Peritoneal dialysis-related peritonitis: challenges and solutions

Introduction

The use of peritoneal dialysis (PD) for renal replacement therapy varies widely in different regions of the world and in individual countries.1 In economically developed countries, the choice of PD versus hemodialysis is sometimes a matter of patient preference and sometimes due to lack of a hemodialysis unit that is easily accessible to the patient’s home. In less economically privileged areas, PD may be the first choice, due to higher costs and difficulty accessing a hemodialysis unit. In this paper, the pathogenesis, clinical features, diagnosis, and therapy of the commonest microorganisms causing PD peritonitis are reviewed, as well as measures to reduce the occurrence of peritonitis.

PD-related peritonitis – pathogenesis

The PD catheter is the source of infection for the vast majority of PD-related cases of peritonitis. The catheter provides a portal of entry for organisms into the normally sterile peritoneum. Most cases of PD-related peritonitis are the result of “touch contamination”, where the patient or their helper inadvertently breaks sterile technique and contaminates the catheter or its connections. The most common pathogens are coagulase-negative staphylococcal species (eg, Staphylococcus epidermidis) that commonly colonize human skin and hands, and Staphylococcus aureus, which together are responsible for 50% or more of infections in most series.2–4 Exit-site and tunnel infections may also lead to peritonitis. Less commonly, the abdomen itself may be the source. Diverticulitis, appendicitis, cholecystitis, or a perforated viscus may be the source, as well as intra-abdominal surgery, colonoscopy, hysteroscopy, and transmigration of bowel flora from constipation. In cases with an intra-abdominal source, the infecting organisms are usually Gram-negative enteric bacteria, streptococci and anaerobic bacteria. Bacteremia from another source may also seed the peritoneum.

Upon entry to the peritoneum, microorganisms find a very hospitable environment. It is warm, dark, and there are lots of nutrients like glucose. Also, in the uninflamed peritoneum, there is very little host defense, with a small number of peritoneal macrophages, and very few host-defense proteins like immunoglobulins or complement. In this environment, organisms can rapidly proliferate unimpeded. Within hours, bacterial products, cell-wall components for Gram-positive and endotoxin for Gram-negative bacteria induce an inflammatory response. Polymorphonuclear leukocytes (PMNLs) and activated macrophages enter the peritoneum and induce inflammation, which is manifested as abdominal pain, fever, peripheral blood leukocytosis, and cloudy dialysate from the increased number of cells in the peritoneal fluid.

PD-related peritonitis – diagnosis

During their PD, patients must be trained to be alert for the signs and symptoms of peritonitis. New onset of abdominal pain, fever, or the appearance of cloudy effluent should prompt immediate notification of their dialysis provider for urgent evaluation. In patients receiving automated dialysis, the first drain is the most likely to be cloudy and have an elevated white blood cell (WBC) count. If the patient presents with a dry abdomen, 1 L dialysate should be infused and allowed to dwell for 2 hours before sampling. Ideally, samples of dialysis effluent should be obtained for WBC count, differential, Gram stain, and culture before the administration of antibiotics. If immediate access to a facility is not possible, due to travel or distance, a sample of dialysate should be obtained under sterile conditions and refrigerated if antibiotics will be administered prior to formal sampling. Prompt fluid analysis and initiation of empiric antibiotic therapy improves outcomes. WBC count and differential should be performed on dialysis effluent. The presence of >100 WBCs/μL with >50% neutrophils on a 2-hour dwell sample usually indicates peritonitis.2

Culture with identification of the infecting organism and determination of its antimicrobial-drug susceptibility is essential for focused antimicrobial therapy. Ideally, peritoneal fluid should be inoculated into blood-culture media at the bedside. Direct inoculation into BACTEC/Alert culture bottles at the bedside has been shown to increase yield and reduce culture-negative cases.8 Obtaining a 50 mL sample of peritoneal fluid effluent, centrifuging at 3,000 g for 15 minutes, and resuspending the pellet in 3–5 mL buffer followed by Gram staining and culture of the resuspended pellet can increase the yield of cultures and Gram stains. A positive Gram stain will facilitate more focused initial antimicrobial therapy directed at Gram-positive or Gram-negative bacteria or yeast. In most cases, however, fluid Gram stains are negative. Bacterial cultures generally take 1–3 days to yield an organism. Identification of an organism and testing for drug susceptibility allows focused antimicrobial therapy.

Initial empiric antibiotic therapy for peritonitis

After obtaining PD fluid for microbiologic testing, empiric antibiotic therapy should be started as soon as possible. In the absence of a positive Gram stain, empiric therapy should include antibiotics that cover both Gram-negative and Gram-positive bacteria. The choice of antibiotics should be determined by the prevalence and types of antibiotic-resistant bacterial isolates from peritonitis patients in the program. Antibiotics should be administered intraperitoneally in most cases.2 For empiric coverage of Gram-positive bacteria, recommended drugs are cefazolin or vancomycin. In programs with a low incidence of MRSA species and enterococci, cefazolin would be preferred. In many programs, MR coagulase-negative staphylococci and MRSA are common pathogens in peritonitis patients, and vancomycin should be used initially, pending culture results. For empiric coverage of Gram-negative bacteria, initial therapy should include a third-generation cephalosporin (ceftazidime or cefepime) or an aminoglycoside (gentamicin, tobramycin, or amikacin). Again, the choice of antibiotics for empiric Gram-negative coverage is dependent on the species of bacteria and the prevalence and types of antibiotic-resistant pathogens in the program.

Definitive therapy for PD-related peritonitis

In most cases, culture and susceptibility results will be available in 3–5 days, and antibiotic therapy can be focused on a single agent. In culture-negative cases, particularly those that are not severe, the most likely pathogen is a Gram-positive organism, most often a coagulase-negative Staphylococcus sp., and Gram-negative coverage can be discontinued. If the patient has not responded clinically after 3–5 days, as described earlier, repeat peritoneal fluid sample should be cultured for unusual pathogens.

PD-related peritonitis: clinical features, diagnosis, and therapy by organism

Peritonitis caused by nonfermenting Gram-negative rods: Pseudomonas, Acinetobacter, and Stenotrophomonas

Pseudomonas, Acinetobacter, and Stenotrophomonas are strict aerobes (nonfermenters) that individually account for less than 5% of peritonitis cases in most programs. The importance of these organisms is that they are usually resistant to most antibiotics, making them more difficult to treat, and have high failure rates, often resulting in catheter removal.

Polymicrobial peritonitis

Polymicrobial peritonitis, the isolation of more than one organism in a single peritonitis episode, is reported in about 10% of cases in most series.56,57 Polymicrobial peritonitis is more common in patients with prior episodes of peritonitis. Polymicrobial peritonitis with only Gram-positive organisms makes up about 20% of cases and has the best prognosis in terms of cure rates and catheter retention. Infections that include Gram-negative bacteria, anaerobes, or fungi have worse outcomes, with higher failure rates, catheter removal, and permanent transfer to hemodialysis.56–58 Isolation of multiple species, especially Gram-negative enteric bacteria and anaerobes should raise suspicion for an intra-abdominal infection, which is present in less than 10% of cases. Antimicrobial therapy should be guided by culture and sensitivity results and continued for 3 weeks. Patients with a poor response to therapy should have their catheters removed promptly to preserve their peritoneal membrane.57

Culture-negative peritonitis

Culture-negative peritonitis, as the name implies, is a case with clinical findings of peritonitis: abdominal pain, elevated peritoneal fluid WBCs, and peritoneal fluid cultures not growing a pathogen. Potential causes of culture-negative cases are antibiotic administration prior to peritoneal fluid cultures, suboptimal handling or processing of cultures or culture techniques,59–61 or the presence of fastidious organisms, AFB, or filamentous fungi. Guidelines recommend a benchmark of less than 20% culture-negative cases. Generally, patients with culture-negative peritonitis do well. Peritoneal fluid should be reevaluated at day 3 to assess response to therapy.2 Those who respond to initial empiric therapy can have their Gram-negative antibiotic discontinued, and can be treated with 2 weeks of vancomycin or cefazolin.2,59 Patients who do not respond to empiric therapy with a reduction in abdominal pain and/or improvement in peritoneal WBC count need to be reevaluated for infection with fastidious bacteria, fungi, or mycobacterial infection with more involved bacterial cultures and cultures for AFB and fungi. A lack of response should also prompt consideration for catheter removal after 5–7 days.

Fungal peritonitis

The incidence of fungal peritonitis varies from center to center, from <5% to 15% of cases.62 Candida spp. account for 90% or more of episodes of fungal peritonitis. In older studies, the majority of Candida peritonitis cases were caused by Candida albicans. More recent series have reported Candida albicans in less than half their cases, with frequent isolation of Candida parapsilosis, Candida tropicalis, and Candida krusei.62–65 Candida spp. are part of the normal flora in most people’s skin and GI and GU tracts, and antibiotic therapy increases their density of colonization. Therefore, most cases of Candida peritonitis follow a recent course of antibiotics for peritonitis or other indications. Touch contamination is the usual route of infection.

The clinical presentation of Candida peritonitis resembles bacterial peritonitis, with abdominal pain and elevated peritoneal fluid WBC count with neutrophilic predominance. Candida exists only in yeast form, and grows readily on routine bacteria-culture media. Specific fungal cultures are unnecessary. Antifungal drug-susceptibility testing is widely available, and tests for fluconazole, flucytosine, amphotericin B, and caspofungin. In cases of Candida peritonitis, initial empiric therapy should be with fluconazole, pending species identification and drug-susceptibility testing. Fluconazole is administered at 200 mg intraperitoneally every 24–48 hours or given orally at a loading dose of 200 mg followed by 50–100 mg daily. Drug-susceptibility testing should be obtained, because C. krusei is always resistant to fluconazole and Candida glabrata often resistant. In addition, other Candida spp. may become resistant.65 In the event of fluconazole-resistant organisms, therapy with amphotericin B 0.75–1 mg/kg/day IV along with oral flucytosine 1 g daily has been used successfully. Intraperitoneal amphotericin is very irritating and difficult to use. If flucytosine is used, trough serum levels should be measured with a target level of 25–50 μg/mL to avoid toxicity.66 Voriconazole is a newer triazole antifungal that is active on many fluconazole-resistant strains.67 There is little experience using voriconazole to treat Candida peritonitis, but it has been used successfully in the treatment of peritonitis caused by filamentous fungi at a dose of 200 mg intraperitoneally once daily or 200 mg orally twice a day.68,69

Candida peritonitis is difficult to treat effectively, and results in a high rate of catheter loss and permanent transfer to hemodialysis. ISPD guidelines and a number of other sources recommend immediate catheter removal upon diagnosis of Candida peritonitis, followed by 2 weeks of antifungal therapy.2,62,64,65,70 However, two published series showed fairly good success with other treatment modalities. Wang et al treated 13 Candida peritonitis patients with IV amphotericin B and oral fluconazole, leaving the catheter in place until the effluent cleared.66 These patients were treated with antifungals for 1–2 more weeks, followed by catheter replacement about 4 weeks after the onset of treatment. However, of these 13 patients, none successfully returned to PD. Boer et al successfully treated eight Candida peritonitis patients with catheters in place.71 Patients received fluconazole 150 mg intraperitoneally every 48 hours, oral flucytosine 500 mg twice daily, and catheters were locked with 10 mL amphotericin B 0.1 mg/mL after each continuous ambulatory PD exchange.

The majority of patients with Candida peritonitis have received a recent course of antibiotics for peritonitis or other indications prior to the diagnosis of Candida peritonitis.72 Broad-spectrum antibiotics reduce the normal bacterial flora of the skin and GI and GU tracts, and facilitate overgrowth with Candida spp. Early studies suggested that therapy with oral nystatin, a nonabsorbable antifungal, taken during antibiotic therapy might reduce the incidence of secondary fungal peritonitis, but the degree of protection was not large.73 A more recent randomized controlled trial in which patients who were receiving antibiotics for bacterial peritonitis, administration of fluconazole 200 mg orally every 48 hours reduced the incidence of secondary fungal peritonitis by more than 80%.74 This is now recommended in the ISPD guidelines.2

Peritonitis caused by filamentous fungi or molds is less common than Candida, accounting for less than 10% of cases of fungal peritonitis.72 These organisms are ubiquitous in the environment, and probably cause peritonitis via touch contamination. Clinical presentation and peritoneal fluid studies resemble bacterial peritonitis.75 These organisms do not grow well on standard bacteria-culture medias, so in culture-negative cases that fail to improve by day 3 of empiric antibiotic therapy, fluid should be obtained for fungal cultures. These cultures are inoculated on fungal-culture media, and the organisms grow as molds. The most frequently reported organisms are Aspergillus, followed by Mucor (mucormycosis), but a variety of other species have been reported to cause fungal peritonitis.62,75 Upon diagnosis, the catheter should be removed promptly. These organisms are almost always resistant to fluconazole, but may be susceptible to voriconazole or posaconazole and are usually susceptible to amphotericin B. There is not a lot of published experience with these infections, but most would treat with effective antifungal therapy for 2–8 weeks before attempting catheter replacement. Case reports have had success with intraperitoneal and oral voriconazole for Aspergillus peritonitis and liposomal amphotericin B and oral posaconazole for Mucor peritonitis.68,69 Despite optimal management, half or more of these patients will experience technique failure and transfer to hemodialysis.76,77

Mycobacterial peritonitis

Human mycobacterial infections are lumped into two groups: those caused by Mycobacterium tuberculosis (MTB) and those caused by non-tuberculous mycobacteria (NTM). MTB infection is spread from one person to another, usually establishing a latent infection that may reactivate. NTM are environmental organisms that do not spread from person to person, and although uncommon causes of PD peritonitis, seem to be increasing in incidence.

Tuberculous peritonitis

Tuberculous peritonitis usually arises as reactivation of a latent tuberculous infection. Chronic renal insufficiency is immunosuppressive and associated with a 100-fold increase in the incidence of reactivation disease.78 It should be routine practice to screen patients for latent tuberculous infection as they prepare for dialysis or enter a dialysis program, especially if they live in or have emigrated from an area that has a high incidence of latent tuberculous infection (Asia, Africa, South or Central America). This is easily done with a tuberculin skin test or an IFNγ-release assay.79 Patients who are diagnosed with a latent tuberculous infection should receive preventive therapy with isoniazid 300 mg daily or 900 mg three times a week with pyridoxine 50 mg daily for 9 months. This will greatly reduce their risk of developing active TB.

Of PD patients who develop active TB, peritonitis is the site of infection (37%) nearly as often as pulmonary TB (40%).80 The clinical presentation of tuberculous peritonitis resembles bacterial infection, with fever, abdominal pain, and cloudy dialysate with elevated WBCs that are usually predominantly PMNLs.81,82 The main difference is TB peritonitis tends to have more subacute onset of signs and symptoms. Routine bacterial cultures of peritoneal fluid are negative and AFB smears of fluid are rarely positive. At the time of presentation, TB skin tests are usually negative, due to anergy.83,84 In cases of culture-negative peritonitis, TB should be considered and fluid sent for AFB smears and cultures. The rate of positive AFB smears of peritoneal fluid is less than 20% in most series, and AFB cultures using the BacT system are positive in 70%–90%, but take 10–14 days to become positive. Peritoneal biopsy is usually positive with granulomas present and positive cultures, but is invasive. A more rapid means of diagnosis is a direct PCR of PD fluid. PCR for MTB yields results in a few hours, and is very sensitive and specific for TB peritonitis.81,83–85

Upon diagnosis of TB peritonitis, four-drug antituberculous therapy should be started. ISPD guidelines recommend isoniazid 300 mg once daily, rifampin 600 mg once daily, pyrazinamide 25–35 mg/kg three times weekly, and oral ofloxacin 200 mg once daily, with oral pyridoxine 50 mg once weekly.2 Ethambutol is not recommended, because of the risk of optic neuritis. With drug-susceptible strains, pyrazinamide and ofloxacin may be stopped after 2 months and isoniazid and rifampin continued for a total of 12–18 months. In several series, treatment without catheter removal resulted in good outcomes.80,82–84 Despite optimal diagnosis and therapy, mortality rates are 20%–30%.

Nontuberculous mycobacterial peritonitis

NTM are a group of 150 or more species, many of which have been identified as human pathogens. These organisms exist in the environment in water, soil, animals, and birds, are usually acquired from water or other environmental sources, and are not transmitted from one person to another.86 In most centers in the USA, peritonitis caused by NTM is more common than MTB. NTM may also cause exit-site infections, which may lead to peritonitis. Use of gentamicin for exit-site prophylaxis has been associated with an increased incidence of NTM exit-site infection.6,87

The clinical presentation of NTM peritonitis resembles bacterial peritonitis, with abdominal pain and cloudy effluent with a neutrophil predominance, but bacterial cultures are usually negative at 3 days. AFB smears of the fluid are usually negative. The most frequent causative organisms are the rapidly growing Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum.88–92 These organisms will often grow on routine bacteria-culture media within 5 days. They are Gram-positive rods on Gram staining, and may be misidentified as diphtheroids. If that occurs, request the lab to perform an AFB stain on the isolate. Species identification and antimicrobial-susceptibility testing are necessary for effective therapy. These organisms are usually resistant to standard antituberculous drugs like isoniazid, rifampin, and pyrazinamide. Treatment should be guided by antimicrobial drug-susceptibility testing, and often includes aminoglycosides, macrolides, and fluoroquinolones. Over 80% of reported cases require catheter removal with antimicrobial therapy continued for at least 6 weeks thereafter.

Preventing peritonitis

Rates of PD-associated peritonitis have decreased substantially over the years through improvements in equipment, techniques, and prophylactic measures. The 2016 ISPD guidelines recommended a benchmark of 0.5 episodes per year or one episode every 2 years.2 Reduction in peritonitis cases is a multifaceted process, starting with extensive patient training, focusing on proper technique.93,94 The use of two-bag, flush-before-fill with Y connectors is thought to be partially responsible for reducing peritonitis rates. Administration of prophylactic antibiotics with vancomycin or first- or second-generation cephalosporins prior to catheter placement has been shown to reduce postoperative catheter infections and is recommended in ISPD guidelines.2,95 Some evidence suggests that screening patients for nasal carriage of S. aureus and treating carriers with intranasal mupirocin reduces postoperative Staphylococcus infections.6,95 The choice between double-cuff, swan-neck, or Tenckhoff catheters seems to have little effect on peritonitis rates, nor does choice of dialysis fluids.2

In the event of a break in technique, like touch contamination, the patient should be educated to notify their provider immediately. If fluid has not been infused, the patient may need to have the end of the tubing exchanged. If it is likely contamination has occurred and fluid has been infused, a short course of prophylactic antibiotics is probably indicated, depending on the nature of the contamination. This usually consists of a single intraperitoneal dose of cefazolin or a 2-day course of an oral antibiotic, such as cephalexin.95

Patients should be trained in proper exit-site care. Good hand hygiene prior to any exit-site care is very important. The exit site should be cleansed at least twice a week and after showering with antibacterial soap and water or chlorhexidine soaps.2,6 Daily application of antimicrobials to the exit site has been shown to reduce exit-site infections and peritonitis. Mupirocin cream applied daily to the exit site has been shown to reduce S. aureus exit-site infections and peritonitis by 73%.96

Mupirocin only has activity against Staphylococcus, Streptococcus, and other Gram-positive bacteria. Gentamicin cream is also effective in reducing exit-site infections caused by S. aureus, Pseudomonas, and other Gram-negative bacteria.97 However, some studies have reported increased incidence of exit-site infections with S. aureus, Gram-negative enteric bacteria, Pseudomonas,98 and NTM in patients using gentamicin for exit-site prophylaxis.6,87

Invasive diagnostic and therapeutic procedures that result in transient bacteremia have been implicated as causes of peritonitis. Antibiotic prophylaxis with a single 2 g oral dose of amoxicillin 2 hours prior to dental procedures that induce bleeding of the gums is recommended.95 Periprocedural antibiotic prophylaxis with parenteral ampicillin and gentamicin is also recommended for patients undergoing colonoscopy, hysteroscopy, or other invasive procedures that disrupt colonized mucosal surfaces to prevent peritonitis.2,95 As mentioned earlier, antifungal prophylaxis with oral fluconazole is recommended for PD patients who are receiving antibiotics for peritonitis or other infections.2