Candida esophagitis following cardiac operation and short-term antibiotic prophylaxis

J

THORAC CARDIOVASC SURG

80:661-668, 1980

Candida esophagitis following cardiac operation and short-term antibiotic prophylaxis Dysphagia and retrosternal pain are common complaints in patients after cardiac operations, and most often they result from the median sternotomy and lor endotracheal intubation. Although Candida esophagitis is a recognized cause of similar symptoms, it is usually not suspected except in immunologically compromised hosts. This report describes the case histories offive patients, not immunosuppressed or cachectic, who developed persistent dysphagia during recovery from cardiac operations; four patients received only 4 days of preoperative and postoperative prophylactic antibiotic treatment with cefazolin (Kefzol) and cephalexin (Keflex). A nasogastric tube had been used for less than 24 hours in the postoperative period. The fifth patient developed symptoms following prolonged and varied antibiotic therapy. Candida esophagitis was diagnosed by a combination of coexisting oral candidiasis (515), roentgenographic appearance on barium swallow (515), endoscopy (414), and biopsy or culture (214). Initial therapy consisted of antireflux measures and antacids (415), cimetidine (415), oral nystatin in methylcellulose base (1,000,000 units every 4 hours) (415), and termination of other antibiotic therapy (l 15). These measures were effective in clearing the infection in only two patients. A third patient required prolonged massive oral nystatin therapy, and in two patients intravenous Amphotericin B was necessary to control infection. Two patients subsequently developed strictures which necessitated multiple esophageal dilatations. One of these patients developed endocarditis during home dilatation therapy. All patients are currently free of disease. Current measures utilized to recognize and treat the disease are discussed.

Steven R. Gundry, M.D. (by invitation), A. Michael Borkon, M.D. (by invitation) Charles L. McIntosh, M.D., Ph.D. (by invitation), and Andrew G. Morrow, M,D., Bethesda, Md.

Retrosternal chest pain and dysphagia are frequent complaints in the postoperative period following cardiac operations. Most often these complaints are caused by the median sternotomy and pharnygeal trauma during endotracheal intubation. Although oral candidiasis is often seen postoperatively in patients receiving broad-spectrum antibiotics, Candida esophagitis usually is not suspected postoperatively in patients with chest pain and dysphagia because of its reported occurrence primarily in immunosuppressed or severely cachectic patients.":" Furthermore, not until recently have its potentially serious sequalae, stricture or septicemia, been reported. 6-8 We present the case histories From the Clinic of Surgery, National Heart, Lung, and Blood Institute, Bethesda, Md. Read at the Sixtieth Annual Meeting of The American Association for Thoracic Surgery, San Francisco, Calif., April 28 to 30, 1980. Address for reprints: Andrew G. Morrow, M. D., Clinic of Surgery, National Heart, Lung, and Blood Institute, Bethesda, Md. 20205.

of four patients, with no history of immunosuppression or cachexia, who exhibited Candida esophagitis in the postoperative period; all received prophylactic antibiotics. In a fifth patient, Candida esophagitis developed postoperatively following an extended period of antibiotic administration. All patients initially received 1.0 gm of a cephalosporin compound intravenously or intramuscularly every 6 hours for 48 hours perioperatively, followed by 500 mg of a cephalosporin compound orally for 48 hours. In the first four patients nasogastric tubes were in place for less than 24 hours postoperatively. Case reports CASE I. A 41-year-old woman underwent tricuspid and mitral valve replacements. Her recovery was rapid and uneventful until oral candidiasis developed on the seventh postoperative day. She was treated with 500,00 units of nystatin orally every 6 hours. The oral infection resolved, and she did well until postoperative day 14, when severe retrosternal chest pain and dysphagia developed. A barium swallow examination revealed an 11 em irregular lesion of the

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Fig. 1. Case I . a . Barium swallow roentgenogram showing an II cm irregular lesion involving the midesophagus, which represents a pseudomembrane and mucosal edema. b. Barium swallow film following 3 weeks of nystatin therapy . Pseudomembrane outlined by the barium column appears as a double lumen . (', Complete obstruction of the barium column locates stricture to the midesophagus following apparent resolution of Candida esophagitis . rnidesophagus , diagnostic of Candida esophagitis (Fig . I, a ) . Nystatin in methylcellulose base was administered orally every 2 hours, and her symptoms slowly improved over the following week. Endoscopic examination on postoperative day 21, revealed a 10 ern area of leukoplakia in the midesophagus, which appeared to be resolving candidiasis. Specimens obtained by brushings contained no hyphae, but no biopsy specimens or cultures were taken . A repeat barium swallow examination showed partial resolution of the lesions (Fig . l , b) . Reflux esophagitis was not seen. The patient was discharged with instructions to continue a 3 week course of nystatin every 2 hours and cimetidine every 6 hours . One week following discharge she returned with obstruction to all solid foods . Barium swallow studies demonstrated an area of total obstruction at the midesophagus (Fig . I, c). At esophagoscopy a midesophageal stricture was found and dilated up to the size of a No . 20 Mallory bougie . During her sub sequent convalescence oral dilatations were continued at home. During this period streptococcal endocarditis developed, for which she was treated successfully at another hospital. The patient is currently symptom free; follow-up barium swallow roentgenogram demonstrates resolution of the stricture. CAS E 2. A 63-year-old woman underwent an aortacoronary bypass operation . Her postoperative recovery was uneventful until the third postoperative day. when she complained of dysphagia; oral candidiasis was apparent. Her antibiotic was stopped, and she was treated with nystatin . Be-

cause of continued dysphagia, a barium swallow examination was made . It revealed changes compatible with early Candida esophagitis (Fig. 2, a). The esophagus had been normal when examined preoperatively . Three days later the patient's dysphagia worsened, despite copious use of antacids, and sudden retrostemal chest pain developed. At another hospital both barium swallow and endoscopic examinations revealed Candida esophagitis involving the midesophagus . No gastroesophageal reflux was seen . The patient was treated with cirnetidine, magnesium and aluminum hydroxides (Maalox) , and a liquid diet. Following 3 weeks of such treatment her condition gradually improved and she was discharged. When seen at our hospital 6 months postoperatively she had no dysphagia and was symptom free. The radiograph ic appearance of the esophagus was normal (Fig. 2, b). CAS E 3. A 63-year-old man underwent aorta-coronary bypass grafting. On the third postoperative day oral candidiasis was found. He was treated with nystatin and the oral lesions cleared. Ten days postoperatively, severe dysphagia and retrostemal pain developed . Barium swallow (Fig . 3, a and b) and the endoscopic appearance were diagnostic of Candida esophagitis, but endoscopic brushings did not reveal Candida on direct stain or in culture. Nevertheless, he was treated with nystatin and cimetidine. His condition improved on this regimen and he was discharged on postoperative day 15, with instructions to continue to take nystatin for 3 weeks. Two days after discharge, increasing dysphagia and retrosternal chest pain developed, and he was admitted to another

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Fig. 2. Case 2. a, Barium swallow roentgenogram showing fine mucosal irregularities of the midesophagus characteristic of early Candida esophagitis. b. Follow-up barium examination showing complete resolution of lesions after cessation of antibiotics.

Fig. 3. Case 3. a, Barium column outlines mucosal irregularities in the midesophagus. Endoscopy confirmed presence of pseudomembrane of Candida. h. Cobblestone appearance of lumen with apparent esophageal narrowing, characteristic of moderate Candida esophagitis.

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Fig. 4. Case 4 . a . Mucosal irregularities in midesophagu s and distal esophagus. h. Shelflike abrupt ending of pseudomembrane is well outlined by barium column . hospital, where repeat endoscopic study revealed severe Candida esophagitis , confirmed by biop sy . He was treated with amphotericin Band ftucytosine for 10 days . Repeat endoscop ic examination prior to discharge showed clearing of all lesion s. He is now symptom free and has no sequelae. e AS E 4. A 60-year-old man had an aorta-coronary bypass operat ion . On the seventh postoperative day oral candidiasis was recogn ized . He was immediately begun on oral nystatin, but by the eighth postoperative day severe dysphagia and retro stemal pain had developed . Barium swallow was diagnostic of Candida esophagitis with ulceration and pseudomembrane formation (Fig. 4, a and h) . He was continued on nystatin every two hours, and after 3 days the dysphagia improved . No endoscopic examination was performed. A barium swallow roentgenogram prior to discharge showed clearing of all lesions. Nystatin was cont inued for 3 weeks after discharge . The patient is symptom free. e A s E 5 . A 60-year-old woman had low cardiac output and renal failure follow ing mitral and tricuspid valve replace ments . Postoperatively , Pseudomonas pneumonia and Staphylococcus epidermidis sepsis developed , for which she was treated successfully with carbenicillin , tobramycin, and vancomycin . During this period she was given nystatin , 500,000 units , as an oral mouthwash and the drug was instilled into the nasogastric tube every 6 hours. One and one-half months postoperatively she complained of substernal che st pain and dysphagia . A barium swallow was diagnostic of Candida esoph agitis (Fig . 5, a) . As noted at endoscop y and confirmed by biopsy, the midesophagus was severely involved with Cand ida . She was treated with nystatin and cimetidine with no improvement in symptoms during the ensuing 48 hours. She was then given amphotericin B for 7 days . Endoscopic and barium swallow examinations later revealed significant resolution of the lesions (Fig . 5, h) . She was discharged but

returned 6 months later with severe dysphagi a. A barium swallow study demonstrated a midesophageal stricture (Fig. 5, c ), which was successfully dilated with Hurst-Maloney dilato rs. She cont inued with daily self-dilatations at home . She is currentl y symptom free but continues to dilate the esophagus every other day.

Discussion Candida infections in the postoperative period are most frequently seen in those patients who have received broad-spectrum antibiotics.:': 6 . 9 These infections usually involve the oral or vaginal mucous membranes and are discovered during a routine oral examination or when attention is directed to these areas by the patient's complaints of a sore mouth or throat or vaginal itching and discharge. Tetra cycline or chloramphenicol administration has a recognized association with subsequent superficial mucous membrane infections by Candida 9 - 11; additionally, an increase in absolute numbers of Candida in the mouth and gastrointestinal tract occurs following administration of many antibiotics .1 . 9 Most superficial Candida infections respond to cessation of antibiotic therapy alone , but administration of nystatin is also effective in rapidly clearing these infections .v 6. 9. 10. 12 . 13 Although the diagnosis of superficial oral candidiasi s is frequently and easily made, reports of esophageal candidiasi s have been limited to approximately 100 patients. The great majority were patients who had leu-

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Fig. 5. Case 5. a, Ulceration and pseudomembrane formation of severe Candida esophagitis. b, Clearing of most lesions following amphotericin B treatment. The esophagus distends well. c. Stricture in midesophagus outlined by barium column. This occurred 6 months postoperatively. Radiolucencies are tablets of medication.

kemia, lymphoma, or severe cachexia or who had received corticosteroids or antineoplastic agents.t ": 7. 14 The infection is reported infrequently in patients who have hypoparathyroidism, 12 chronic mucocutaneous candidiasis," 15 or mechanical trauma to the intestinal tract'" and in those who have had long-term broadspectrum antibiotic therapy. 5. 6, 9 Reports of esophageal candidiasis after short-term antibiotic administration in otherwise healthy individuals are rare. 10 Esophageal candidiasis manifests itself by severe dysphagia and pain in the upper retrosternal part of the chest, which is usually sudden in onset. 4 The chest pain may actually precede dysphagia, mimicking the pain of myocardial ischemia or infarction. 5 Although coexisting oral candidiasis in a patient with these symptoms increases the suspicion of esophageal candidiasis, it has been absent in up to 50% of reported cases. 4 Once suspected, the diagnosis of Candida esophagitis frequently can be established by means of a barium swallow examination. Primary and secondary peristaltic waves usually are diminished in amplitude and may reflect the severity of esophageal involvement. 4 Spasm is frequently reported, but the exact cause of this finding is unclear; the esophageal lumen may appear diminished simply because of ingestion of an inadequate bolus of contrast material. 6 Abnormal

contours of the esophageal wall are the most diagnostic features of Candida infection. Early in the disease, a cobblestone pattern of the esophageal lumen is apparent (Figs. 2, a, 4, a, and 4, b), usually as a result of yeast colonies growing on the luminal surface or from submucosal edema.": 5 Later in the course of the disease, the lumen takes on a shaggy appearance, caused by a large pseudomembrane of Candida colonies and debris (Figs. I, a and 5, a). This membrane may end or separate from the mucosa abruptly, forming a shelflike or double-lumen appearance (Figs. I, band 4, b). These lesions usually occur in the midesophagus;"" in contrast to those occurring from peptic esophagitis, which develop in the distal esophagus." Furthermore, the ulcerations of Candida esophagitis are usually multiple, in contrast to single peptic ulcerations. 4 Co-existing oral candidiasis with the symptoms and roentgenographic appearance just described usually is sufficient to establish the diagnosis and indicate the need for therapy. 2. 4-6, 10. 13 However, when oral candidiasis is not found, or if response to treatment is not prompt, endoscopic examination is indicated and usually is diagnostic. In 1,400 consecutive patients studied by Kodsi and colleagues, 13 the endoscopic findings correctly predicted that biopsy specimens would show Candida in 88 patients with suspected Candida esoph-

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agitis. Further, in no instance was there a positive diagnosis from biopsy without a characteristic gross lesion. Early Candida infection of the esophagus appears endoscopically as small, raised, white plaques with surrounding hyperemia and edema. Moderate-to-severe candidiasis appears as confluent plaques with frank ulceration and friability of the mucosa. Although biopsy or brushing specimens of untreated lesions usually contain mycelial forms or subsequently grow Candida from culture, others have reported that results of biopsies or brushings may not indicate Candida.>: 6 These nondiagnostic results may occur when nystatin therapy has been instituted prior to endoscopy, as in several of our patients. Additionally, although endoscopy appears to be easily performed in these patients, the esophagus may be especially friable in severe forms of the disease, so that any instrumentation is dangerous.": 17 Recently, a further specific test for Candida tissue invasion has been developed which has aided in the diagnosis of Candida esophagitis. Candida serum agglutinin titers of at least I : 160 have been shown to correlate well with the presence of active Candida esophagitis. 6. 1:1. 16 A declining titer is said to correlate with cure of the Candida infection." 16 Unfortunately, this test is not specific for esophagitis, but detects any Candida invasion, including visceral candidiasis or candidemia." Complications and sequelae of Candida esophagitis are poorly reported in the literature, presumably because of the high mortality rate from the infected patient's primary disease. Nevertheless, as immunosuppression for transplantation and the use of broad-spectrum antibiotics increases, sequelae of Candida esophagitis probably will soon be recognized with greater frequency. By far the most ominous complication is dissemination of the disease from an oral or esophageal site, resulting in candidernia, visceral implants, and endocarditis. Seelig and associates" reported 87 cases of Candida endocarditis in patients undergoing cardiac operations, and they implicated a spread of the infection from oral or tracheobronchial sources in several of these patients. This was especially true following prolonged antibiotic therapy. A recently recognized sequel of Candida esophagitis is esophageal stricture, which now has been described in approximately 10 patients. Orringer and Sloan," Ott and Gelfand," and Kantrowitz and associates" all have described cases in which strictures developed after oral or esophageal candidiasis, several occurring following apparently successful treatment of the esophagitis, as in two of our patients. Differentiation of these midesophageal strictures from carcinoma may be especially

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difficult without a history of antecedent Candida infection. The finding of pseudodiverticulosis on barium swallow roentgenogram may suggest a Candida origin for a stricture, 6 although there is no conclusi ve agreement as to the cause of this roentgenographic appearance.:": 20 Treatment Candida esophagitis may occur in mild-to-severe forms as demonstrated by our patients. The treatment thus varies with the severity and the response of the infection. Small mucosal patches may respond to cessation of antibiotic therapy and general supportive measures, as illustrated by our second patient. 5. 9. 11 However, because of the often aggressive course of the disease, oral administration of nystatin, 500,000 to 1,000,000 units every 2 to 6 hours, is recommended. This treatment is usually successful in improving symptoms within 48 hours to I week. 1-:1. 5. 6. 9. 12. 1:1 Combination of nystatin with methylcellulose, 250,000 units/ cc, is used at this institution and others to provide increased viscosity, which prolongs contact in the esophagus.P Treatment is continued for I to 3 weeks. From 10% to 50% of patients may not improve symptomatically or roentgenographically with this regimen, as demonstrated by two of our patients. I. :I. 6. 9. 12. I:l. 19 Patients recovering from cardiac operations, who are at risk for Candida endocarditis" and who do not respond promptly to nystatin therapy, should be given amphotericin B intravenously or flucytosine orally, either alone or in combination. 1. :I. 6. 6. 1:1. 17 Unlike the treatment of other systemic mycoses, esophageal candidiasis usually responds to low doses of amphotericin B, I to 10 mg/ day, continued for 7 to 10 days. Oral flucytosine, 50 to 150 mg/kg/day in divided oral doses, for 4 to 6 weeks, may also be effective. Recently, intravenous miconazole , 600 to 2,000 mg/day in divided doses, has been shown to treat esophageal candidiasis effectively without side-effects. 15 Caution must be exercised in determining when a patient is cured. As Orringer and Sloan" have described, and as we demonstrate here, symptomatic and/or roentgenographic improvement does not prevent the late sequelae of stricture formation. Whether these strictures represent inadequately treated chronic infection or residua of the acute process is not known, but patients treated for Candida esophagitis should receive close follow-up including several radiographic or fluoroscopic examinations. Likewise, continuation of therapy for 2 to 4 weeks following resolution of the symptoms is recommended. However, as demonstrated in our patients, this may not prevent sequelae.

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From our experience, we have adopted the following procedures for treating Candida esophagitis. Antibiotic therapy, unless urgently required for control of active infections, is stopped if oral candidiasis is found. Nystatin, 500,000 units orally every 6 hours, is given. If dysphagia or retrostemal pain occurs, a barium swallow roentgenogram is obtained. If the lesions described previously are found, nystatin in methylcellulose, 1,000,000 units orally every 2 hours, is administered for 3 weeks. If symptoms increase during the next 48 to 72 hours, endoscopy is performed to obtain brushing and biopsy specimens and to assess visually the response to therapy. Severe Candida esophagitis, confirmed by biopsy, is then treated with amphotericin B for 7 to 10 days. Failure to improve in patients without biopsy confirmation prompts repeat endoscopy with visual and biopsy reassessment of the lesions. Response to therapy can then be monitored by serial barium swallow roentgenograms. These examinations are also obtained at discharge and 6 months postoperatively. In summary, Candida esophagitis occurs in mild-tosevere forms following prophylactic antibiotic administration in patients recovering from cardiac operations. Diagnosis of this disease is often delayed or missed by the frequent occurrence of dysphagia and retrostemal chest pain in these patients. Candida esophagitis probably occurs with much greater frequency in patients recovering from operation than formerly suspected. Early detection and aggressive treatment may prevent the development of serious sequelae, including endocarditis and stricture formation. REFERENCES

2 3 4

5 6

7 8

Eros P, Goldstein MJ, Sherlock P: Candida infection of the gastrointestinal tract. Medicine 51:367-379, 1972 Grieve NWT: Monilial esophagitis. Br J Radiol 37: 551554, 1964 Holt JM: Candida infection of the oesophagus. Gut 9:227 -231, 1968 Lewicki AM, Moore FP: Esophageal moniliasis-a review of common and less frequent characteristics. AJR 125:218-225, 1975 Sheft OJ, Shrago G: Esophageal moniliasis-the spectrum of the disease. JAMA 213:1859-1862, 1970 Orringer MB, Sloan H: Monilial esophagitis. An increasingly frequent cause of esophageal stenosis. Ann Thorac Surg 26:364-374, 1978 Ott DJ, Gelfand DW: Esophageal stricture secondary to candidiasis. Gastrointest Radiol 2:323-325, 1978 Seelig MS, Speth CP, Kozinn PJ, Toni EF, Taschdjian CL: Candida endocarditis after cardiac surgery. Clues to earlier detection. J THORAC CARDIOVASC SURG 65:583601, 1973

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9 Seelig MS: The role of antibiotics in the pathogenesis of Candida infections. Am J Med 40:887-917, 1966 10 Brown JW, McKee WM: Acute monilial esophagitis occurring without underlying disease in a young male. Dig Dis 17:85-88, 1972 11 Woods JW, Manning IH Jr, Patterson CN: Monilial infections complicating the therapeutic use of antibiotics. JAMA 145:207-211,1951 12 Kantrowitz PA, Fleischli OJ, Butler WT: Successful treatment of chronic esophageal moniliasis with a viscous suspension of Nystatin. Gastroenterology 57:424-430, 1969 13 Kodsi BE, Wickremesinghe PC, Kozinn PJ, 1swara K, Goldberg PK: Candida esophagitis-a prospective study of 27 cases. Gastroenterology 71:715-719, 1976 14 Moulinier B, Lambert R, Grenier-Boley P, Bruhiere J: Les mycoses de I'oesophage. Nouv Presse Med 4:26292632, 1972 15 Rutgeerts L, Verhaegen H: Intravenous miconazole in the treatment of chronic esophageal candidiasis. Gastroenterology 72:316-318, 1977 16 Khuroo MS, Naik SR, Sehgal SC, Naik S, Kaushik SP, Katariza RN, Datta D V, Mehta SK: Candida infection of the upper gastrointestinal tract superadded upon chemical injury with acids. Am J Gastroenterol 72:276-281, 1979 17 Sehhat S, Hazeghi K, Bajoghli M, Touri S: Oesophageal moniliasis causing fistula formation and lung abscess. Thorax 31:361-364, 1976 18 Taschdjian CL, Seelig MS, Kozinn PJ: Serological dianosis of Candida infection. CRC Crit Rev Clin Lab Sci 4:19-59, 1973 19 Stillman AE, Larter W, Goldman DS: Longitudinal esophageal bands associated with esophageal aperistalsis. Speculations on pathogenesis. Gastroenterology 74:592594, 1978 20 Castillo S, Aburashed A, Kimmelman J, Alexander LC: Diffuse intramuralesophageal pseudodiverticulosis. New cases and review. Gastroenterology 72:541-545, 1977

Discussion DR. MARK B. ORRINGER Ann Arbor, Mich.

I would like to commend Dr. Gundry for a very nice presentation, which emphasizes an observation that we made several years ago in treating patients requiring esophageal replacement for benign disease, that is, more strictures from monilial esophagitis than had been reported in the past. The earliest series of monilial esophagitis involved patients with overwhelming systemic disease, such as leukemia, patients who had been receiving immunosuppressive and chemotherapeutic agents. Monilial esophagitis was a frequent postmortem finding in such patients. Now, however, with potent broad-spectrum antibiotics that suppress normal gut flora and allow the usually innocuous Candida to become pathogenic, we are beginning to see this entity more often clinically, as we predicted. This is a problem that all of us have to be

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concerned with, particularly in our patients recovering from cardiac and thoracic operations, who receive broad-spectrum antibiotics. In treating acute monilial esophagitis, I would emphasize that the standard 400,000 units of nystatin (mycostatin) by mouth every 4 to 6 hours is often inadequate. The success of nystatin in this situation is dependent upon its duration of contact with the mucosal surface of the involved esophagus. This is the reason that the addition of methylcellulose, which increases the viscosity of the medication and therefore prolongs contact, is so important. Strictures resulting from monilial esophagitis are among the most difficult to dilate. It is imperative, therefore, that early bougienage be instituted when such a stricture begins, to prevent the development of a nondilatable panmural fibrosis resulting in an esophagus that simply cannot be salvaged. Finally, as was illustrated by one of Dr. Gundry's patients and as has been emphasized in a report by Dr. Haller and his associates from Johns Hopkins, patients undergoing dilatation

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of esophageal strictures frequently develop a bacteremia. Therefore, in cardiac patients requiring dilatation of esophageal strictures, it is important to institute prophylactic antibiotics to prevent the development of infective endocarditis. Streptococcus was the offending organism in Dr. Gundry's patient and in those reported by Haller's group. DR. GUN 0 R Y (Closing) I would like to thank Dr. Orringer for his remarks. It was his work presented before the Society of Thoracic Surgeons in 1978 which first prompted our investigation at the National Institutes of Health. We have been very impressed with the potency of broadspectrum antibiotics in allowing Candida overgrowth both as oral candidiasis and as esophageal candidiasis. We do not know whether this is due in part to our increased recognition of this disease or to an actual increase in these cases. We are currently conducting a study as to whether the cephalosporins tend to potentiate oral or esophageal Candida infections.