had a significant impact on the transplant patient. Experience with the flexible bronchoscope has increased our ability to obtain appropriate secretions and/or tissues without increased morbidity in the patient with the onset of fever and a pulmonary infiltrate. A more complete understanding of newer, readily curable infections such as those caused by Legionella pneurrwphila, which have been identified as common causes of pulmonary infection in immunosuppressed patients, has contributed to patient survival. Serologic tests and other microbiologic tools have also become available, and the early use *Associate Professor of Medicine, Division of Infectious Diseases, St. Luke's Episcopal Hospital, Houston, Texas t Assistant Clinical Professor of Medicine, Division of Infectious Diseases, St. Luke's Episcopal Hospital, Houston, Texas
Surgical Clinics of North America-Vol. 66, No.3, June 1986
459
460
LAYNE
O.
GENTRY AND BARRY
J.
ZELUFF
of these diagnostic tests frequently provides the necessary information that stimulates us to initiate specific therapy. The purpose of this article is to update the practicing physician on the frequent and often perplexing infections that occur in the cardiac transplant patient.
PROPHYLACTIC ANTIBIOTICS FOR SURGERY Most modern cardiovascular surgery services use some form of antibiotic prophylaxis for patients undergoing surgical procedures that involve cardiopulmonary bypass. Because cardiac transplantation is such an operation, it has been a natural trend to include this type of surgery in routine prophylactic antibiotic orders. The choice of prophylactic antibiotic agents varies from center to center, but in general, broad-spectrum cephalosporins have continued to be widely used for cardiovascular surgery. In our initial experience, cefamandole (Mandol), 2 gm intravenously every 6 hours, starting preoperatively in the surgical suite and continuing for a total of eight doses, was used routinely in all cardiac transplant patients. After approximately 1 year of this routine prophylaxis, we began to notice an increasing number of pulmonary and pleural space infections caused by Enterobacter cloacae, an organism that is consistently resistant to cefamandole. This organism has been consistently isolated in our postoperative recovery and intensive care areas for the past 2 years. After our experience with two cardiac transplant patients who subsequently required further decortication procedures, because of E. cloacae empyema, we elected to change our prophylaxis from cefamandole to cefotaxime (Claforan), 2 gm intravenously every 6 hours, starting in the surgical suite and continuing for at least 8 doses, because of its increased antibacterial spectrum and particularly because of its activity against our hospital strains of E. cloacae. Since making this change, we have had no further difficulty with significant pulmonary or pleural space infection caused by E. cloacae. Because the causes of hospital-acquired infections vary from center to center, such prophylaxis may not be appropriate in other medical centers where E. cloacae and similar resistant gram-negative organisms do not commonly occur. We recommend that the choice of antibiotic prophylaxis be based on a thorough evaluation of the common causes of postoperative infection, particularly in the recovery and intensive care areas of the transplantation center. The duration of antibiotic prophylaxis has also remained controversial and varies from three doses given on the first day to as many as 20 doses given over several days. The experience in our center has suggested to us that there is some correlation between the duration of indwelling chest tubes, intravenous lines, and indwelling urinary catheters and the incidence of hospital-acquired infection. Our current approach to this problem is to continue the prophylaxis until the chest tubes are removed. In some specialized cases, where chest tubes need to remain in place because of underlying complications, we have discontinued prophylaxis prior to chest tube removal. In addition, should the patient require reoperation or further chest manipulation, we reinstitute prophylaxis if it
DIAGNOSIS AND TREATMENT OF INFECTION IN CARDIAC TRANSPLANT PATIENTS
461
becomes apparent that the patient will recover in a patient care area where hospital-acquired infections create an additional risk.
INFECTIONS FROM THE DONOR ORGAN Donor organs infected with Toxoplasma gondii, cytomegalovirus, and herpesviruses have all been documented. Documentation of donor-transmitted cases of toxoplasmosis is important to recognize because treatment with the combination of sulfisoxazole (1 gm intravenously every 6 hours) and pyrimethamine (50 mg every day) will effectively prevent total dissemination of this infection. However, the duration of treatment with these two agents remains controversial, but it has been our policy to continue treatment for approximately 1 month after the diagnosis has been established. There is no currently available therapy for any of the viral infections transmitted in this manner.
INFECTIONS OCCURRING IN THE FIRST MONTH AFTER TRANSPLANTATION Bacterial infections are the most common group encountered during this early period. In contrast to the difficulty encountered in the renal transplant patient, wound infections in the cardiac transplant patient are relatively uncommon and occur in as few as 3.6 per cent of the patients. 2 In our experience to date, the most significant wound infections encountered have been one sternotomy infection caused by Staphylococcus aureus and two pleural space infections caused by E. cloacae. Since modifying our antibiotic prophylaxis, we have had no further significant wound infections.
INTRAVASCULAR CATHETEl\-ASSOCIATED INFECTIONS The cardiac transplant patient frequently has multiple central venous lines in place, which unfortunately must often be kept there for longer than 72 hours. Bacteremia and candidemia associated with these lines have been encountered in our transplant patients, and the current incidence is approximately the same as in nonimmunosuppressed patients who are in our intensive care facilities. Of the gram-negative infections, E. coli, Serratia marcescens, and Pseudomonas aeruginosa are the most commonly encountered. S. aureus and Candida albicans are also common causes of these cathete.o-associated infections. 2 Such infections are relatively easy to identify, as the patient presents with a febrile illness without an obvious source of infection. Upon removal of the infected catheter, the patient usually becomes afebrile, and subsequent cultures of the tip of the catheter usually reveal the causative pathogen. Once this information is available, we try to use specific, rather than broad-spectrum, antibiotic therapy. The duration of antibiotic therapy for such infections continues to be controver-
462
LAYNE
O.
GENTRY AND BARRY
J.
ZELUFF
sial; however, it has been our policy to continue parenteral therapy for a minimum of 10 days or until the patient has been afebrile for 5 to 7 days. URINARY TRACT INFECTION Infection of the urinary tract is much less of a problem in the cardiac transplant patient than in the renal transplant patient. 16 The risk of urinary tract infection is directly related to the presence of the indwelling bladder catheter. E. coli is the most common organism, followed by Proteus spp., Klebsiella pneumoniae, and P. aeruginosa. In addition, we commonly encounter the Group D Enterococcus and C. albicans, especially in those in whom the long-term indwelling catheters have been in place in the hospital. Removal of the catheter as soon as possible after surgery is the best way to prevent such infections; however, if infection is documented after the catheter is removed, we would suggest treatment with the appropriate antibiotics for 7 to 10 days. Occasionally, recurrent infection will be documented. In the male patient, the prostate may be a common site from which recurrent infection can occur. The use of specific antibiotic therapy that penetrates well into prostatic tissues for 2 to 4 weeks frequently will resolve the prostatitis and stop the recurrence. PNEUMONIA Pulmonary infections are by far the most common problem in all transplant patients but appear to be more specifically the problem in the cardiac transplant patient. The presence of underlying lung disease, prolonged endotracheal intubation, increased immunosuppression for acute rejection, and associated generalized diseases such as diabetes and arteriosclerotic heart disease are thought to influence this increased incidence of pneumonia. Gram-negative bacteria, usually hospital-acquired strains, continue to be the most common cause of pneumonia in this early posttransplant period. 17 Because these patients have frequently been hospitalized in other institutions or have had previous endotracheal intubation, we rely on routine surveillance cultures in the immediate postoperative period to guide us in determining the appropriate antibiotic therapy for any episodes of acute pneumonia that occur. Similarly, prior to the removal of chest tubes, we routinely culture chest tube drainage to determine if there has been any evidence of colonization by these nosocomial pathogens. The careful daily review of sequential radiographs is probably the most important feature in the early detection of pneumonia. CARDIAC TRANSPLANT PATIENTS WITH ACUTE REJECTION EPISODES WITHIN THE FIRST MONTH The more unusual pathogens, such as Pneumocystis carinii, Aspergillus spp., Nocardia spp., and Legionella spp., must be included in the differ-
DIAGNOSIS AND TREATMENT OF INFECTION IN CARDIAC TRANSPLANT PATIENTS
463
ential diagnosis of any cardiac transplant patient with pulmonary infection during this period related to the treatment of an episode of acute rejection. In the patient who has an interstitial infiltrate that is diffuse and progresses rapidly, it is frequently necessary to perform bronchoscopy with transbronchial biopsy and/or bronchial brushing to detect the pathogen responsible for such infections. In patients in whom inadequate tissue is obtained or in those patients who are critically ill, the most rapid and safest diagnostic technique is frequently open lung biopsy.g, 14, 15
INFECTIONS OCCURRING MORE THAN 1 MONTH AFTER TRANSPLANTATION Pneumocystis carinii pneumonia has consistently been the most common late pulmonary infection encountered in most cardiac transplant series. 1, 6,13 A diffuse interstitial infiltrate with associated hypoxemia should make one consider the diagnosis of P. carinii pneumonia. Early transbronchial biopsy will frequently demonstrate the presence of organisms with the methenamine silver stain. This infection can be rapidly fatal if not recognized and treated early. The differential diagnosis of interstitial pneumonia occurring more than 1 month after transplantation should also include viral infections such as cytomegalovirus and Herpes simplex. 17 Of these two, herpes infection is treatable with currently available antiviral therapy. 12, 1S-20 It is therefore important to have an actual culture diagnosis to document the presence of this treatable virus. Although serologic tests to detect herpes antibody are available, such data have not been helpful in the diagnosis of acute infections. Infection caused by L. pneumophila has become common in all compromised hosts, including cardiac transplant patients. This infection presents as what initially looks like an interstitial infiltrate and then rapidly progresses to an alveolar infiltrate. Nodular densities are not uncommon, and cavitation has occurred in a few cases. 3 , 5 Culturing Legionella may be difficult, and many laboratories cannot culture these organisms from sputum or tissue. The greatest yield for culture is from tissue taken at the time of open lung biopsy.8 Several serologic techniques have recently been introduced. These include direct fluorescent antibody, as well as an indirect fluorescent antibody test, to determine the presence of active disease or recent infection. 7 Because the diagnosis is sometimes difficult in these patients, it has been common practice to treat patients empirically for L. pneumophila infection with intravenous erythromycin, 500 mg intravenously every 6 hours, while waiting for the fluorescent stains, antibody titers, or culture results. We have encountered numerous cases of Legionella pneumonia in our cardiac transplant patients, including one recurrence after what was initially thought to be a full course of erythromycin treatment. It may be necessary to treat these recurren~es for up to 2 months with oral erythromycin following a clinical relapse. The most serious infection occurring in the late period after cardiac transplantation is caused by the Aspergillus ~pecies. These organisms are so ubiquitous in nature that one is never totally aware of the source for
464
/
LAYNE
O.
GENTRY AND BARRY
J.
ZELUFF
infection. The most common presenting syndrome is that of a nodular infiltrate that enlarges rather rapidly, usually related to a period of increased corticosteroid treatment for acute rejection. The most rapid diagnostic technique in our experience has been a percutaneous needle biopsy of a nodular lesion or a trans bronchial lung biopsy into an area of pulmonary infiltrate. Unfortunately, the treatment for this type of Aspergillus infection in the lung with conventional amphotericin B has been more than disappointing. Six of our seven patients who have been so treated have died, with Aspergillus being identified at autopsy. We have had one survivor who had tissue biopsy evidence of Aspergillus pulmonary infection and who was treated with a new liposomal preparation of amphotericin B. II He is still alive some 11 months later. Further studies with this particular new antifungal agent are ongoing at this time. Pulmonary infection with Nocardia asteroides also occurs in this late period after transplantation. 10 The presence of a pulmonary infiltrate, which enlarges rapidly, is the most common clinical syndrome. Bronchial brushings, trans bronchial lung biopsy, and percutaneous aspiration will frequently reveal the presence of beaded, branching, gram-positive rods. Cultures for N. asteroides are relatively easy to obtain from this material. SUMMARY Despite major advances in the management of rejection and the development of newer and more potent antimicrobials, infection still constitutes a major problem in transplant patients and other immunosuppressed hosts. Infectious complications in transplant patients clearly occur in two phases. The first phase includes the first 30 to 60 days after transplantation. During this period, nosocomial bacterial infections are most commonly encountered. Pulmonary, renal, and wound infections have all been encountered, and prophylactic antibiotics appear to decrease their frequency. Opportunistic infections usually do not occur during this period unless the patient undergoes treatment for acute rejection. The second phase of infectious complications usually follows the first month after transplantation. In this period, the level of immunosuppression is high, and opportunistic infections are common. Opportunistic pulmonary infections caused by P. carinii, L. pneumophila, cytomegalovirus, Aspergillus, and Nocardia spp. all are potentially life-threatening complications to the transplant patient. Aggressive diagnostic tests such as bronchoscopy, percutaneous needle biopsy, or open lung biopsy are frequently needed to make a diagnosis. Empiric broad-spectrum antimicrobial therapy is indicated in the ill patient; however, more specific therapy should be instituted once the diagnosis is confirmed. REFERENCES 1. Bandt, P. D., Blank, N., and Castellino, R. A.: Needle diagnosis of pneumonitis; value in high risk patients. J.A.M.A., 220:1578-1582, 1972.
DIAGNOSIS AND TREATMENT OF INFECTION IN CARDIAC TRANSPLANT PATIENTS
465
2. CaIne, R. Y., Rolles, K., White, D. J. G., et aI.: Cyclosporin A initially as the only immunosuppressant in 34 receipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet, 2:1033-1036, 1979. 3. Carrington, C. B.: Pathology of Legionnaires' disease. Ann. Intern. Med., 90:496-499, 1979. 4. Copeland, D. J., and Stinson, E. B.: Human heart transplantation. Curr. Probl. Cardiol., 3:4-51, 1980. 5. Copeland, W., Wieden, M., Feinberg, W., et al.: Legionnaires' disease following cardiac transplantation. Chest, 79:669-671, 1981. 6. Dummer, J. S., Bahnson, H. T., Griffith, B. P., et a!.: Infections in patients on cyclosporine and prednisone following cardiac transplantation. Transplant. Proc., 15(SuppU and 2):2779-2781, 1983. 7. Edelstein, P. H.: Laboratory diagnosis of Legionnaires' disease. In Thornsberry, C., Balows, A., Feeley, J. c., et al. (eds.): Legionella: Proceedings of the 2nd International Symposium. Washington, D. C., American Society of Microbiology, 1984. 8. Edelstein, P. H., Meyer, R D., and Finegold, S. M.: Laboratory diagnosis of Legionnaires' disease. Am. Rev. Respir. Dis., 121:317-322, 1980. 9. Hedemark, L. L., Kroneberg, R. S., and Rasp, F. L.: The value of bronchoscopy in establishing the etiology of pneumonia in renal transplant recipients. Am. Rev. Respir. Dis., 126:981-985, 1982. 10. Krick, J. A., Stinson, E. B., and Remington, J. S.: Nocardia infection in heart transplant patients. Ann. Intern. Med., 82:18-26, 1975. 11. Lopez-Berestein, G., Fainstein, V., Hopfer, R., et al.: Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: A preliminary study. J. Infect. Dis., 151 :704-710, 1985. 12. Mindel, A., Adler, M. W., Sutherland, S., et a!.: Intravenous acyclovir treatment for primary genital herpes. Lancet, 1:697-700, 1982. 13. Montgomery, J. R, Barrett, F. F., and Williams, T. W.: Infectious complications in cardiac transplant patients. Transplant. Proc., 5: 1239-1243, 1973. 14. Murray, J. R., Felton, C. P., and Garaz, S. M.: Pulmonary complications of the acquired immunodeficiency syndrome. N. Engl. J. Med., 310:1682-1688, 1984. 15. Palmer, D. L., Davidson, M., and Lusk, R: Needle aspiration of the lung in complex pneumonias. Chest, 78:16-20, 1980. 16. Rubin, R H.: Infection in the renal transplant patient. In Rubin, R H., and Young, L. S. (eds.): Clinical Approach to Infection in the Compromised Host. New York, Plenum Press, 1981, pp. 553-606. 17. Stinson, E. B., Bieber, C. P., Griepp, R. B., et al.: Infectious complications after cardiac transplantation in man. Ann. Intern. Med., 74:22-36, 1971. 18. Wade, J. C., Newton, B., McLaren, C., eta!': Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation. Ann. Intern. Med., 96:265-270, 1982. 19. Whitley, R. J., Nahmias, A. J., Soong, S.-J, et al.: Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics, 66:495-500, 1980. 20. Whitley. R. J., Soong, S-J, Hirsch, M. S., et a!.: Herpes simplex encephalitis: Vidarabine therapy and diagnostic problems. N. Engl. J. Med., 304:313-318, 1982. Division of Infectious Diseases St. Luke's Episcopal Hospital 6720 Bertner, Box 233 Houston, Texas 77030
0039-6109/86 $0.00
+ .20
Diagnosis and Treatment of Infection in Cardiac Transplant Patients
Layne O. Gentry, M.D.,* and Barry]. Zeluff, M.D.t
Infections continue to be the most common cause of death after cardiac transplantation and account for more than half the deaths in the first 90 days after transplantation. 4 Although the incidence of infection is somewhat lower after the first 90 days have passed, the incidence of all infection continues to be related to the level of immunosuppression and is definitely increased following attempts to suppress acute organ rejection episodes. There is uniform agreement, however, that the overall incidence of infection has decreased with the introduction of cyclosporine as the major component of immunosuppressive therapy used following transplantation. An important additional factor in the overall reduction of infectious complications and death can be attributed to the cumulative experience that has been collected with all infections in the various types of transplantation patients. During the past decade, recognizable clinical patterns of infections occurring both early and late after renal, bone marrow, and cardiac transplantation have been published, and newer and more potent antimicrobial agents have become available, including broad-spectrum antibacterials, antivirals, and antifungals. ., The addition of sophisticated diagnostic equipment, such as the CT scanner and certain nuclear imaging techniques, has also had a significant impact on the transplant patient. Experience with the flexible bronchoscope has increased our ability to obtain appropriate secretions and/or tissues without increased morbidity in the patient with the onset of fever and a pulmonary infiltrate. A more complete understanding of newer, readily curable infections such as those caused by Legionella pneurrwphila, which have been identified as common causes of pulmonary infection in immunosuppressed patients, has contributed to patient survival. Serologic tests and other microbiologic tools have also become available, and the early use *Associate Professor of Medicine, Division of Infectious Diseases, St. Luke's Episcopal Hospital, Houston, Texas t Assistant Clinical Professor of Medicine, Division of Infectious Diseases, St. Luke's Episcopal Hospital, Houston, Texas
Surgical Clinics of North America-Vol. 66, No.3, June 1986
459
460
LAYNE
O.
GENTRY AND BARRY
J.
ZELUFF
of these diagnostic tests frequently provides the necessary information that stimulates us to initiate specific therapy. The purpose of this article is to update the practicing physician on the frequent and often perplexing infections that occur in the cardiac transplant patient.
PROPHYLACTIC ANTIBIOTICS FOR SURGERY Most modern cardiovascular surgery services use some form of antibiotic prophylaxis for patients undergoing surgical procedures that involve cardiopulmonary bypass. Because cardiac transplantation is such an operation, it has been a natural trend to include this type of surgery in routine prophylactic antibiotic orders. The choice of prophylactic antibiotic agents varies from center to center, but in general, broad-spectrum cephalosporins have continued to be widely used for cardiovascular surgery. In our initial experience, cefamandole (Mandol), 2 gm intravenously every 6 hours, starting preoperatively in the surgical suite and continuing for a total of eight doses, was used routinely in all cardiac transplant patients. After approximately 1 year of this routine prophylaxis, we began to notice an increasing number of pulmonary and pleural space infections caused by Enterobacter cloacae, an organism that is consistently resistant to cefamandole. This organism has been consistently isolated in our postoperative recovery and intensive care areas for the past 2 years. After our experience with two cardiac transplant patients who subsequently required further decortication procedures, because of E. cloacae empyema, we elected to change our prophylaxis from cefamandole to cefotaxime (Claforan), 2 gm intravenously every 6 hours, starting in the surgical suite and continuing for at least 8 doses, because of its increased antibacterial spectrum and particularly because of its activity against our hospital strains of E. cloacae. Since making this change, we have had no further difficulty with significant pulmonary or pleural space infection caused by E. cloacae. Because the causes of hospital-acquired infections vary from center to center, such prophylaxis may not be appropriate in other medical centers where E. cloacae and similar resistant gram-negative organisms do not commonly occur. We recommend that the choice of antibiotic prophylaxis be based on a thorough evaluation of the common causes of postoperative infection, particularly in the recovery and intensive care areas of the transplantation center. The duration of antibiotic prophylaxis has also remained controversial and varies from three doses given on the first day to as many as 20 doses given over several days. The experience in our center has suggested to us that there is some correlation between the duration of indwelling chest tubes, intravenous lines, and indwelling urinary catheters and the incidence of hospital-acquired infection. Our current approach to this problem is to continue the prophylaxis until the chest tubes are removed. In some specialized cases, where chest tubes need to remain in place because of underlying complications, we have discontinued prophylaxis prior to chest tube removal. In addition, should the patient require reoperation or further chest manipulation, we reinstitute prophylaxis if it
DIAGNOSIS AND TREATMENT OF INFECTION IN CARDIAC TRANSPLANT PATIENTS
461
becomes apparent that the patient will recover in a patient care area where hospital-acquired infections create an additional risk.
INFECTIONS FROM THE DONOR ORGAN Donor organs infected with Toxoplasma gondii, cytomegalovirus, and herpesviruses have all been documented. Documentation of donor-transmitted cases of toxoplasmosis is important to recognize because treatment with the combination of sulfisoxazole (1 gm intravenously every 6 hours) and pyrimethamine (50 mg every day) will effectively prevent total dissemination of this infection. However, the duration of treatment with these two agents remains controversial, but it has been our policy to continue treatment for approximately 1 month after the diagnosis has been established. There is no currently available therapy for any of the viral infections transmitted in this manner.
INFECTIONS OCCURRING IN THE FIRST MONTH AFTER TRANSPLANTATION Bacterial infections are the most common group encountered during this early period. In contrast to the difficulty encountered in the renal transplant patient, wound infections in the cardiac transplant patient are relatively uncommon and occur in as few as 3.6 per cent of the patients. 2 In our experience to date, the most significant wound infections encountered have been one sternotomy infection caused by Staphylococcus aureus and two pleural space infections caused by E. cloacae. Since modifying our antibiotic prophylaxis, we have had no further significant wound infections.
INTRAVASCULAR CATHETEl\-ASSOCIATED INFECTIONS The cardiac transplant patient frequently has multiple central venous lines in place, which unfortunately must often be kept there for longer than 72 hours. Bacteremia and candidemia associated with these lines have been encountered in our transplant patients, and the current incidence is approximately the same as in nonimmunosuppressed patients who are in our intensive care facilities. Of the gram-negative infections, E. coli, Serratia marcescens, and Pseudomonas aeruginosa are the most commonly encountered. S. aureus and Candida albicans are also common causes of these cathete.o-associated infections. 2 Such infections are relatively easy to identify, as the patient presents with a febrile illness without an obvious source of infection. Upon removal of the infected catheter, the patient usually becomes afebrile, and subsequent cultures of the tip of the catheter usually reveal the causative pathogen. Once this information is available, we try to use specific, rather than broad-spectrum, antibiotic therapy. The duration of antibiotic therapy for such infections continues to be controver-
462
LAYNE
O.
GENTRY AND BARRY
J.
ZELUFF
sial; however, it has been our policy to continue parenteral therapy for a minimum of 10 days or until the patient has been afebrile for 5 to 7 days. URINARY TRACT INFECTION Infection of the urinary tract is much less of a problem in the cardiac transplant patient than in the renal transplant patient. 16 The risk of urinary tract infection is directly related to the presence of the indwelling bladder catheter. E. coli is the most common organism, followed by Proteus spp., Klebsiella pneumoniae, and P. aeruginosa. In addition, we commonly encounter the Group D Enterococcus and C. albicans, especially in those in whom the long-term indwelling catheters have been in place in the hospital. Removal of the catheter as soon as possible after surgery is the best way to prevent such infections; however, if infection is documented after the catheter is removed, we would suggest treatment with the appropriate antibiotics for 7 to 10 days. Occasionally, recurrent infection will be documented. In the male patient, the prostate may be a common site from which recurrent infection can occur. The use of specific antibiotic therapy that penetrates well into prostatic tissues for 2 to 4 weeks frequently will resolve the prostatitis and stop the recurrence. PNEUMONIA Pulmonary infections are by far the most common problem in all transplant patients but appear to be more specifically the problem in the cardiac transplant patient. The presence of underlying lung disease, prolonged endotracheal intubation, increased immunosuppression for acute rejection, and associated generalized diseases such as diabetes and arteriosclerotic heart disease are thought to influence this increased incidence of pneumonia. Gram-negative bacteria, usually hospital-acquired strains, continue to be the most common cause of pneumonia in this early posttransplant period. 17 Because these patients have frequently been hospitalized in other institutions or have had previous endotracheal intubation, we rely on routine surveillance cultures in the immediate postoperative period to guide us in determining the appropriate antibiotic therapy for any episodes of acute pneumonia that occur. Similarly, prior to the removal of chest tubes, we routinely culture chest tube drainage to determine if there has been any evidence of colonization by these nosocomial pathogens. The careful daily review of sequential radiographs is probably the most important feature in the early detection of pneumonia. CARDIAC TRANSPLANT PATIENTS WITH ACUTE REJECTION EPISODES WITHIN THE FIRST MONTH The more unusual pathogens, such as Pneumocystis carinii, Aspergillus spp., Nocardia spp., and Legionella spp., must be included in the differ-
DIAGNOSIS AND TREATMENT OF INFECTION IN CARDIAC TRANSPLANT PATIENTS
463
ential diagnosis of any cardiac transplant patient with pulmonary infection during this period related to the treatment of an episode of acute rejection. In the patient who has an interstitial infiltrate that is diffuse and progresses rapidly, it is frequently necessary to perform bronchoscopy with transbronchial biopsy and/or bronchial brushing to detect the pathogen responsible for such infections. In patients in whom inadequate tissue is obtained or in those patients who are critically ill, the most rapid and safest diagnostic technique is frequently open lung biopsy.g, 14, 15
INFECTIONS OCCURRING MORE THAN 1 MONTH AFTER TRANSPLANTATION Pneumocystis carinii pneumonia has consistently been the most common late pulmonary infection encountered in most cardiac transplant series. 1, 6,13 A diffuse interstitial infiltrate with associated hypoxemia should make one consider the diagnosis of P. carinii pneumonia. Early transbronchial biopsy will frequently demonstrate the presence of organisms with the methenamine silver stain. This infection can be rapidly fatal if not recognized and treated early. The differential diagnosis of interstitial pneumonia occurring more than 1 month after transplantation should also include viral infections such as cytomegalovirus and Herpes simplex. 17 Of these two, herpes infection is treatable with currently available antiviral therapy. 12, 1S-20 It is therefore important to have an actual culture diagnosis to document the presence of this treatable virus. Although serologic tests to detect herpes antibody are available, such data have not been helpful in the diagnosis of acute infections. Infection caused by L. pneumophila has become common in all compromised hosts, including cardiac transplant patients. This infection presents as what initially looks like an interstitial infiltrate and then rapidly progresses to an alveolar infiltrate. Nodular densities are not uncommon, and cavitation has occurred in a few cases. 3 , 5 Culturing Legionella may be difficult, and many laboratories cannot culture these organisms from sputum or tissue. The greatest yield for culture is from tissue taken at the time of open lung biopsy.8 Several serologic techniques have recently been introduced. These include direct fluorescent antibody, as well as an indirect fluorescent antibody test, to determine the presence of active disease or recent infection. 7 Because the diagnosis is sometimes difficult in these patients, it has been common practice to treat patients empirically for L. pneumophila infection with intravenous erythromycin, 500 mg intravenously every 6 hours, while waiting for the fluorescent stains, antibody titers, or culture results. We have encountered numerous cases of Legionella pneumonia in our cardiac transplant patients, including one recurrence after what was initially thought to be a full course of erythromycin treatment. It may be necessary to treat these recurren~es for up to 2 months with oral erythromycin following a clinical relapse. The most serious infection occurring in the late period after cardiac transplantation is caused by the Aspergillus ~pecies. These organisms are so ubiquitous in nature that one is never totally aware of the source for
464
/
LAYNE
O.
GENTRY AND BARRY
J.
ZELUFF
infection. The most common presenting syndrome is that of a nodular infiltrate that enlarges rather rapidly, usually related to a period of increased corticosteroid treatment for acute rejection. The most rapid diagnostic technique in our experience has been a percutaneous needle biopsy of a nodular lesion or a trans bronchial lung biopsy into an area of pulmonary infiltrate. Unfortunately, the treatment for this type of Aspergillus infection in the lung with conventional amphotericin B has been more than disappointing. Six of our seven patients who have been so treated have died, with Aspergillus being identified at autopsy. We have had one survivor who had tissue biopsy evidence of Aspergillus pulmonary infection and who was treated with a new liposomal preparation of amphotericin B. II He is still alive some 11 months later. Further studies with this particular new antifungal agent are ongoing at this time. Pulmonary infection with Nocardia asteroides also occurs in this late period after transplantation. 10 The presence of a pulmonary infiltrate, which enlarges rapidly, is the most common clinical syndrome. Bronchial brushings, trans bronchial lung biopsy, and percutaneous aspiration will frequently reveal the presence of beaded, branching, gram-positive rods. Cultures for N. asteroides are relatively easy to obtain from this material. SUMMARY Despite major advances in the management of rejection and the development of newer and more potent antimicrobials, infection still constitutes a major problem in transplant patients and other immunosuppressed hosts. Infectious complications in transplant patients clearly occur in two phases. The first phase includes the first 30 to 60 days after transplantation. During this period, nosocomial bacterial infections are most commonly encountered. Pulmonary, renal, and wound infections have all been encountered, and prophylactic antibiotics appear to decrease their frequency. Opportunistic infections usually do not occur during this period unless the patient undergoes treatment for acute rejection. The second phase of infectious complications usually follows the first month after transplantation. In this period, the level of immunosuppression is high, and opportunistic infections are common. Opportunistic pulmonary infections caused by P. carinii, L. pneumophila, cytomegalovirus, Aspergillus, and Nocardia spp. all are potentially life-threatening complications to the transplant patient. Aggressive diagnostic tests such as bronchoscopy, percutaneous needle biopsy, or open lung biopsy are frequently needed to make a diagnosis. Empiric broad-spectrum antimicrobial therapy is indicated in the ill patient; however, more specific therapy should be instituted once the diagnosis is confirmed. REFERENCES 1. Bandt, P. D., Blank, N., and Castellino, R. A.: Needle diagnosis of pneumonitis; value in high risk patients. J.A.M.A., 220:1578-1582, 1972.
DIAGNOSIS AND TREATMENT OF INFECTION IN CARDIAC TRANSPLANT PATIENTS
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