Diagnosis and Treatment of Peritonitis in Peritoneal Dialysis Patients
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The following treatment recommendations provide a summary of best clinical practices based on the revised guidelines of the International Society of Peritoneal Dialysis (ISPD) issued in 2010. For complete data, please refer to the original publication by Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010. The recommendations are applicable to adult PD patients. The treatment of peritonitis in pediatric PD patients may be found in other sources. This article discusses the monitoring and reporting of peritonitis rates, presentation and initial empiric management of peritonitis and subsequent organism specific management of peritonitis. Exit-site and tunnel infections are discussed in a separate series of articles on the ADVANCED RENAL EDUCATION website.
Peritonitis is an inflammation of the peritoneum, or abdominal cavity lining. It typically has an infectious etiology, mainly due to bacteria or fungus. Bacterial infections come from contamination during peritoneal dialysis and fungal infections may occur subsequent to antibiotic use. Peritonitis is a major complication of peritoneal dialysis (PD), but only about 4% of episodes result in death of the patient. However, peritonitis does contribute to the death of approximately 16% of patients on PD. Peritoneal dialysis contributes to structural changes of the peritoneum and peritonitis is the most common cause of patients switching from PD to hemodialysis. Peritonitis treatment goals include rapidly resolving inflammation by eradicating the causative organism(s) and preserving the function of the peritoneal membrane.
Monitoring and reporting of peritonitis rates and outcome evaluation
Peritoneal-dialysis infection (exit-site and peritonitis) rates should be monitored and reported for every program annually. A goal rate of 1 episode per 18 months (0.67/year) is expected; although, rates of 1 episode per 41-52 months (0.29 – 0.23/year) are preferred. Additionally, the PD team comprised of physicians and nurses, should review the presumed etiology, causative organisms and antibiotic sensitivity of each infection. When infection rates are increasing or undesirably high, interventions should be employed. The three main methods of reporting infections due to peritoneal dialysis include using rates, percentages and median rates for each program. Rates may be calculated for individual organisms, in addition to all infections. Percentages may be reported as how many patients are considered to be free from peritonitis for a specified amount of time. Median rates may be calculated by taking the median from a list of individual peritonitis rates.
It is important to monitor and report peritonitis rates, as well as evaluate outcomes. In order to properly evaluate outcomes, a collection of data for analysis should be performed. The data should include the date when the culture was collected, any organism identified and subsequent drug therapy utilized. In addition, the date when the infection resolved should also be included. If another infection occurs, the recurrent organisms and date of treatment should be noted along with the chosen method of temporary renal replacement therapy. If the catheter is removed and a new catheter is inserted, the date of each (as applicable) should be noted. Documentation of potential contributing factors such as break in technique, exit-site infections, patient factors or tunnel infections, along with the date of re-education and training should also be completed. The purpose of documentation of data is to evaluate the program’s treatment regimen to ensure best possible outcomes for patients. If the protocol is not effective in treatment and prevention of peritonitis, it should be reassessed and changes should be implemented to achieve satisfactory results.
PD patients could have a clinical presentation consistent with cloudy effluent and abdominal pain, which can range from mild to severe. The severity of pain can be related to specific organisms (e.g., mild pain with CoNS and severe pain with gram-negative rods, streptococcus, and S. aureus). The effluent cell count with differential should be obtained, and if after 2 hours of dwell time, the WBC is greater than 100/µL with a minimum of half being polymorphonuclear neutrophilic cells, inflammation is present and peritonitis is deemed the probable cause. The gram stain should be used to define presence of yeast and permit initiation of antifungal therapy and timely removal of catheter; however, the gram stain should not be used for empiric therapy guidance. Sometimes the effluent may be clear despite abdominal pain. The differential diagnosis should include other causes aside from peritonitis, such as constipation, peptic ulcer disease, renal or biliary colic, acute intestinal perforation, and pancreatitis.
Obtaining dialysate cultures and initiating empiric antibiotic treatment
Obtaining the correct microbiological culture from the peritoneal effluent is necessary to identify the responsible organism, as well as the antibiotic sensitivities. It can also help designate the likely source of infection and guide appropriate antibiotic selection. Using standard culture technique, culture-negative peritonitis rates of 10% maximum would be ideal; however, a rate of less than 20% of episodes is acceptable. It is very important to quickly obtain a bacteriological diagnosis in order to reduce necessary time for cultures. The diagnosis should be established within 3 days. If the cultures are not positive after an incubation period of three to five days but an infection is suspected based upon clinical signs and symptoms, it may be necessary to perform subcultures for an additional 3-4 days in order to reveal slow-growing bacteria or yeast.
When considering empiric antibiotic treatment, it is important for the selection to encompass gram-negative and gram-positive organisms concurrently. Additionally, center-specific selection for peritonitis-causing organisms should be based upon the sensitivities of the local history. Gram-positive antibiotic options include vancomycin or cephalosporins. Gram-negative coverage may be obtained through the use of aminoglycosides or third-generation cephalosporins. Microbiological specimens should be collected as quickly as possible and prior to the initiation of empiric antibiotics. The preferred administration of antibiotics is intraperitoneal; intermittent and continuous dosing is equally effective (see below: Intermittent or Continuous Dosing of Antibiotics).
Figure 1: Empiric Antibiotic Treatment. Modified from: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010
Specific peritonitis treatment according to culture results
Subsequent to obtaining the results of the culture and sensitivities, it is recommended that the empiric antibiotic therapy be changed to a narrow spectrum antibiotic to cover the specific organism as appropriate. Dose adjustments for renally-excreted drugs may be necessary in patients with considerable residual renal function. The clinical response is used to guide treatment and to determine the length of therapy. In general, clinical improvement should occur within the first 3 days after antibiotic initiation. In uncomplicated cases, a total of 14 days is usually an adequate duration, with the antibiotic being continued 7 days after clearing of effluent. Duration of 3 weeks may be necessary when patients are slower to respond to therapy, usually in the context of a severe infection often caused by gram-negative organisms, S. aureus, or enterococcus.
Figure 2: Culture Results. Modified from: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010
Gram positive culture
Coagulase-negative staphylococcus (CoNS) is a very common cause of peritonitis and consists of about 20 species that are clinically relevant. The route of infection is mainly due to touch contamination. It is important for the laboratories to obtain identification of the precise species level whenever possible. This assists in differentiation between contaminated cultures and true infections. In general, S. epidermidis responds well to therapy and is rarely associated with catheter infections. Mild pain is a common symptom and outpatient therapy is typically used. However, when relapsing peritonitis is caused by S. epidermidis, the catheter is often colonized by biofilm and treatment with catheter replacement in a single procedure is the best option. Often programs have methicillin-resistant organisms present in high rates and therefore vancomycin should be used as empiric therapy. Touch contamination and catheter infection can lead to a severe form of peritonitis caused by Staphylococcus aureus. Vancomycin is the drug of choice, but rifampicin may be added for up to one week. Teicoplanin can also be used for 3 weeks, where available.
Peritonitis caused by streptococcus and enterococcus may have originated from the gastrointestinal tract, mouth, touch contamination, or exit site and tunnel infection. Severe pain is commonly associated with this type of peritonitis. Ampicillin is the drug of choice, provided that the organism is susceptible. Addition of an aminoglycoside, such as gentamicin, for synergy against enterococcus is useful provided there is no high-level antibiotic resistance. Recent hospitalization and previous antibiotic therapy are risk factors associated with peritonitis caused by vancomycin-resistant Enterococcus (VRE). Amipicillin may be used for VRE if it is susceptible, and linezolid, quinupristin/dalfopristin, and daptomycin are alternative choices.
Corynebacterium may be difficult to identify as pathogens due to normal colonization of the skin. This species is not a common cause of peritonitis, but does pose significant risks such as relapse, repeat peritonitis, removal of catheter, hospitalization, transfer to permanent hemodialysis and death. Treatment usually consists of vancomycin therapy for up to 3 weeks and removal of catheter within 1 week of onset of infection, to prevent transfer to permanent hemodialysis.
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Figure 3: Gram-positive culture. Modified from: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010
1If vancomycin-resistant S. aureus, use linezolid, daptomycin, or quinupristin/dalfopristin; 2consider oral rifampin 600 mg/day (in single or split dose) for 5-7 days (450 mg/day if body weight < 50 kg), especially if patient is infected with methicillin-resistant S. aureus. Limit use to 5-7 days; 3If linezolid is used for vancomycin-resistant enterococcus, bone marrow suppression has been noted after 10-14 days; 4 Allow a minimum rest period of 3 weeks before reinitiating peritoneal dialysis; 5Consider adding an aminoglycoside for synergy, however, do not mix in same bag; 6The duration of antibiotic therapy following catheter removal and timing or resumption of peritoneal dialysis may be modified depending on the clinical course.
Gram negative culture
Pseudomonas aeruginosa is another common cause of severe peritonitis. It is also often associated with a catheter infection, and therefore removal of the catheter is recommended for better outcomes. P. aeruginosa is linked to increased frequency of hospitalizations and transfer to permanent hemodialysis. It is important to always use two antibiotics with two different mechanisms to ensure complete eradication of the organism.
Single Gram-negative organisms (for example, Klebsiella, E.coli, or Proteus) that cause peritonitis may originate from exit-site infections, touch contamination or a bowel source (constipation, colitis or diverticulitis). Although treatment should be based upon sensitivity results, it is important to consider these organisms may be present in the biofilm state, which can lead to treatment failure. This occurs because the organisms are significantly less sensitive than laboratory results may indicate. For risk reduction of recurrence and relapse, it is suggested that two antibiotics should be used.
Stenotrophomonas is an infrequent cause of peritonitis that has limited sensitivity to antibiotics. Previous use of fluoroquinolones, carbapenems, and third and fourth-generation cephalosporins is associated with infection caused by this organism. Treatment with two drugs for 3-4 weeks is recommended provided the patient is improving clinically: oral minocycline or trimethoprim/sulfamethoxazole, and intraperitoneal (IP) ticarcillin/clavulanate
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Figure 4: Gram-negative culture. Modified from: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010
1Antibiotics must be continued for 2 weeks while the patient is on hemodialysis; however, the duration of antibiotic therapy following catheter removal and timing or resumption of peritoneal dialysis may be modified depending on clinical course; 2TMP/SMZ is preferred. TMP/SMZ: Trimethoprim and Sulfamethoxazole.
Polymicrobial, fungal and culture negative peritonitis
Multiple Gram positive organisms come from contamination or infections of the catheter. This type of peritonitis should resolve with antibiotic therapy and only when the catheter is the infection source, is removal indicated. This type of peritonitis has a superior prognosis compared to when multiple enteric organisms are the cause. In this case, pathology may arise from an intra-abdominal source such as diverticulitis, ischemic bowel, cholecystitis, or appendicitis. A computed tomographic (CT) scan or laparotomy may be useful to identify an abdominal cause. Antibiotics such as metronidazole plus ampicillin, an aminoglycoside, or ceftazidime are recommended.
A serious complication that can occur subsequent to an episode of bacterial peritonitis treated with antibiotics is fungal peritonitis. Approximately 25% of fungal peritonitis episodes result in death. The catheter should be removed as soon as possible to decrease risk of death. Flucytosine and amphotericin B can be used empirically for infections caused by Candida species, while echinocandins such as caspofungin, anidulafungin, and micafungin, are recommended for Aspergillus. Combination therapy with casposfungin and amphotericin has been used effectively, as well as caspofungin alone. Amphotericin B may be replaced by an echinocandin, fluconazole, voriconazole or posaconazole when indicated by culture and sensitivity results. Azoles should be used only when sensitivities are available due to emerging resistance. The prevention of fungal peritonitis may be achieved by the use of antifungal prophylaxis during antibiotic treatment, as it is commonly associated with antibiotic use. However, this therapeutic decision has only been demonstrated to be beneficial in programs that have high fungal peritonitis baseline rates. Optional agents for fungal prophylaxis include fluconazole and nystatin, although there is limited data on fluconazole use.
Culture-negative peritonitis rates should be less than 20% for all programs. If this is not the case, then review of culture methods is needed for improvement. Negative cultures may be observed due to clinical or technical reasons. For example, antibiotic use of any kind can produce a negative culture. Some organisms are difficult to diagnose in routine culture. When under clinical consideration, atypical causes of peritonitis can be determined by using special culture techniques. Unusual causes include lipid-dependent yeast, mycobacteria, Legionella, Campylobacter, slow-growing bacteria, fungi, enteroviruses, Ureaplasma, and Mycoplasma. Initial therapy may be continued for 2 weeks if clinical improvement is noted and the effluent clears quickly. However, if improvement is not observed in 5 days, catheter removal is recommended.
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Figure 5: Polymicrobial, Fungal or Culture Negative. Modified from: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010.1The duration of antibiotic therapy following catheter removal and timing or resumption of peritoneal dialysis depends on the clinical course; 2Hypotension, sepsis, lactic acidosis, or elevation of peritoneal amylase should raise immediate concern for “surgical“ peritonitis; 3IP use of amphotericin causes chemical peritonitis and pain, while IV leads to poor peritoneal bioavailability; 4Flucytosine requires monitoring of serum concentrations to avoid bone marrow toxicity (goal trough 25-50 µg/mL and transiently not greater than 100 µg/mL); 5Azole resistance is emerging, if azole is used treatment should be continued orally with flucytosine 1000mg and fluconazole 100-200 mg daily for an additional 10 days after catheter removal.
Drug Dosing and Stability
Drugs that can be admixed in one dialysis solution bag include aminoglycosides, vancomycin, and cephalosporins; however, chemical incompatibility exists between penicillins and aminoglycosides and therefore should not be mixed. The use of separate syringes is necessary for admixture of antibiotics into the same bag, in conjunction with sterile technique. When dialysis solutions contain dextrose, the time of stability of added antibiotics is variable (Table 1).
Antibiotic Stability1 in Dextrose-Containing2Dialysis Solutions
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Table 1: Antibiotic Stability in Dextrose-Containing Dialysis Solutions. Modified from: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010. 1It is possible that these antibiotics are stable for longer periods; more research is needed to identify the optimal stability conditions for antibiotics added to dialysis solutions; 2Icodextrin-containing dialysis solutions are compatible with vancomycin, cefazolin, ampicillin, cloxacillin, ceftazidime, gentamicin and amphotericin; 3Heparin reduces stability. RT: room temperature.
Intermittent or Continuous Dosing of Antibiotics: Special Considerations for APD
It is well known that the preferred method of dosing antibiotics in peritonitis is intraperitoneal (IP). IP dosing is favored over intravenous (IV) dosing because the local levels that can be achieved are higher with IP. Additionally, IP route is advantageous because the patient can perform it at home after adequate training. It also avoids venipuncture necessary for IV access. Optional dosing regimens of IP antibiotics include once daily (intermittent) or per each exchange (continuous). The antibiotic must dwell for a minimum of 6 hours to ensure adequate absorption.
There are few antibiotic dosing recommendations for APD patients and when given equivalent doses as CAPD patients, significant under-dosing could occur. This can be due to rapid exchanges, where there is not enough time given for the antibiotic to be absorbed in the systemic circulation. This can be avoided by utilizing the 6 hour dwell time. Refer to Table 2 for dosing recommendations for CAPD and APD, where evidence exists. The debate between increased efficacies of continuous dosing versus intermittent dosing is still lacking evidence. It is a concern that with quick exchanges in APD there is inadequate time for achievement of IP levels. The possibility of biofilm-associated organisms is raised when there are only daytime exchanges of a single cephalosporin, resulting in IP levels that are below MIC at nighttime. It is unclear at this time if patients on a cycler should convert to CAPD temporarily or reset the cycler to permit a longer exchange time. Another consideration is the practicality of switching patients on APD to CAPD, since necessary supplies or training may not be accessible to the patient.
Additional data support that APD leads to increased peritoneal clearance of antibiotics when compared to CAPD, which results in dialysate concentrations lower than the MIC for sensitive organisms. Clinicians should choose the higher end of the dosing range for patients that have a rapid removal of antibiotics. Clinical improvement should be seen within 48 hours as a clearing of effluent; if there is no improvement, a repeat cell count and culture is necessary.
Antibiotic Dosing Regimens
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Table 2: Antibiotic dosing regimens. Based on: Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393-423, 2010.
1Dosing of drugs in patients with residual renal function (defined as >100mL/day urine output), should be empirically increased by 25%; 2Vancomycin should be re-dosed if serum trough levels fall below 15 µg/mL; 3Given in conjunction with 500 mg quinupristin/dalfopristin intravenous twice daily. CAPD: continuous ambulatory peritoneal dialysis. LD: loading dose. MD: maintenance dose.
Refractory, Relapsing, Recurrent, and Repeat Peritonitis
The 2010 ISPD Guidelines give the following definitions:
Refractory peritonitis results when there is failure of the effluent to clear after 5 days of appropriate antibiotics. Relapsing peritonitis can be defined by an episode that occurs within 4 weeks of completion of a therapy of a prior episode with the same organism or 1 sterile episode. Recurrent peritonitis refers to an episode that occurs within 4 weeks of completion of therapy of a prior episode but with a different organism. Repeat peritonitis occurs more than 4 weeks after completion of therapy of a prior episode with the same organism. Catheter-related peritonitis is in conjunction with an exit-site or tunnel infection with the same organism or 1 site sterile.
When peritonitis rates are calculated, relapsing episodes are not considered another peritonitis episode; however, repeat and recurrent episodes are counted.
Catheter removal is indicated in refractory and relapsing peritonitis, refractory exit-site and tunnel infections, and fungal peritonitis. It may also be considered for repeat peritonitis, mycobacterial peritonitis, and multiple enteric organisms. In the case of relapsing peritonitis, once the effluent is cleared, the catheter can be removed and replaced in a single procedure with use of antibiotic coverage. It is recommended that a time period of 2-3 weeks be utilized between catheter removal and reinsertion when cases are refractory or fungal.
Refractory peritonitis should be managed by removing the catheter to protect the peritoneal membrane for future use. The catheter may be replaced after infection resolution, provided that both the previous and current episode is caused by the same organism. The primary goal of peritonitis treatment is to focus on the patient and protect the peritoneum, not to save the catheter. Severe episodes of peritonitis may prevent patients from returning to PD. Adhesions may prevent catheter reinsertion or the peritoneal membrane may have been permanently damaged, thus no longer able to be used for PD. Prolonged treatment attempts lead to longer hospital stays, damage to the peritoneum, greater risk for fungal infection, and potentially death. Death should be very infrequent, and risk is highest with fungus and gram-negative bacilli as causative organisms.
Worse outcomes are associated with recurrent, relapsing and repeat peritonitis and catheter removal should be performed in a timely manner. It is common for relapsing and recurrent episodes to be caused by a different bacterial species. Recurrent episodes are associated with a worse prognosis.
Prevention of Further Peritonitis
An analysis should always be performed to determine the cause of the peritonitis episode, as well as any interventions against reversible risk factors in prevention of further episodes. Touch contamination is a common cause, and whenever necessary, the patient should be retrained to ensure proper technique for further prevention. Additional information regarding prevention of peritonitis will be discussed in detail in another chapter.
Patient should immediately report to the PD nurse any symptoms of abdominal pain, cloudy effluent, or fever. The cloudy dialysate fluid should be drained and saved to be brought to the clinic for analysis. The patient should understand that treatment involves antibiotic therapy for approximately 3 weeks. Upon completion of therapy, the patient should report any persistent cloudiness or worsening symptoms to the PD nurse. Retraining to address technique issues should also be scheduled.
In summary, this article discussed the presentation and initial empiric management of peritonitis, subsequent organism specific management of peritonitis, and monitoring and reporting of peritonitis rates. The main symptoms of peritonitis include abdominal pain and cloudy dialysate. Empiric antibiotic therapy should be given as soon as samples are taken for culture. Upon receiving results of culture and sensitivity, empiric therapy should be tailored to the most narrow spectrum antibiotic as appropriate and should be continued for up to 3 weeks depending on clinical response. The goals of treatment of peritonitis include rapid resolution of inflammation by eradication of causative organism and preservation of peritoneal membrane function. Monitoring and reporting peritonitis rates, as well as evaluating outcomes of peritonitis treatment are important to ensure patients are receiving the best possible treatment.
P/N 101349-01 Rev 00 11/2010