YALE JOURNAL OF BIOLOGY AND MEDICINE 75 (2002), pp. 285-291. Copyright @2003. All rghts reserved.

MEDICAL REVIEW

Staphylococcus aureus : A Report of Three Cases with Review of the Literature

Shehzad S. Merchanta and Ann R. FalseyaAb7c aDepartment of Medicine, Rochester General Hospital and bUniversity of Rochester School of Medicine and Dentistry, Rochester, New York

Infection of the hepatobiliary system is most commonly dtue to enteric bacteria. We report three unusual cases of acute cholecystitis in which Staphylococcus aureus was the primary pathogen. Infection of the gallbladder with this organism has been rarely described and may be associated with and obstnrctive disease as well as acalculous cholecystitis in the setting ofstaphylococcal bacteremia and endocarditis. Two ofourpatients had multiple chronic medical conditions and were infected with oxacillin-resistant S. aureus (ORSA) suggesting nosocomial acquisition. Including our cases with a review ofthe literature, three ofnine reports ofS. aureus cholecvstitis were associated with infectious endocarditis. Thus, thefinding ofS. aureus cholecystitis with bacteremia is rare and shouldpromnpt an investigation for a possible endovascularfocus ofinfection.

INTRODUCTION primary mechanism by which bacteria Acute cholecystitis is most commonly enter the bile. The organisms most com- associated with obstruction of the cystic monly isolated in infections duct leading to ischemia and are Escherichia coli, Klebsiella species [1]. In normal individuals the biliary tract (Sp.)d, Enterococcus sp. and aniaerobes [5, is sterile, however, 20 to 50 percent of 6]. Staphylococci are usually associated patients with chronic cholecystitis and 40 with infections of the skin and soft tissues to 75 percent of patients with acute chole- and are rarely reported as pathogens in dis- cystitis have positive bile cultures [2, 3]. eases of the gallbladder. In this report, we Several modes of infection have been pos- describe three patients with Staphylococ- tulated, including ascending infection due cus aureus acute cholecystitis seen over a to reflux ofduodenal contents, blood-borne two-year period and summarize the pub- infection and infection spread through the lished English literature on staphylococcal portal-venous channels [4]. Ascending infec- infections of the gallbladder. tion from the is felt to be the

CTo whom all correspondence should be addressed: Ann R. Falsey, M.D., Rochester General Hospital, 1425 Portland Avenue, Rochester, NY 14621. Tel.: 585-922-4339; Fax: 585-922-5168; E-mail: [email protected]. dAbbreviations: CT, computed tomography; IV, intravenous; NIDDM, non-insulin dependent diabetes mellitus; ORSA, oxacillin-resistant S. aureus; sp., species; TEE, transesophageal echocardiogram; WBC, white blood cell. Received: August 10, 2002; Returned for revisions: November 12, 2002; Accepted: March 17, 2003 285 286 Merchant and Falsey: Staphylococcus aureus cholecystitis

METHODS discontinued. By hospital day eight, the S aureus was isolated from blood or patient became afebrile, abdominal tender- bile cultures by the Rochester General ness resolved and the WBC count returned Hospital Clinical Microbiology Laboratory. to normal. Trans-esophageal echocardiogram Identification ofstaphylococci was initially (TEE) revealed normal cardiac valves. She based on colony morphology and Gram was discharged on a three-week course of stain with confirmation by positive cata- nafcillin and did well. lase reaction. Suspected S. aureus isolates Patient two was a 73-year-old female were confirmed by positive coagulase tube admitted to the hospital with one day of test. susceptibility was performed severe epigastric pain, , and nausea. with the Vitek automated system (bioMerieux She had an extensive past medical history Vitek Inc., Hazelwood, Missouri). Oxacillin that included diverticular , coronary resistance was confirmed by growth of the disease, aortic valve replacement, isolate on Mueller-Hinton agar plates con- , atrial fibrillation, menin- taining 6 ,ug/ml of oxacillin. gioma, psoriasis, and non-insulin depen- dent diabetes mellitus (NIDDM). She had a recent prolonged hospital admission for CASE REPORTS gastrointestinal bleeding and a hip fracture. Patient one was a 64-year-old woman During that time she had no S. aureus infec- admitted with right upper quadrant pain, tions or active skin problems. fever and nausea for 48 hours. Her history On admission she was afebrile. Cardiac was significant for cholelithiasis, hyper- exam revealed a 3/6 systolic murmur, and tension, hypothyroidism, and pernicious her abdomen was tender in the epigastrium anemia. She had no history of diabetes and left upper quadrant. Because of poor mellitus, recent infections, skin disorders, venous access, a central venous catheter was or antibiotic use. On admission her tem- placed. She was treated with IV fluids alnd perature was 101.4'F and her abdomen . on hospital day two was tender in the right upper quadrant. No showed no evidence of bleeding. Her ini- cardiac munrur was heard. White blood tial hospital course was complicated by cell (WBC) count was 17.4 x 109 cells/L Clostridium difficile that responded and liver function tests (serum bilirubin, to oral metronidazole. Blood cultures at that alkaline phosphatase and transaminases) time were sterile. On hospital day 13, her IV were with in normal limits. Abdominal catheter site was noted to be purulent and ultrasound showed a distended gall bladder the central line was removed. The catheter tip with pericholic fluid. Despite intravenous grew S. aureus resistant to oxacillin, clin- (IV) fluids and ampicillin-sulbactam, she damycin, erythromycin, and quinolones. remained symptomatic and underwent The following day, the patient became cholecystectomy on hospital day two. The febrile and lethargic, and she was begun on gallbladder contained many stones, and IV vancomycin. She required intubation histopathologic evaluation showed acute and transfer to the medical intensive care and chronic inflammation. Tissue Gram stain unit on hospital day 15. Two sets of blood was not done. The postoperative course was cultures grew ORSA with the same antibi- complicated by delirium and high fever. ogram as the catheter tip. A TEE revealed Admission blood cultures grew oxacillin- a normal mechanical valve and no vegeta- sensitive S. aureus in one of four bottles, tions. Blood cultures were persistently pos- and culture ofthe gallbladder was positive itive one week after removal ofthe catheter, for 3+ £. aureus and 3+ alpha-hemolytic and gentamicin and rifampin were added. streptococci. On hospital day five, nafcillin Gradually, the patient improved and by hos- was given and previous antibiotics were pital day 20 fevers resolved and blood cul- Merchant and Falsey: Staphylococcus aureus cholecystitis 287 tures became sterile. On hospital day 22, sage of gallstones and that were managed she developed fever, right upper quadrant medically. During an episode ofpancreatitis tenderness, elevated levels ofserum alkaline three months earlier, he underwent endo- phosphatase (225 U/L [39-117, normal]) scopic retrograde cholangio-pancreatography and gammaglutamyl transpeptidase (212 with sphincterotomy. He had no history of U/L [1-64 normal]) and WBC of 14.0 x staphylococcal infections or skin problems 109 cells/L. Abdominal computed tomog- during previous admissions. raphy (CT) revealed a distended, thick- On admission, the patient appeared walled gallbladder, pericholic fluid, and a uncomfortable and had mild icterus. He was calculus in the cystic duct. Under ultra- afebrile. The abdomen was tender in the sound guidance, a percutaneous cholecys- right upper quadrant. The remainder ofthe tomy tube was placed, and thick fluid with exam was unremarkable. Total bilirubin several stones was drained. Gram stain of was 2.1 mg/dL (0-1.0, normal range), alkaline the bile showed many Gram-positive cocci phosphatase was 165 U/L (39-117), and in clusters and cultures grew 4+ ORSA. SGOT was 107 U/L (7-37). Abdominal Blood cultures at the time ofthe procedure ultrasound revealed a distended, thick were negative. After drainage, fever and walled gallbladder with stones and sludge. abdominal tenderness resolved. Gentamicin The patient was started on ampicillin-sul- was discontinued after two weeks, and she bactam and ciprofloxacin. He was felt to be completed six weeks of vancomycin and high risk for surgery, and medical manage- rifampin for presumed endovascular infec- ment was undertaken. On hospital day two, tion given her prolonged bacteremia. On admission blood cultures grew Gram-posi- hospital day 70, the gallbladder drain was tive cocci in clusters, and IV vancomycin dislodged. Over the next two months, the was added. The organism was subsequently patient developed progressive azotemia identified as ORSA with resistance to ery- requiring hemodialysis. In her fifth month thromycin, clindamycin, and quinolones. of hospitalization, she again developed Transthoracic echocardiogram showed no right upper quadrant tenderness and blood vegetations, and TEE was not performed cultures grew ORSA. Abdominal ultra- because of esophageal varices. Abdominal sound did not reveal stones or obstruction. CT confirmed a distended gallbladder with She was re-started on antibiotics, however, pericholecystic fluid. The liver was enlarged her family decided against aggressive treat- and irregular consistent with , but ment and she died on hospital day 150, no abscess was identified. Despite antibiotics from multiple organ failure. An autopsy his pain continued and a percutaneous was not performed. cholecystostomy tube was placed under Patient three was a 48-year-old man ultrasound guidance on hospital day six. admitted because of severe right upper The bile contained several small stones and quadrant pain and vomiting. One week grew 3+ ORSA. His symptoms improved prior to admission he had an episode of significantly and broad-spectrum antibi- mild epigastric and right-upper quadrant otics were discontinued on hospital day pain that resolved spontaneously. Severe eight. Vancomycin was continued for four pain radiating to the back returned on the weeks. The patient underwent a trans- day of admission. He had no fevers or jugular intrahepatic porto-systemic shunt- chills. The patient had a history ofalcoholic ing procedure after finishing the course of cirrhosis with esophageal varices, vancomycin. Two weeks later, he had an C, hypertension, and NIDDM. He denied uneventful laproscopic cholecystectomy. intravenous drug use. The patient had two Blood cultures were negative at the time of previous episodes ofcholecystitis and pan- surgery, and the patient made a full recovery. creatitis presumed to be secondary to pas- 288 Merchant and Falsey: Staphylococcus aureus cholecystitis

DISCUSSION received an oral antibiotic, which was dis- continued, and the patient underwent a bat- Staphylococcal infections are typically tery of diagnostic tests and cultures. After associated with skin and soft tissue infec- ten days his blood cultures were negative, tions, pneumonia, osteomyelitis, septic his condition improved, and he was dis- arthritis, and infective endocarditis. The charged without a diagnosis. He was re- usual portal of entry for the organism is admitted two days later with similar symp- through a break in the skin or aspiration into toms and blood cultures grew S. aureus. the lungs. Hence, the presence ofS. aureus Several days later he developed severe in the gallbladder is surprising, since the right upper quadrant pain and at laparoto- does not usually harbor my was found to have a necrotic gallblad- S. aureus as normal flora. In our three der without stones which grew S. aureus patients, S. aureus grew from both blood [7]. He was treated with antibiotics and and bile indicating that it was the primary recovered. pathogen. Although the usual enteric bac- In 1990, a case ofS. aureus empyema teria associated with cholecystitis were not of the gallbladder in a patient with HIV found in our patients, suppression of other infection was reported [11]. The clinical organisms by broad-spectrum antibiotics presentation was notable for indolent cannot be entirely ruled out. symptoms. A review of the English literature The fifth case, reported in 1993, was revealed only six cases of cholecystitis in an 1 1-year-old boy who had S. aureus aortic which S. aureus was cultured from the valve endocarditis, pneumonia, and osteo- gallbladder or bile [7-12]. Five of the six myelitis. His course was complicated by a cases involved acalculous cholecystitis splenic abscess and acute cholecystitis and were associated with bacteremia. after two days of appropriate antibiotic The first case, from 1966, is the only therapy [9]. Cholecystectomy was required report ofS. aureus-associated cholelithiasis and a gangrenous gallbladder was removed and was similar to our first patient [10]. A and was sterile. The patient received six healthy 26-year-old woman with a history of weeks of antibiotics. biliary colic was admitted with four days Lastly, a 71-year-old Japanese man of severe right upper quadrant pain, fever, with diabetes and renal cell carcinoma who and leukocytosis. She underwent cholecys- presented with staphylococcal scalded skin tectomy, and the gallbladder was found to syndrome was found to have ORSA bac- contain 25 stones and 150 cc. of purulent teremia and cholecystitis [12]. He recovered material that grew S. aureus in pure cul- after cholecystomy and antibiotics. ture. She received antibiotics and made a In addition to these six case reports, a full recovery. review ofthe literature revealed six studies In 1970, a case series of post-opera- in which S. aureus was rarely isolated from tive acalculous cholecystitis was reported bile or gallbladder of patients with biliary in twelve casualties from the Vietnam War. disease (Table 1) [1, 4, 6, 13-15]. In all One soldier had S. aureus isolated from his reviewed studies, the percentage of S. wound, blood, and gallbladder, but details aureus was very low with only 16 of 2611 of the case were not provided [8]. (0.6 percent) positive cultures. No infor- The third case report, from 1981, mation was given as to whether the S. describes a 19-year old man with an asymp- aureus was isolated as a single organism or tomatic ventricular septal defect who pre- in combination with other bacteria. Several sented to the hospital with a four-day his- studies identified coagulase-negative staphy- tory of hip pain, malaise, fever, and a loud lococci in a substantial number of bile cardiac murmur. Prior to admission he specimens [4, 13, 16, 17]. A report by Merchant and Falsey: Staphylococcus aureus cholecystitis 289

Table 1. Series of gallbladder and bile cultures from patients with biliary tract diseases.* Author Flemma Fukunaga Chaifin Haff Lou Brook Mason [161 Vanous [1] [4] [13] [14] [151 [6] Pitt[17] [2, 3, 5, 18, 19] Year 1967 1973 1973 1976 1977 1989 1968,1982 1976-1983 Patients with positive cultures/Total tested 32/75 2341501 75/150 2/18 16/74 123/145 300/487 359/1161 Organisms' E coli 25 75 25 1 2 71 71 195 Klebsiella sp. 0 33 7 0 6 29 37 85 Other GNR 13 23 18 0 6 57 58 135 Streptococcal sp. 5 37 11 0 4 51 50 70 Anaerobes 2 25 0 0 1 70 28 36 S. aureus 1 7 5 1 1 1 0 0 CNS 0 52 20 0 0 6 24 0 Miscellaneous 1 35 3 0 0 0 19 7 *Biliary tract diseases included acute and chronic cholecystitis, cholangitis, malignancy, and parasitic . **The total number of individual organisms isolated is greater than the total number of patients with a positive culture since many patients had more than one organism isolated from the gallbladder wall or its contents. E. Coli = Escherichia Co/i; sp = species; GNR = Gram-negative rods, CNS = Coagulase-negative staphylococci

Nielson et al. described recovery ofstaphy- aureus [20]. Approximately 20 percent of lococcal species from gallbladder contents healthy people consistently carry a strain only when cultures were obtained at the ofS. aureus, and 60 percent harbor staphy- end of surgery but not immediately after lococci intermittently [20]. It seems plausible incision, suggesting these organisms were that her duodenum may have become con- contaminants introduced during surgery taminated with staphylococci if she were a [2]. Although several studies have demon- naspharyngeal carrier. Patient three had an strated staphylococcal species in the bile, endoscopic sphincterotomy three months in five large studies that included over prior to admission that may have allowed 1100 subjects, investigators never isolated reflux of duodenal bacteria into the biliary staphylococci [2, 3, 5, 18, 19]. tract and may have become colonized with There did not appear to be a common ORSA during previous hospitalizations. risk factor or pathologic process linking our Unfortunately, cultures ofthe anterior nares three patients. Patients two and three had were not done to investigate this possibility multiple medical problems which placed in either ofthese patients. Although S. aues them at higher risk for infections in general, is not a common isolate from the duodenal however, patient one was relatively healthy flora, it can occasionally be recovered. and had no obvious risk factors for devel- Keighley et al. isolated S. aureus from the oping invasive staphylococcal disease. Her duodenum in four out of47 patients under- history was consistent with a typical case of going biliary tract procedures [21]. How- acute cholecystitis associated with cholelithi- ever, none had S aureus recovered from asis. The anterior nares are reservoirs for S. their bile fluid. It has been postulated that 290 Merchant and Falsey: Staphylococcus aureus cholecystitis bile is bacteriastatic against Gram-positive quency ofthis organism in the biliary tract, cocci making isolation of staphylococci empiric coverage for acute cholecystitis from the bile difficult [21, 22]. should be directed at common enteric bac- Patient two was presumed to have teria and therapy adjusted according to the prosthetic valve endocarditis despite a nor- culture results. However, if S. aureus is mal echocardiogram given her prolonged isolated, it should not be dismissed as a bacteremia following removal of her contaminant. In addition, in view of the infected IV catheter. It seems most likely rarity ofthis condition and the fact that 33 that she either seeded her gallbladder with percent of the reported cases were associ- S. aureus during her initial high-grade bac- ated with probable endocarditis, an evalu- teremia or had a septic embolus to the gall- ation for an endovascular focus should be bladder later in her course. Secondary done in bacteremic cases. infection of the gallbladder from bac- ACKNOWLEDGEMENTS teremia was felt to be the mechanism of in The authors wish to thank Drs. Edward Walsh infection two ofthe previously described and Paul Bernstein.for their thoughtful review case reports ofS. aureus cholecystitis. One ofthe manuscript. patient had confirmed endocarditis and another with a VSD and bacteremia likely REFERENCES: had cardiac involvement. Thus, in three of 1. Flemma, R.J., Flint, L.M., Osterhout, S., the nine cases of S. aureus Shingleton, W.W. Bacteriologic studies of cholecystitis biliary tract infection. Ann. 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