Mayo Clin Proc, February 2004, Vol 79 247Gram-Negative Cellulitis Complicating Cirrhosis

Mayo Clin Proc. 2004;79:247-250 247 © 2004 Mayo Foundation for Medical Education and Research

Case Report

From the Medical Intensive Care Unit (Y.H., Y.A.) and Division ofGastroenterology (A.D.S.), Soroka University Medical Center, Fac-ulty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.

Individual reprints of this article are not available. Address corre-spondence to Yaniv Almog, MD, Medical Intensive Care Unit, SorokaUniversity Medical Center, PO Box 151, Beer-Sheva 84101, Israel(e-mail: almogya@bgumail.bgu.ac.il).

Gram-Negative Cellulitis Complicating Cirrhosis

YAEL HOROWITZ, MD; AMI D. SPERBER, MD, MSPH; AND YANIV ALMOG, MD

Gram-negative infections are common in patients withcirrhosis, but skin infections are usually caused by gram-positive cocci. Gram-negative bacteria should be consid-ered as a potential etiologic agent in patients with cirrhosisand severe bullous cellulitis. Culture of the bullous fluidmay facilitate diagnosis and management. Early recogni-tion is important because the course of the disease is usu-

ally rapid and fatal. We report 4 cases of fulminant gram-negative bullous cellulitis and septic shock in patients withcirrhosis.

Mayo Clin Proc. 2004;79:247-250

Cirrhosis predisposes patients to serious bacterial infec-tions. The incidence of bacteremia in patients with

chronic liver disease is 5 to 7 times higher than that in otherhospitalized patients.1,2 This increased susceptibility is dueto multiple immune system defects, including complementdeficiency, reduced chemoattractant activity, decreasedpolymorphonuclear leukocyte activity, impaired bacteri-cidal function of IgM for certain strains of Escherichia coli,and a reduced number of Kupffer cells.3 Furthermore, thegastrointestinal mucosa seems to be more permeable inthese patients, allowing the transmural passage of entericbacteria into the circulation.4 In a prospective study ofbacterial infections in patients with cirrhosis, spontaneousbacterial peritonitis was the most common infection (31%),followed by urinary tract infection (25%), pneumonia(21%), and skin infections (11%).5 Gram-negative entericorganisms, especially E coli, are the most commonly iden-tified pathogens.1,3,5 Soft tissue infections are found in 2%to 11% of cirrhotic patients, with gram-positive cocci, pri-marily staphylococci and streptococci, being the mostprevalent pathogens.5,6 We describe 4 patients with cirrho-sis who presented to our institution between March 2000and June 2002 with fulminant gram-negative cellulitis as-sociated with septic shock and death. Early recognition ofthis complication of cirrhosis is extremely important be-cause its course is usually rapid and fatal.

REPORT OF CASESCase 1

A 53-year-old man was admitted to the burn unit withthird-degree burns on his left calf and buttocks. He had

MELD = model for end-stage liver disease; MICU = medicalintensive care unit

biopsy-proven cryptogenic cirrhosis with portal hyperten-sion (Child-Pugh class B; model for end-stage liver dis-ease [MELD] score, 22). During hospitalization, he had 4distinct episodes of sepsis, 2 caused by methicillin-sensi-tive Staphylococcus aureus and 1 each by coagulase-negative staphylococci and Acinetobacter. Despite initialclinical improvement, he subsequently experienced me-lena and hepatic encephalopathy. Gastroscopy, sigmoid-oscopy, and colonoscopy did not identify the source ofbleeding. Septic shock associated with local erythema,edema, and warmth of the left calf developed. Chest radi-ography yielded normal findings, and urine culture resultswere negative. Ascites was minimal, and aspiration wasnot performed. Vancomycin and piperacillin-tazobactamwere given empirically. The left leg rapidly became swol-len and red with numerous serous bullae and patchesof necrosis. Cultures from blood specimens and from aswab taken from the fluid in one of the bullae werepositive for E coli, and the antibiotic regimen waschanged to imipenem. Septic shock with multiorgan fail-ure ensued, and the patient died despite full supportivetreatment.

Case 2A 73-year-old woman presented with a 1-day history of

fever (maximum temperature, 39°C) and erythema of theleft calf. Fulminant septic shock developed within 1 hour,and she was admitted to the medical intensive care unit(MICU). Her medical history included cirrhosis due tohepatitis C virus infection with portal hypertension andhypersplenism (Child-Pugh class C; MELD score, 30).Multiple hemorrhagic bullae, necrosis, and gangrene werenoted on the left calf. Chest radiographic findings werenormal, and a urine culture was sterile. Blood culture waspositive for Pseudomonas aeruginosa. The bullae were notcultured. Cefuroxime and ofloxacin were administered, butmultiorgan failure developed within a few hours, and thepatient died.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mayo Clin Proc, February 2004, Vol 79248 Gram-Negative Cellulitis Complicating Cirrhosis

Case 3A 42-year-old woman was admitted to the hospital with

a fracture of the left femur and distal radius. Her medicalhistory was remarkable for biopsy-proven cryptogenic cir-rhosis (Child-Pugh class C; MELD score, 30) and vasculi-tis of unknown etiology. Eleven days after orthopedic sur-gery, she had fever and development of local erythema atthe surgical site on her left leg. A day later, the patientexperienced septic shock associated with adult respiratorydistress syndrome, and she was transferred to the MICU.Her left leg was erythematous, edematous, and warm, andlarge bullae were noted. A culture taken from the infectedsite was positive for Acinetobacter and methicillin-resis-tant S aureus. All blood and urine cultures yielded negativeresults. The bullae were not cultured. Initial treatment withvancomycin and piperacillin-tazobactam was subsequentlychanged to imipenem. Despite therapy, her clinical condi-tion worsened, and multiorgan failure and death occurredwithin 5 days after admission. Autopsy revealed irregularnodules, scarring, centrilobular hemorrhagic necrosis, bileduct hyperplasia, and microvesicular fatty changes, all con-sistent with cirrhosis of undetermined etiology.

Case 4A 55-year-old woman was admitted to the hospital with

diffuse abdominal pain, vomiting, and right leg pain. Hermedical history included cirrhosis due to hepatitis C virusinfection (Child-Pugh class C; MELD score, 31) and hy-pothyroidism. Her condition rapidly deteriorated, hypoten-sion and oliguria developed, and the patient was intubated.Ofloxacin and clindamycin were administered, and she wastransferred to the MICU. Her right leg had become swollen,and several hemorrhagic bullae were noted (Figures 1 and2). Abdominal ultrasonography revealed only mild ascites.

Chest radiography yielded normal findings, and urine cul-ture was sterile. Cultures from blood specimens and from aswab taken from the fluid in one of the bullae were positivefor E coli. Septic shock and multiorgan failure developed,and the patient died despite full supportive treatment.

DISCUSSIONPatients with cirrhosis are extremely susceptible to bacte-rial infections. Although gram-negative enteric bacteria arethe most commonly involved pathogens, they are not usu-ally the etiologic agent in skin infections.5,6 We report 4patients with fatal septic shock due to bullous cellulitiscaused by gram-negative bacteria. All 4 had severe cutane-ous manifestations and a similar clinical course.

In case 1, the cellulitis and septic shock appeared simul-taneously, making it difficult to determine whether thecellulitis was a cause or a consequence of the septic shock.Some investigators have suggested that gram-negative cel-lulitis could be a sequela of bacteremia from the gas-trointestinal tract.6 The incidence of transient bacteremiaduring or closely following endoscopy has been reported tobe as high as 50%,7 and it has been suggested that patientswith chronic diseases such as cirrhosis should receive pro-phylactic gut-sterilizing antibiotic therapy before the pro-cedure.7,8 Our patient underwent gastroscopy, sigmoidos-copy, and colonoscopy, any or all of which could havecontributed to the gram-negative sepsis. The third-degreeburn on the patient’s left calf could also have been a portalof entry. Cellulitis was most probably the cause of thesepsis in case 2 because blood cultures were positive for Paeruginosa, an organism that rarely causes bacteremia incirrhotic patients.6 Case 3 had septic shock and bullouscellulitis following surgery on the left femur. Althoughcultures were positive for Acinetobacter and S aureus,

Figure 1. Case 4. Hemorrhagic bulla and cellulitis on the medialaspect of the inner thigh. Note patchy areas of edema, necrosis,and inflammation.

Figure 2. Case 4. Bullous cellulitis on the inner aspect of the leftcalf. Cultures were obtained from this large bulla.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mayo Clin Proc, February 2004, Vol 79 249Gram-Negative Cellulitis Complicating Cirrhosis

Table 1. Summary of Reported Cases of Gram-Negative Cellulitis Complicating Cirrhosis*

Patient Child-age (y) Type of Pugh Culture results Cellulitis

Reference and sex cirrhosis class Blood Skin complications Outcome

Corredoira et al6† 50/M … C Negative Proteus mirabilis, Abscess RecoveredKlebsiellapneumoniae

53/M … C Pseudomonas P aeruginosa Bullae Recoveredaeruginosa

53/F … C Aeromonas A hydrophila None Diedhydrophila

55/F … C K pneumoniae K pneumoniae Bullae, ulcers Died57/F … C K pneumoniae K pneumoniae Bullae, necrosis Recovered65/F … C Escherichia coli E coli Bullae, necrosis Recovered68/F … C Negative P aeruginosa Abscess Died76/F … C E coli E coli Bullae Died

Yoon et al9 56/M NA NA NA E coli Bullae NA60/M NA NA NA E coli Bullae, pustule Recovered

Castanet et al10 77/F Hepatitis C NA E coli E coli Bullae, ulcers, Diednecrosis, pustule

72/M Presumed NA E coli Negative None Recoveredalcoholic‡

Current study 53/M Cryptogenic B E coli E coli Bullae, necrosis Died73/F Hepatitis C C P aeruginosa ND Bullae, necrosis, Died

gangrene42/F Cryptogenic C Negative Acinetobacter, Bullae Died

Staphylococcusaureus§

55/F Hepatitis C C E coli E coli Bullae Died

*NA = data not available; ND = not done.†Alcoholic cirrhosis in 5 cases and cryptogenic cirrhosis in 2; causes not reported for individual patients (indicated by ellipses).‡Alcoholism specified, cirrhosis assumed.§Cultured from surgical site.

either of which could have caused the cellulitis and sepsis,the clinical and dermatologic manifestations were similarto those of the other 3 patients who had culture-positivegram-negative infections.

To our knowledge, only 16 cases (including our 4 pa-tients) of gram-negative cellulitis in patients with cirrhosishave been reported in the literature (Table 1),6,9,10 56% ofwhich were fatal. The mean age of the 16 patients was 60years, and 63% were women. The type of cirrhosis wasalcoholic in 37%, cryptogenic in 25%, hepatitis C virus–related in 19%, and not specified in 19%. In all but 1 case inwhich a skin culture was done (either by a swab, fine-needle aspiration, or biopsy), results were positive for thecausative organism, 50% of which were E coli. Needleaspiration is considered to be an unrewarding technique forthe isolation of the causative organisms in patients withcellulitis, with positive results obtained in only 5% to12.5% of cultures.11 Skin biopsy specimens yield positiveresults in 20% of cultures.11 In contrast, needle aspirationcultures have higher positive rates in patients with an un-derlying disease such as diabetes, hematologic malignancy,or cirrhosis.11,12

Because none of our patients had skin changes consis-tent with necrotizing fasciitis, more invasive therapy such

as débridement or therapeutic drainage was not considered.However, 5 of the patients reported by Corredoira et al6 andCastanet et al10 required surgical débridement, 3 of whomdied. Nonetheless, in patients with findings suggestive ofnecrotizing fasciitis or extensive skin necrosis, surgicaldébridement should be considered.

Eight of the previously reported patients and 3 of ourpatients had a grade C Child-Pugh score, suggesting thatthe severity of the underlying liver disease is an importantpredisposing factor. However, the uniform mortality ob-served in our patients is more likely related to the severityof the infectious process and not to the extent of the under-lying liver disease. The prognosis for cirrhotic patientswith septic shock is grave, with mortality rates approaching100%.13 Indeed, in the 12 cases reported previously in theliterature, only 2 patients experienced septic shock anddied, whereas all 4 patients in the current report presentedwith severe sepsis and multiorgan failure. Thus, the mortal-ity rate for patients with cirrhosis in whom gram-negativecellulitis and septic shock develop is exceedingly high,approaching 100%.

Gram-negative bacilli should be considered when se-vere bullous cellulitis is observed in patients with cirrhosis.We recommend that cultures be obtained from the bullous

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mayo Clin Proc, February 2004, Vol 79250 Gram-Negative Cellulitis Complicating Cirrhosis

fluid because they may aid in the identification of thecausative organism. Therapy with antibiotics that are effec-tive against gram-negative bacteria should be institutedrapidly. The prognosis for those in whom septic shockdevelops is grave. With mortality rates approaching 100%,the importance of early recognition and prompt manage-ment cannot be overemphasized.

REFERENCES1. Thulstrup AM, Sorensen HT, Schonheyder HC, Moller JK, Tage-

Jensen U. Population-based study of the risk and short-term prog-nosis for bacteremia in patients with liver cirrhosis. Clin Infect Dis.2000;31:1357-1361.

2. Barnes PF, Arevalo C, Chan LS, Wong SF, Reynolds TB. Aprospective evaluation of bacteremic patients with chronic liverdisease. Hepatology. 1988;8:1099-1103.

3. Wyke RJ. Problems of bacterial infection in patients with liverdisease. Gut. 1987;28:623-641.

4. Runyon BA. Bacterial infections in patients with cirrhosis. JHepatol. 1993;18:271-272.

5. Caly WR, Strauss E. A prospective study of bacterial infections inpatients with cirrhosis. J Hepatol. 1993;18:353-358.

6. Corredoira JM, Ariza J, Pallares R, et al. Gram-negative bacillarycellulitis in patients with hepatic cirrhosis. Eur J Clin MicrobiolInfect Dis. 1994;13:19-24.

7. Schlaeffer F, Riesenberg K, Mikolich D, Sikuler E, Niv Y. Seriousbacterial infections after endoscopic procedures. Arch Intern Med.1996;156:572-574.

8. Thornton JR, Losowsky MS. Septicaemia after colonoscopy inpatients with cirrhosis. Gut. 1991;32:450-451.

9. Yoon TY, Jung SK, Chang SH. Cellulitis due to Escherichia coli inthree immunocompromised subjects. Br J Dermatol. 1998;139:885-888.

10. Castanet J, Lacour JP, Perrin C, Bodokh I, Dor JF, Ortonne JP.Escherichia coli cellulitis: two cases. Acta Derm Venereol.1992;72:310-311.

11. Sachs MK. Cutaneous cellulitis. Arch Dermatol. 1991;127:493-496.12. Kielhofner MA, Brown B, Dall L. Influence of underlying disease

process on the utility of cellulitis needle aspirates. Arch Intern Med.1988;148:2451-2452.

13. Moreau R, Hadengue A, Soupison T, et al. Septic shock in patientswith cirrhosis: hemodynamic and metabolic characteristics andintensive care unit outcome. Crit Care Med. 1992;20:746-750.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.