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Abstract

Peritonitis is the most common complication in patients undergoing peritoneal dialysis (PD). Peritoneal dialysis-related peritonitis caused by Brucella species has been reported in only 7 patients before. Here, we report a further case of Brucella peritonitis. This patient was successfully treated with both intraperitoneal and prolonged oral antibiotics, without removal of the PD catheter. We review relevant literature and make recommendations for the diagnosis and treatment of Brucella PD-related peritonitis from the cumulative published clinical experience.

Keywords

China PD-related peritonitis

Despite the improving outcomes of peritoneal dialysis (PD), PD-related peritonitis remains a common complication and the major cause of technique failure and transfer to hemodialysis (HD). The most common etiological agents of peritonitis are gram-positive bacteria, while gram-negative bacteria, fungi, and mycobacteria are less common (1,2). Brucella is a rare etiological agent, and to our knowledge, only 7 cases have been reported. Our case report below is the 8^th such case, and also the first case in China. We review the insights we gained from the case, as well as the cumulative clinical experience of others from the relevant literature.

Case Report

A 54-year-old female PD patient presented with a 1-day history of abdominal pain, nausea, vomiting, diarrhea, fatigue, anorexia, bilateral knee pain, cloudy PD effluent, and ultrafiltration decrease. Upon enquiry, she reported eating beef at a restaurant the day before the onset of symptoms and performing a single PD exchange without using her usual sanitary measures while at the restaurant.

Her past history was of end-stage kidney failure from chronic glomerulonephritis, and a history of PD for 11 years. She had no other medical history of note. Her course of PD had been rather quiet, with only 1 previous peritonitis episode due to Streptococcus salivarius 2 years earlier. Her PD regimen at the time of presentation was continuous ambulatory PD (CAPD), using a single 2-L exchange of 1.5% and 4 times 2-L exchanges of 2.5% dextrose per day.

Physical examination showed her body temperature to be 36.2°C, blood pressure 150/80 mmHg. The patient had umbilical tenderness during palpation and slight bilateral lower-limb edema. Other examination results were unremarkable. Her PD catheter exit site was normal. Her full blood count showed a white blood cell (WBC) count of 17.16 x 10⁹/L with 86.2% neutrophils, a hemoglobin of 102 g/L, and platelet count of 168 x 10⁹/L. Her serum biochemistry showed a serum potassium of 2.97 mmol/L, serum creatinine of 1,056 μmol/L, and electrolytes and liver function tests that were otherwise normal.

Her PD effluent was turbid, with WBC 1,950/μL with 87% neutrophils. Gram stain of the peritoneal fluid did not show any microorganisms. The patient was diagnosed as having PD-related peritonitis and received outpatient empirical antibiotic treatment with ceftazidime 1 g daily, and vancomycin 1 g daily for the first 2 days, and then 0.5 g intraperitoneally every 2 days. The effluent WBC decreased to 351, 207, and 170/ μL on the 3^rd, 5^th, and 7^th days, respectively, with neutrophil predominance, and was slower to resolve than expected. On day 7, the PD effluent culture from the time of her admission was reported as growing Brucella spp. After involvement of the infectious disease service, we adjusted treatment to amikacin 200 mg and levofloxacin 200 mg once a day intraperitoneally, together with oral doxycycline 100 mg twice a day and rifampicin 600 mg daily. Her PD catheter was not removed, and PD was continued as usual.

On the 8^th day, her blood WBC was 9.85 x 10⁹/L with 70.1% neutrophils, her erythrocyte sedimentation rate (ESR) was 97 mm/h, her C-reactive protein (CRP) 28 mg/L, serum potassium 3.07 mmol/L, and serum creatinine 860 μmol/L. On the 6^th day after modifying the antibiotic regimen, the effluent WBC decreased to 9/μL, and there was clear evidence of ultrafiltration recovery. Levofloxacin and amikacin treatments were used for a total of 3 weeks, and then modified to oral minocycline, rifampicin, and levofloxacin for a total treatment duration of 18 weeks.

The patient's progress was closely monitored during follow-up, with frequent clinical assessments as well as measurement of effluent WBC, nutritional parameters, ultrafiltration, serum potassium, liver transaminase, etc. She was reviewed every 6 weeks by the infectious disease specialists. Upon completion of treatment, the PD effluent was clear, and her effluent WBC was 4/μL. No recurrence was observed after 10 months follow-up.

Discussion

Brucellosis is a worldwide epidemic infectious disease, which is hyperendemic in the Mediterranean Basin, the Arabian Peninsula, India, Mexico, Central and South America, and Turkey, where the prevalence is more than 10 per 100,000 of the population (3). In China, the epidemic has risen significantly since 1996 and the average incidence rate during 2015 – 2016 was 3.81 per 100,000 of the population. There is significant regional variation, however, and the corresponding incidence rate from the northern provinces was higher at 7.7 per 100,000 (4).

Brucellosis is caused by Brucella, which can invade the body through skin and mucous membranes, the digestive tract, and the respiratory tract (5). As a zoonotic disease, the main sources of infection are sheep and cattle. The mode of transmission can be by inhalation (during slaughtering and meat packing), direct entry through skin wounds or mucous membranes (during routine animal care and dealing with excretions or products of conception), and ingestion of undercooked meat or unpasteurized dairy products, including milk, cheese, and ice cream (6). The disease is most commonly reported in male farm workers.

Systemic brucellosis can involve multiple organs and systems, such as the liver, spleen, lymph nodes, bone marrow, and so on (7). In the acute stage of brucellosis, the main manifestations include fever, fatigue, sweating, muscle and joint pain, and enlargement of the liver, spleen, and lymph nodes. In the chronic phase, joint damage can be seen. Brucella is a rare cause of peritonitis, sometimes occurring as a complication of systemic brucellosis (8 9 10 11 12-13), but also as spontaneous episodes in the setting of hepatic cirrhosis (14 15 16 17 18 19 20-21) or concurrently with neurobrucellosis in those with ventriculoperitoneal shunts (22 23-24).

Given the impaired peritoneal defenses in patients with PD, these patients have a higher risk of peritonitis than the general population (25,26). However, only 7 cases of Brucella PD-related peritonitis have been reported prior to ours: 6 cases from Turkey and 1 case from Saudi Arabia. We have summarized these cases in Tables 1 to 3. As expected, 6 of the total reported 8 cases were male, with the most frequently identified risk factors being ingestion of unpasteurized milk or cheese and direct contact with cattle and sheep.

In these cases, PD-related peritonitis due to Brucella presented in much the same way as PD-related peritonitis from other causes (Table 1). Abdominal pain and cloudy PD effluent were common, but fever and the specific clinical symptoms of brucellosis, such as fatigue and sweating, were not. There was usually an accompanying elevated WBC count, high ESR and CRP, and a high leukocyte count in PD effluent with either lymphocyte or neutrophil predominance. Peritoneal dialysis-related peritonitis due to Brucella has been reported presenting as either acute peritonitis or in a more relapsing indolent manner (27).

Table 1

General Information and Clinical Findings in Reported Cases of Brucella PD-Related Peritonitis

Reference	Country	Age	Gender	Vintage on PD (months)	Previous peritonitis	Presenting complaints	Temperature at presentation (°C)	Systemic brucellosis	Predisposing factors
Taskapan et al., 2002 (8)	Turkey	47	M	12	No	Fatigue, sweating, back pain, cloudy dialysate	38.2	Yes	Ingestion of unpasteurized dairy products
Ozisik et al., 2006 (7)	Turkey	39	F	60	Yes, 4 episodes	Nausea, abdominal pain	37.3	No	Contact with sheep and cattle
Alothman et al., 2008 (27)	Saudi Arabia	67	M	4	NR	Abdominal pain, cloudy dialysate	Afebrile	No	Ingestion of unpasteurized dairy products
Aydin Unal et al., 2009 (29)	Turkey	38	M	2	No	Nausea, vomiting, abdominal pain, cloudy dialysate	37.3	Yes	Ingestion of unpasteurized dairy products
Aydin Unal et al., 2009 (29)	Turkey	52	M	6	No	Nausea, vomiting, abdominal pain, joint pain, cloudy dialysate	37.2	Yes	Ingestion of unpasteurized dairy products
Solak et al., 2012 (30)	Turkey	48	M	36	NR	Abdominal pain and bloating, constipation	Afebrile	No	Contact with sheep and cattle
Koz et al., 2014 (28)	Turkey	49	M	NR	NR	Myalgia, malaise, abdominal pain, cloudy dialysate	Afebrile	No	NR
Present report	China	54	F	132	Yes, 1 episode	Fatigue, nausea, vomiting, abdominal pain, diarrhea, joint pain, cloudy dialysate	Afebrile	No	Possible ingestion of undercooked beef, single PD exchange while in restaurant

PD = peritoneal dialysis; NR = not reported.

There are 5 teaching points arising from our case. First, PD-related Brucella peritonitis can and does occur in the absence of systemic brucellosis. If Brucella growth is seen in both blood and effluent cultures, the microorganisms might have spread from the circulation to the peritoneum via the hematogenous route (8). Our patient's blood culture was negative, however. In cases such as ours, the isolated PD-related peritonitis is surmised to arise from direct entry of the bacteria though the PD catheter (7).

Second, infections due to Brucella can occur in patients without obvious environmental risk factors. In China, PD is widely used in rural settings, which obviously exposes patients to transmission of the bacteria from infected animals. However, the entire general population is susceptible to Brucella. In urban settings, exposure is most likely to occur from under-cooked meat and unpasteurized dairy products. In our patient, Brucella is surmised to have been transmitted from contaminated ingredients in her restaurant meal. Of note, freezing, smoking, drying, and pickling do not kill the bacteria that cause brucellosis, and routine restaurant precautions other than thorough cooking are not protective.

Third, the diagnosis of Brucella PD-related peritonitis is often delayed. Brucella grows slowly in culture medium, and identification of the bacteria usually requires extended culture duration (see Table 2). In addition, some of the new expanded spectrum cephalosporins show reasonable activity against Brucella and are an increasingly common part of empirical regimens for PD-related peritonitis. In the case of our patient, empirical antibiotics resulted in a partial response to treatment, which delayed our search for a less conventional cause and impeded our recognition of peritonitis from an atypical organism. One possible way of expediting diagnosis might be the use of Brucella immunocapture–agglutination tests on PD effluent, which are generally positive and might be preemptively ordered if the clinician's index of suspicions were high enough. Enzyme-linked immunosorbent assay (ELISA) tests for serum Brucella immunoglobulin M (IgM) and G (IgG) antibodies have also been used, although there is not enough experience to make a recommendation.

Table 2

Laboratory Findings in Reported Cases of Brucella PD-Related Peritonitis

	PD Effluent		Culture		Blood			Brucella agglutinin titer
Reference	WBC (per μL)	Initial Gram stain	Effluent	Blood	WBC (x10⁹/L)	ESR (mm/h)	CRP (mg/L)	Serum	Effluent	ELISA IgG	ELISA IgM
Taskapan et al., 2002 (8)	300 (NE predominance)	No organisms	B. melitensis on day 6	B. melitensis on day 6	6.2	NR	NR	1:2,560	NR	NR	NR
Ozisik et al., 2006 (7)	3,140 (NE 80%)	No organisms	B. melitensis, on day 21	Neg.	14.5 (NE 95%)	NR	259	Neg.	1:160	Neg.	Neg.
Alothman et al., 2008 (27)	3,356 (NE 85%)	No organisms	Brucella spp. on day 6	NR	8.1	63	NR	B. melitensis: 1:2,560 B. abortus: 1:640	NR	NR	NR
Aydin Unal et al., 2009 (29)	1,600 (NE predominance)	No organisms	B. melitensis on day 5	B. melitensis on day 5	4.08	30	NR	1:640	Neg.	NR	NR
Aydin Unal et al., 2009 (29)	5,100 (NE predominance)	No organisms	B. melitensis on day 6	B. melitensis on day 6	8.1	130	13.1	1:640	1:20	NR	NR
Solak et al., 2012 (30)	820 (LY 48%, MO 36%)	No organisms	Brucella spp.	Neg.	7.16	NR	54	1:5120	NR	Pos.	Pos.
Koz et al., 2014 (28)	1,300 (LY 70.4%)	No organisms	Brucella spp. on day 3	Neg.	7.1 (NE 69%)	NR	NR	1:1,280	1:80	NR	NR
Present report	1,950 (NE 87%)	No organisms	Brucella spp. on day 7	Neg.	17.2 (NE 86.2%)	97	28	NR	NR	NR	NR

PD = peritoneal dialysis; WBC = white blood cell; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; ELISA = enzyme-linked immunosorbent assay; Ig = immunoglobulin; NE = neutrophil; NR = not reported; Neg. = negative; MO = monocyte; LY = lymphocyte; Pos. = positive.

Fourth, best results are seen when antimicrobial treatment is administered early, in combination therapy, with adequate dosing, and for several months (see Table 3). In the case of our patient with PD-related peritonitis, we administered antibiotics intraperitoneally for 3 weeks according to the ISPD guidelines, as would be done for any PD-related peritonitis. Logically, intraperitoneal antibiotics in the early stage will facilitate control of the local infection, and reduce the colonization or formation of PD-catheter biofilm, thereby preventing recurrence (28,31). Of note, we also administered standard treatment for systemic brucellosis, with oral administration of minocycline, rifampicin, and levofloxacin for a total of 18 weeks. It goes without saying that all decisions should be made with the input of infectious disease or microbiology specialists.

Table 3

Treatment and Outcomes in Reported Cases of Brucella Peritonitis in PD

Reference	Initial empirical treatment	Induction treatment for Brucella	Maintenance treatment for Brucella	Total treatment duration for Brucella (weeks)	Catheter removal
Taskapan et al., 2002 (8)	Amikacin, IP Vancomycin, IP	Doxycycline 100 mg twice daily, PO	Doxycycline 100 mg twice daily, PO	6	Yes
		Rifampin 600 mg daily, PO	Rifampin 600 mg daily, PO
Ozisik et al., 2006 (7)	Piperacillin-tazobactam IV	Doxycycline 100 mg twice daily, PO	Doxycycline 100 mg twice daily, PO	6	Yes^a
	Vancomycin IV	Rifampin 450 mg daily, PO	Rifampin 450 mg daily, PO
Alothman et al., 2008 (27)	Cefazolin, IP	Doxycycline 100 mg, PO Rifampin 600 mg daily, PO	Doxycycline 100 mg, PO Rifampin 600 mg daily, PO	21	Yes
Aydin Unal et al., 2009 (29)	Amikacin, IP Vancomycin, IP	Doxycycline 100 mg twice daily, PO	Doxycycline 100 mg twice daily, PO	6	No
		Rifampin 600 mg daily, PO	Rifampin 600 mg daily, PO
Aydin Unal et al., 2009 (29)	Amikacin, IP Cefazolin, IP	Doxycycline 100 mg twice daily, PO	Doxycycline 100 mg twice daily, PO	6	No
		Rifampin 600 mg daily, PO	Rifampin 600 mg daily, PO
Solak et al., 2012 (30)	Ceftriaxone, IV Vancomycin, IV	Doxycycline 100 mg twice daily, PO	Ceftriaxone 1 g twice daily, IV	8	No
		Rifampin 600 mg daily, PO	Rifampin 600 mg daily, PO
Koz et al., 2014 (28)	Amikacin, IP Cefazolin, IP	Amikacin IP Doxycycline 100 mg twice daily, PO Rifampin 600 mg daily, PO	Doxycycline 100 mg twice daily, PO Rifampin 600 mg daily, PO	6	No
Present report	Ceftazidime, IP Vancomycin, IP	Minocycline 100 mg twice daily, PO Rifampin 600 mg daily, PO Amikacin 200 mg and levofloxacin 200 mg daily, IP	Levofloxacin 200 mg, PO Minocycline 100 mg twice daily, PO Rifampin 600 mg daily, PO	18	No

IP = intraperitoneal; IV = intravenous; PO = oral.

Catheter removed prior to diagnosis of Brucella peritonitis.

Finally, catheter removal is clearly not necessary for every case of Brucella PD-related peritonitis. In the earlier literature, catheters were often removed due to ineffective initial treatment or recurrence of peritonitis (7,27). In our case, treatment was effective without catheter removal, as was the case for all the other more recently reported cases (8,28 –30). This experience suggests that catheter removal should be reserved for patients with severe local manifestations, and disease that is unresponsive or recurrent despite optimal treatment with IP antibiotics combined with a prolonged course of appropriate oral antibiotics.

In summary, Brucella PD-related peritonitis is rare but associated with excellent outcomes if appropriately treated. Clinicians should have a low index of suspicion in those with risk factors, especially if there is a delayed or incomplete response to empirical antibiotics. Diagnosis may require prolonged culture of PD effluent, or the use of serological tests. In our opinion, the keys to good outcomes are initial IP antibiotics followed by a suitably prolonged course of oral antibiotics, as guided by infectious disease or microbiological specialists. Removal of the PD catheter should be reserved for severe, unresponsive, or recurrent disease.

Footnotes

Huiping Zhao has received a research grant from Baxter. Mark R. Marshall is a fully employed by Baxter Healthcare Asia (Pty) Ltd. The other authors have no financial conflicts of interest to declare.

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