Are Nectarines to Blame? A Case Report and Literature Review of Spontaneous Bacterial Peritonitis Due to Listeria monocytogenes

Abstract

Spontaneous bacterial peritonitis (SBP) is a frequent and potentially deadly complication of ascites in patients with end-stage liver disease. Unlike other pathogens more commonly implicated in SBP, Listeria monocytogenes is a nonenteric organism that may be acquired either sporadically or in the setting of foodborne outbreaks. Listeria is an unusual cause of SBP that presents particular management challenges because of the organism’s intrinsic resistance to first-line and empiric SBP treatment that would otherwise include third-generation cephalosporins. We present here a case of Listeria SBP in a 68-year-old man with previously unidentified cirrhosis. His infection occurred in the context of a nationwide fruit recall for Listeria contamination, prompting an epidemiologic investigation. After describing the case, we then review the extant literature on Listeria peritonitis. To date, no case studies on Listeria SBP have systematically described risk factors for Listeria acquisition. As incidence of Listeria SBP is increasing, however, knowledge of patient risk factors, especially foodborne exposure risks, may be important in preventing future episodes of Listeria SBP, and in accurately monitoring foodborne outbreaks.

Introduction

Spontaneous bacterial peritonitis (SBP) is a frequent complication of end-stage liver disease (ESLD) associated with significant morbidity and mortality. In the United States, SBP affects an estimated 10–30% of hospitalized cirrhotic patients, and is associated with a 10–50% in-hospital mortality rate.¹ The guideline-recommended empiric treatment of SBP is a third-generation cephalosporin, which has activity against the most common causative pathogens, including E. coli, Klebsiella pneumoniae, Streptococci spp., and Enterobacteriaceae spp.² In a minority of cases (<5%), Candida, anaerobes, and Listeria are implicated.² In an era of widespread antibiotic use and overuse, shifting patterns of antimicrobial resistance have resulted in an increased reported incidence of SBP caused by multidrug resistant pathogens such as extended spectrum beta-lactamase (ESBL)-producing gram-negative bacteria.^3–6

Listeria monocytogenes is a gram-positive rod that is ubiquitous in the environment and a facultative anaerobe with a unique intracellular pathogenesis. Patients with depressed cellular-mediated immunity, such as those who are pregnant, at extremes of age, or otherwise immunocompromised are at risk of severe Listeria infection because of an impaired ability to clear the pathogen. The most common clinical syndromes associated with Listeria are bacteremia, meningo encephalitis, endocarditis, infection in pregnancy, neonatal infection, and febrile gastroenteritis. In contrast, peritonitis is a relatively rare focal manifestation of Listeria infection that can occur as a result of direct inoculation or transient bacteremia with secondary seeding of peritoneal ascites.^7,8 Although most cases of listeriosis are sporadic, a minority of Listeria infections occur within the context of foodborne outbreaks.⁸

Given these difficulties in recognizing and managing listeriosis as a rare cause of SBP, a number of related case reports have previously been published in the scientific literature.^9–20 Missing from these previous descriptions, however, is any thorough examination of risk behaviors that place the isolated case in the context of existing epidemiology. Moreover, there are few descriptions of Listeria peritonitis in patients with cirrhosis, particularly in the U.S. Here, we present a case of Listeria SBP that occurred in the context of a nationwide recall of Listeria-contaminated stone fruits. In doing so, we contribute to existing literature on SBP listeriosis by describing clinical challenges and risk behaviors particular to cirrhotic patients, notably foodborne exposure, and further contextualize the case in terms of a nationwide outbreak investigation.

Case Report

A 68-year-old man with a history of coronary artery disease, hypertension, and stage four chronic kidney disease due to IgA nephropathy was admitted to our hospital with increasing abdominal pain and distention. One week prior, he had presented to the emergency department for two weeks of ongoing malaise, decreased appetite, and watery diarrhea. At that time, he was found to have acute chronic kidney injury (see Table 1 for laboratory values) attributed to volume depletion from his diarrheal illness. He was rehydrated with four liters of intravenous saline and his creatinine subsequently normalized. At the time of this presentation he did not have any notable abdominal distention; an abdominal ultrasound was therefore not performed. One set of liver function tests was elevated relative to baseline (Table 1); however, due to the overall improvement of his symptoms and lab values with rehydration, the patient was discharged. At home, he continued to experience progressive fatigue, abdominal distention, and persistent diarrhea over the following week and thus represented for admission.

Table 1.

Clinical Laboratory Values

	Reference Range, Adults	Baseline (2 months prior)	Emergency Department (1 week prior)	Current Presentation
Leukocytes (cells/μL)	4.0–10.5 x 1000	8.2	9.9	11.4
% neutrophils	42–75	74.3	80	84
% lymphocytes	21–51	12.3	8	5
Hg/Hct (g/dL)	13.5–18.0	8.7/25.9	11.2/35.1	11/34.8
Creatinine (mg/dL)	0.6–1.2	2.9	6.48	4.3
Glucose (mg/dL)	70–100	96	148	107
AST (U/L)	0–37	37	82	79
ALT (U/L)	0–40	19	25	27
Total bilirubin (mg/dL)	<1.2	0.6	0.65	0.67
Total protein (g/dL)	5.8–7.6	6.1	7.3	6.1
Albumin (g/dL)	3.9–4.8	3	2.8	2.2
Ascitic profile
nucleated cells (cells/μL)	<500	--	--	2,710
ANC (cells/μL)	<250	--	--	2,176
albumin (g/dL)	--	--	--	1.1
glucose (mg/dL)	>50	--	--	106
red blood cells (cells/μL)	0			6,000

Hg: Hemoglobin; Hct: Hematocrit; AST: Aspartate Transaminase; ALT: Alanine Transaminase; ANC: Absolute Neutrophil Count

His medical history was significant for chronic kidney disease due to biopsy-proven IgA nephropathy, coronary artery disease, and hypertension; he had no known history of any underlying liver disease. His medications included allopurinol, amiodarone, pravastatin, sucralfate, and torsemide. He lived at home with his wife in Connecticut and denied any ongoing tobacco or illicit drug use. When directly queried, he admitted a 15-year history of alcohol consumption, drinking two scotches nightly, though a follow-up CAGE screen was negative for “problematic” alcohol use. He denied any recent travel, illness exposures, or consumption of unusual foods.

On presentation, his vitals were notable for a temperature of 98.2°F, blood pressure of 108/47 mmHg, pulse 81 beats/min, respiratory rate 26 breaths/minute, and oxygen saturation 85% while breathing ambient air. His abdomen was noted to be tense and distended, with tenderness to palpation of both lower quadrants. Laboratory analysis was remarkable for a neutrophilic-predominant leukocytosis (Table 1). Bedside ultrasound revealed significant ascites and a subsequent diagnostic paracentesis was consistent with SBP (Table 1). He was thus admitted to our hospital and immediately started on piperacillin-tazobactam for empiric treatment of presumed SBP. A formal abdominal ultrasound demonstrated a heterogeneous liver suggestive of cirrhosis without evidence of portal vein thrombosis or masses. Further workup for underlying causes of his liver disease, including serology for viral hepatitides, autoimmune, or inherited liver disorders, was unrevealing. A liver biopsy was deferred due to clinical instability.

On day two of admission, the patient was transferred to the intensive care unit because of hypotension and increasing oxygen requirements. On day four, a repeat paracentesis revealed slightly improved fluid counts (absolute neutrophil count=1,383), but he experienced profound abdominal distention requiring daily therapeutic large volume paracenteses, persistent hypotension requiring pressors, and oliguria requiring initiation of hemodialysis. Peritoneal cultures from admission ultimately grew Listeria monocytogenes; blood cultures drawn on admission remained negative. Infectious Diseases consultation was requested and we recommended changing his antibiotics to ampicillin-sulbactam, based on the presumed susceptibilities of the cultured Listeria. With this regimen change, the patient experienced rapid clinical improvement. He was treated with a 14-day course of ampicillin-sulbactam, with subsequent paracentesis revealing complete resolution of his SBP.

Concurrent with the patient’s presentation, a California-based packaging company issued a nationwide recall of peaches, nectarines, plums, and pluots from several large food distributors due to documented contamination with Listeria monocytogenes.²¹ The patient was therefore queried more closely on his dietary habits. Although he had recently purchased nectarines from one of the affected food stores, he did not recall ingesting them prior to developing symptoms, but was unsure. He also denied eating any soft cheeses, smoked fish, or unpasteurized milk products. He did, however, report eating refrigerated, delicatessen meats within the expiration date. Given the coinciding national recall in our case, the appropriate public health department officials were notified and the isolate was submitted for molecular subtyping by pulse-field gel electrophoresis

Literature Review and Discussion

Though demonstrated by this case, Listeria monocytogenes is an unusual cause of SBP in patients with cirrhosis. A recent systematic review found 86 published cases in the literature between 1977 and 2011.²² Using PubMed and Google Scholar with key words “Listeria” and “peritonitis,” we performed a further search revealing 23 additional cases,^9–20 with just five of these cases reported after 2011.^{10,13,14,19,20} Of the cases of SBP reported in the United States, those due to Listeria are relatively rare.¹ The 11 cases of Listeria peritonitis in the United States that, to our knowledge, have been published to date are summarized in Table 2.^{9,12,17,20,23–28} Interestingly, approximately 60% of the reported cases of Listeria peritonitis worldwide have been from Spain.¹⁰ Possible explanations for the increased number of reports of Listeria peritonitis coming from Spain include a diet richer in unpasteurized cheese and delicatessen meats, although the incidence of listeriosis in general (i.e., manifesting as other clinical syndromes) is not increased in Spain.^29,30 The index of suspicion for Listeria SBP may be appropriately elevated in travelers from Spain.

Table 2.

Clinical Characteristics of the 12 Known Listeria Peritonitis Cases Reported in the United States

Reference	Age/sex	Underlying Disease	Blood Culture	Ascitic Fluid WBC/mm3	% granulocytes	Empiric Treatment	Narrowed Treatment	Outcome
Adeonigbagbe et al. 20009	73 / male	Liver metastases	Negative	171	69	Ampicillin-sulbactam	Ampicillin-sulbactam	Died
Curosh et al. 198912	69 / male	Cirrhosis, AAT Deficiency	Negative	2100	51	Cephapirin, Gentamicin	Ampicillin	Survived
Rheingold et al. 197717	44 / male	Cirrhosis, Hepatitis C and Alcohol	Positive	9460	76	Ceftriaxone, Metronidazole	Ampicillin	Survived
Rheingold et al. 197717	52 / female	Cirrhosis, Hepatitis C	Positive	510	84	Cefotaxime	Ampicillin-sulbactam	Survived
Yecies et al. 201320	66 / male	Cirrhosis, Hepatitis C	Negative	3168	33	Cefotaxime	Ampicillin	Died
Frachtman et al. 200923	49 / male	Cirrhosis, Alcohol	Positive	1720	90	Ampicillin	Cephazolin	Survived
Jayaraj et al. 199824	63 / male	Cirrhosis, Alcohol	Positive	1100	57	Ampicillin	Ampicillin	Survived
Nguyen et al. 199425	70 / female	Cirrhosis, Hepatitis C	Positive	14,987	NR	TMP-SMX	Ampicillin	Survived
Sivalingam et al. 199226	64 / male	Cirrhosis, Alcohol	Positive	7200	78	Ampicillin	Ampicillin+Amikacin	Died
Soto-Hernandez et al. 198827	72 / female	Cirrhosis, Autoimmune	Positive	2,889	NR	Ceftriaxone, Vancomycin	Ampicillin-sulbactam	Died
Tablang 200828	62 / male	Cirrhosis, Alcohol	Negative	6000	86	Cefotaxime	Ampicillin-sulbactam	Survived
Present Case	68 / male	Cirrhosis, Alcohol and CKD	Negative	2710	81	Piperacillin-Tazobactam	Ampicillin-sulbactam	Survived

NR: not reported; AAT: alpha anti-trypsin; CKD: chronic kidney disease; TMP-SMX: trimethoprim-sulfamethoxazole

Patients with chronic liver disease are at higher risk of listeriosis, presumably due to increased intracellular iron stores that foster Listeria growth and virulence factors.³¹ Pathogenesis of Listeria peritonitis is similar to that of gram-negative peritonitis and thought to derive from transluminal migration of the organisms through the intestinal walls with resultant seeding of the peritoneal fluid.³² The prodromal diarrhea in our patient may indeed have been an early manifestation of Listeria gastroenteritis, although diarrhea is itself a frequent symptom of SBP and is thought to be due to colonic bacterial overgrowth.

Our patient had several identifiable risk factors for SBP that deserve mention. Individuals with chronic kidney disease are predisposed to SBP.³³ Up to 30% of patients with SBP ultimately develop renal failure and hepatorenal syndrome, and this risk is significantly increased in those with preexisting kidney disease.³⁴ The patient’s initial presentation of acute kidney injury in the emergency department cannot be attributed to hepatorenal syndrome from SBP because his renal function improved with fluid administration alone, consistent with a prerenal etiology. However, it is possible that this episode increased his risk for subsequently developing SBP. First, aggressive rehydration may have contributed to volume overload, third-spacing, and exacerbation of the ascites, resulting in seeding of the peritoneum. The patient’s rapid development of abdominal distension between admissions is consistent with this explanation. Second, impairment in renal function, regardless of underlying mechanism, has been shown to be independently associated with development of SBP.³³ Acid suppression by chronic use of proton pump inhibitors (PPIs) is thought to facilitate local bacterial permeation from the gut and increase risk for SBP.^35,36 Our patient was not on PPIs but was on sucralfate for reflux symptoms. Data on whether sucralfate is associated with an increased risk for SBP are lacking but studies on H2 blockers and PPIs suggest that the risk of SBP may be in part related to the degree of acid suppression.^35,36

The diagnosis of Listeria peritonitis is predicated on growth of the organism from peritoneal fluid cultures, usually by the fourth day of incubation. Bacteremia is associated with up to 62% of cases and correlates with a poorer outcome.²² First-line treatment for Listeria is ampicillin, with the recommended treatment for Listeria peritonitis being ampicillin-sulbactam for 10–14 days, as was recommended for our patient.²⁸ The addition of the sulbactam beta-lactamase inhibitor serves to broaden the coverage to include possible coinfecting anaerobes that are common in peritonitis.²⁸

The symptoms associated with Listeria peritonitis are indistinguishable from SBP caused by any other pathogen, and include fever, abdominal pain, and distension. ²² Some authors have reported differences in ascitic fluid parameters in the context of Listeria peritonitis, including an increased mean protein level and lymphocytic predominance, as compared to peritonitis due to other causative organisms.^20,25 Differentiating peritonitis caused by Listeria from peritonitis due to other more common etiologies is of great clinical importance, since Listeria is intrinsically resistant in vitro to third-generation cephalosporins, the empiric antibiotic of choice for SBP. Listeria peritonitis is associated with an estimated mortality of 30%, with poorer outcomes in patients started on an incorrect empiric antibiotic, even after transitioning to appropriately targeted therapy.²² In this case, our patient exhibited some clinical improvement as well as cytological improvement of peritoneal fluid while on broad-spectrum piperacillin-tazobactam, which may have indicated the presence of concurrent infection with other organisms or a partial response of Listeria to the extended-spectrum penicillin.

Overall, there has been growing concern about the efficacy of third-generation cephalosporins for empiric treatment of SBP because of resistant or unusual organisms causing peritonitis. Third-generation cephalosporins such as cefotaxime or ceftriaxone are the current recommended empiric treatment for SBP.³⁷ However, two recent studies examining the efficacy of ceftriaxone reported respective failure rates of 41% and 43% in SBP cases due to acquired bacterial resistance and insufficient susceptibility of isolated organisms.^3,4 Though the use of broader-spectrum antibiotics is not generally advisable, patients with an increased risk of drug-resistant or unusual pathogens (such as Listeria) should be considered for broader coverage. In particular, patients with clear risk factors for listeriosis, including those with salient dietary exposures or relevant travel histories, should be considered for empiric treatment with ampicillin or ampicillin-sulbactam. A controlled clinical trial of complications and outcomes with different antimicrobials would be warranted to determine ideal empiric treatment of SBP among patients with risk factors for listeriosis, although it may not be feasible because of the relative rarity of this clinical syndrome.

Our case report highlights the importance of considering epidemiological risk factors in a patient presenting with Listeria peritonitis. Unlike the usual causative pathogens in SBP, such as E. coli that constitutes part of the normal gastrointestinal microbiome, most cases of Listeria are thought to be due to consumption of contaminated food.⁸ Listeria grows at colder temperatures and thus is often found in ready-to-eat deli meats, unpasteurized milk or dairy products, soft cheeses, or raw fruits and vegetables. An estimated 95% of culture-confirmed cases are sporadic, while 5% of cases are due to outbreaks.⁸ Few case reports in the literature identify foodborne exposure risks, yet this piece of historical information is key in the diagnosis of listeriosis. Although Listeria is a rare cause of SBP, there have been increasing reports in the literature.²² This may be a reflection of greater detection rates indicating a higher population-based incidence rate of Listeria SBP than previously thought. Alternatively, a greater awareness of Listeria infections, particularly in the setting of foodborne outbreaks, may have lead to increased awareness and therefore testing.

The importance of determining epidemiological risk factors in Listeria SBP is further underscored by the implication of Listeria in foodborne outbreaks.³⁸ For instance, a 2011 Listeria outbreak linked to whole cantaloupes was reported as the worst foodborne outbreak in terms of mortality rate, and was associated with 147 cases and 33 deaths.³⁸ As a direct result, food packaging companies were mandated to routinely screen all products for Listeria and to recall potentially contaminated products, regardless of whether or not a human case is ever reported. It was this very screening mandate that prompted the stone fruit recall in the case presented here.

Avoiding Listeria ingestion may obviate the need for antibiotic prophylaxis to prevent SBP recurrence, which occurs in up to 70% of patients within one year.³⁹ Our patient endorsed eating refrigerated, delicatessen meats and had an episode of diarrhea shortly before his hospitalization for SBP. Given the high mortality rate of listeriosis and Listeria SBP, it may be prudent to advise avoiding foods at high-risk of Listeria contamination to cirrhotic patients, as is practiced for women who are pregnant. More studies would have to be performed to determine the epidemiological risk factors in Listeria SBP patients and the utility of applying such stringent dietary restrictions to patients with cirrhosis. Currently, trimethoprim-sulfamethoxazole is recommended as secondary SBP prophylaxis given Listeria’s innate resistance to fluoroquinolones after an initial episode of listerial SBP.²⁸ However, if Listeria is fully eradicated during the initial episode of peritonitis with targeted antimicrobials, it is possible that secondary prophylaxis against Listeria is not necessary because the organism is not found naturally in the human microbiome. Decreasing the use of unnecessary antibiotic prophylaxis may significantly reduce the risk of selecting for resistant organisms in future cases of SBP. More studies would need to be performed to determine the need for antibiotic prophylaxis for Listeria SBP. In the case described here, secondary SBP prophylaxis with antibiotics that covered Listeria was not recommended based on the above reasoning.

Conclusion

Listeria monocytogenes is an uncommon etiologic agent of SBP, although its incidence appears to be increasing. Given its inherent resistance to third-generation cephalosporins and association with significant morbidity and mortality, an increased awareness of Listeria peritonitis is paramount. A detailed history of diet and travel, and knowledge of ongoing epidemiologic outbreaks may prove critical to successful diagnosis and prompt treatment of this rare but deadly pathogen.