guias infecciones en dialisis peritoneal

Peritoneal Dialysis International, Vol. 30, pp. 393423doi:10.3747/pdi.2010.00049

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Perit Dial Int 2010; 30:393423 www.PDIConnect.comdoi:10.3747/pdi.2010.00049

Correspondence to: P.K.T. Li, Department of Medicine andTherapeutics, Prince of Wales Hospital, The Chinese Univer-sity of Hong Kong, Shatin, Hong Kong.

[email protected] 12 February 2010; accepted 27 April 2010.

ISPD GUIDELINES/RECOMMENDATIONS

PERITONEAL DIALYSIS-RELATED INFECTIONSRECOMMENDATIONS: 2010 UPDATE

Philip Kam-Tao Li,1 Cheuk Chun Szeto,1 Beth Piraino,2 Judith Bernardini,2 Ana E. Figueiredo,3

Amit Gupta,4 David W. Johnson,5 Ed J. Kuijper,6 Wai-Choong Lye,7

William Salzer,8 Franz Schaefer,9 and Dirk G. Struijk10

Department of Medicine and Therapeutics,1 Prince of Wales Hospital, The Chinese University of Hong Kong,Hong Kong; University of Pittsburgh School of Medicine,2 Pittsburgh, PA, USA; Faculdade de Enfermagem,

Nutrio e Fisioterapia,3 Pontifcia Universidade Catlica do Rio Grande do Sul, Brazil; Sanjay GandhiPostgraduate Institute of Medical Sciences,4 Lucknow, India; Department of Nephrology,5 Princess Alexandra

Hospital, and School of Medicine, University of Queensland, Brisbane, Australia; Department of MedicalMicrobiology,6 Leiden University Medical Center, Leiden, The Netherlands; Centre for Kidney Diseases,7

Mount Elizabeth Medical Centre, Singapore; Section of Infectious Disease,8 Department of Internal Medicine,University of Missouri-Columbia School of Medicine, Columbia, MO, USA; Pediatric Nephrology

Division,9 University Childrens Hospital, Heidelberg, Germany; Dianet Dialysis Centers,10

Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

The authors are members of the ISPD Ad Hoc Advisory Com-mittee on Peritoneal Dialysis Related Infections.

Peritonitis remains a leading complication of perito-neal dialysis (PD). Around 18% of the infection-relatedmortality in PD patients is the result of peritonitis. Al-though less than 4% of peritonitis episodes result indeath, peritonitis is a contributing factor to death in16% of deaths on PD. In addition, severe and prolongedperitonitis can lead to peritoneal membrane failure andperitonitis is probably the most common cause of tech-nique failure in PD. Peritonitis remains a major cause ofpatients discontinuing PD and switching to hemodialy-sis. Therefore, the PD community continues to focus at-tention on prevention and treatment of PD-relatedinfections (19). Peritonitis treatment should aim forrapid resolution of inflammation and preservation ofperitoneal membrane function.

Recommendations under the auspices of the Interna-tional Society for Peritoneal Dialysis (ISPD) were firstpublished in 1983 and revised in 1989, 1993, 1996, 2000,and 2005 (1013). The previous recommendations in-

cluded sections on treatment as well as prevention ofperitonitis. In the present recommendations, the Com-mittee focused on the treatment of peritonitis; preven-tion of PD-related infections will be covered in a separateISPD position statement.

The present recommendations are organized into fivesections:

1. Reporting of peritonitis rate2. Exit-site and tunnel infections3. Initial presentation and management of peritonitis4. Subsequent management of peritonitis (organism

specific)5. Future research

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LI et al. JULY 2010 VOL. 30, NO. 4 PDI

EXIT-SITE AND TUNNEL INFECTIONS

DEFINITIONS

Purulent drainage from the exit site indicates thepresence of infection. Erythema may or may not rep-resent infection (Evidence) (1922).

An exit-site infection is defined by the presence ofpurulent drainage, with or without erythema of the skinat the catheterepidermal interface. Pericathetererythema without purulent drainage is sometimes anearly indication of infection but can also be a simple skinreaction, particularly in a recently placed catheter orafter trauma to the catheter. Clinical judgment is re-quired to decide whether to initiate therapy or to followcarefully. A positive culture in the absence of an abnor-mal appearance is indicative of colonization rather thaninfection. Intensification of exit-site cleaning with an-tiseptics is advised.

A tunnel infection may present as erythema, edema,or tenderness over the subcutaneous pathway but isoften clinically occult, as shown by sonographic stud-ies (22). A tunnel infection usually occurs in the pres-ence of an exit-site infection but rarely occurs alone.In the present article, exit-site and tunnel infectionsare collectively referred to as catheter infections.Staphylococcus aureus and Pseudomonas aeruginosaexit-site infections are very often associated with con-comitant tunnel infections and are the organisms thatmost often result in catheter infection-related perito-nitis; aggressive management is always indicated forthese organisms.

Although many of the general principles could be ap-plied to pediatric patients, recommendations outlinedhere focus on PD-related infections in adult patients.Clinicians who take care of pediatric PD patientsshould refer to other sources for detailed treatment regi-mens and dosages.

These recommendations are evidence based wheresuch evidence exists. The bibliography is not intendedto be comprehensive as there have been nearly 10 000references to peritonitis in PD patients published since1966. The Committee has chosen to include articles thatare more recently published (i.e., after the most recentrecommendation, published in 2005) and those consid-ered key references. These recommendations are notbased solely on randomized controlled trials becausesuch studies in PD patients are limited. Where there isno definitive evidence but the group feels there is suffi-cient experience to suggest a certain approach, this isindicated as opinion based. The recommendations arenot meant to be implemented in every situation but arerecommendations only. Each center should examine itsown pattern of infection, causative organisms, and sen-sitivities and adapt the protocols as necessary for localconditions.

REPORTING OF PERITONITIS RATE

Every program should regularly monitor infectionrates, at a minimum, on a yearly basis (Opinion)(1416).

Programs should carefully monitor all PD-relatedinfections, both exit-site infections and peritonitis,including the presumed cause and cultured organ-isms, as part of a continuous quality improvementprogram.

Causative organisms, their antibiotic sensitivity, andpresumed etiology must be reviewed in a regular fash-ion by the PD team, including both the nurses and thephysician(s) and, if appropriate, the physician assistantor nurse practitioner. In this way, interventions can beimplemented if infection rates are rising or unaccept-ably high. Table 1 provides an easy method to calculateinfection rates. Infection rates for individual organismsshould also be calculated and compared to the litera-ture. The centers peritonitis rate should be no more than1 episode every 18 months (0.67/year at risk), althoughthe rate achieved will depend to some extent on the pa-tient population. However, overall rates as low as 1 epi-sode every 41 52 months (0.29 0.23/year) have beenreported, a goal that centers should strive to achieve(17,18).

TABLE 1Methods for Reporting Peritoneal Dialysis-Related Infections

(Peritonitis, Exit-Site Infections) (16)

1. As rates (calculated for all infections and each organism): Months of peritoneal dialysis at risk, divided by number

of episodes, and expressed as interval in months be-tween episodes

Number of infections by organism for a time period, di-vided by dialysis-years time at risk, and expressed asepisodes per year

2. As percentage of patients who are peritonitis free per pe-riod of time

3. As median peritonitis rate for the program (calculate peri-tonitis rate for each patient and then obtain the median ofthese rates)

Relapsing peritonitis (see Table 6 for the definition) shouldbe counted as a single episode.




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PDI JULY 2010 VOL. 30, NO. 4 PD-RELATED INFECTIONS RECOMMENDATIONS

THERAPY FOR EXIT-SITE AND TUNNEL INFECTIONS

The most serious and common exit-site pathogens areStaphylococcus aureus and Pseudomonas aeruginosa.As these organisms frequently lead to peritonitis (Evi-dence), such infections must be treated aggressively(7,8,19,2341).

Oral antibiotic therapy is generally recommended,with the exception of methicillin-resistant S. aureus(MRSA) (Opinion) (21).

Exit-site and tunnel infections may be caused by a va-riety of micro-organisms. Although S. aureus and P. aeru-ginosa are responsible for the majority of infections,other bacteria (diphtheroids, anaerobic organisms, non-fermenting bacteria, streptococci, nontuberculous my-cobacteria, Legionella, yeasts, and fungi) can also beinvolved. Empiric antibiotic therapy may be initiatedimmediately. Alternatively, the healthcare team may de-cide to defer therapy until the results of the exit-siteculture can direct the choice of antibiotic. Microbiologi-cal examination should preferably include a combina-tion of microscopy with aerobic and anaerobic culture.The Gram stain of exit-site drainage and the microbio-logical culture findings can guide the initial therapy.Cultures should be taken to the laboratory using appro-priate transport materials also allowing anaerobic bac-teria to survive. Oral antibiotic therapy has been shownto be as effective as intraperitoneal (IP) antibiotictherapy.

Empiric therapy should always cover S. aureus. If thepatient has a history of P. aeruginosa exit-site infections,empiric therapy should be with an antibiotic that willcover this organism. In some cases, intensified local careor a local antibiotic cream may be felt to be sufficient inthe absence of purulence, tenderness, and edema.

Gram-positive organisms are treated with oral peni-cillinase-resistant (or broad spectrum) penicillin or afirst-generation cephalosporin, such as cephalexin. Dos-ing recommendations for frequently used oral antibiot-ics are shown in Table 2 (41). To prevent unnecessaryexposure to vancomycin and thus emergence of resis-tant organisms, vancomycin should be avoided in theroutine treatment of gram-positive exit-site and tunnelinfections but will be required for MRSA infections.Clindamycin, doxycycline, and minocycline are some-times useful for the treatment of community-acquiredMRSA and other organisms; these drugs do not requiredose adjustment for end-stage renal disease. In slowlyresolving or particularly severe S. aureus exit-site infec-tions, rifampicin 600 mg daily may be added, althoughthis drug should be held in reserve in areas where tuber-

culosis is endemic. Rifampicin should never be given asmonotherapy. It should also be noted that rifampicin isa potent inducer of drug-metabolizing enzymes andwould reduce the levels of medications such as warfarin,statins, and anticonvulsants.

Pseudomonas aeruginosa exit-site infections are par-ticularly difficult to treat and often require prolongedtherapy with two antibiotics. Oral fluoroquinolones arerecommended as the first choice, preferably not asmonotherapy since resistance develops rapidly. Ifquinolones are given concomitantly with sevelamer,multivalent cations, such as calcium, oral iron, zincpreparations, sucralfate, magnesiumaluminum antac-ids, or milk, chelation interactions may occur that re-duce quinolone absorption. Administration of thequinolone should therefore be separated from thesedrugs by at least 2 hours (with the quinolone adminis-tered first). If resolution of the infection is slow or ifthere is recurrent Pseudomonas exit-site infection, asecond antipseudomonal drug, such as, but not limitedto, IP aminoglycoside, ceftazidime, cefepime, pipera-cillin, imipenemcilastatin, or meropenem, should beadded.

TABLE 2Oral Antibiotics Used in Exit-Site and Tunnel Infection

Amoxicillin 250500 mg b.i.d.Cephalexin 500 mg b.i.d. to t.i.d. (41)Ciprofloxacin 250 mg b.i.d. (29)Clarithromycin 500 mg loading dose, then

250 mg b.i.d. or q.d. (30)Dicloxacillin 500 mg q.i.d.Erythromycin 500 mg q.i.d.Flucloxacillin (or cloxacillin) 500 mg q.i.d.Fluconazole 200 mg q.d. for 2 days,

then 100 mg q.d. (41)Flucytosine 0.51 g/day titrated to re-

sponse and serum troughlevels (2550 m g/mL) (41)

Isoniazid 200300 mg q.d. (42)Linezolid 400600 mg b.i.d. (41)Metronidazole 400 mg t.i.d.Moxifloxacin 400 mg dailyOfloxacin 400 mg first day, then

200 mg q.d.Pyrazinamide 2535 mg/kg 3 times per

week (31)Rifampicin 450 mg q.d. for 50 kgTrimethoprim/sulfamethoxazole 80/400 mg q.d.

b.i.d. = 2 times per day; q.d. = every day; t.i.d. = 3 times perday; q.i.d. = 4 times daily.




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Many organisms can cause exit-site and tunnel infec-tions, including micro-organisms belonging to the nor-mal skin flora, such as corynebacteria (7,32). Therefore,culture with sensitivity testing is important in determin-ing antibiotic therapy. Close follow-up is necessary todetermine the response to therapy and relapse. Unfor-tunately, both S. aureus and P. aeruginosa catheterinfections tend to recur; repeating PD effluent cul-tures 1 2 weeks after the discontinuation of antimi-crobial treatment may be useful for risk assessment.

Ultrasonography of the exit site is a useful adjunc-tive tool in the management of exit-site and tunnel in-fections (33). A sonolucent zone around the externalcuff over 1 mm thick following a course of antibiotictreatment and the involvement of the proximal cuff areassociated with poor clinical outcome. In exit-site in-fections caused by P. aeruginosa, clinical outcome hasbeen uniformly poor irrespective of the sonographicfindings.

Antibiotic therapy must be continued until the exitsite appears entirely normal. Two weeks is the minimumlength of treatment time; treatment for 3 weeks is prob-ably necessary for exit-site infections caused by P. aeru-ginosa. If prolonged therapy (e.g., longer than 3 weeks)with appropriate antibiotics fails to resolve the infec-tion, the catheter can be replaced as a single procedureunder antibiotic coverage (3437). If the cuffs are notinvolved, revision of the tunnel may be performed inconjunction with continued antibiotic therapy. This pro-cedure, however, may result in peritonitis, in which casethe catheter should be removed. Sonography of the tun-nel has been shown useful in evaluating the extent ofinfection along the tunnel and the response to therapyand may be used to decide on tunnel revision, replace-ment of the catheter, or continued antibiotic therapy(38). In general, catheter removal should be consideredearlier for exit-site infections caused by P. aeruginosa orif there is tunnel infection.

A patient with an exit-site infection that progressesto peritonitis, or who presents with an exit-site infec-tion in conjunction with peritonitis with the same or-ganism, will usually require catheter removal. Catheterremoval should be done promptly rather than submit-ting the patient to prolonged peritonitis or relapsingperitonitis. The exception is peritonitis due to coagu-lase-negative staphylococcus (CoNS), which is generallyreadily treated. Simultaneous removal and reinsertionof the dialysis catheter (with a new exit site) is feasiblein eradicating refractory exit-site infections due toP. aeruginosa (39). In selected cases, cuff shaving maybe considered an alternative to catheter replacement fortunnel infection (40).

INITIAL PRESENTATION AND MANAGEMENT OFPERITONITIS

CLINICAL PRESENTATION OF PERITONITIS

Peritoneal dialysis patients presenting with cloudy ef-fluent should be presumed to have peritonitis. This isconfirmed by obtaining effluent cell count, differen-tial, and culture (Evidence) (4352).

It is important to initiate empiric antibiotic therapyfor PD-associated peritonitis as soon as possible.There are potentially serious consequences of perito-nitis (relapse, catheter removal, permanent transferto hemodialysis, and death) that are more likely tooccur if treatment is not initiated promptly (Opinion).

Patients with peritonitis usually present with cloudyfluid and abdominal pain; however, peritonitis shouldalways be included in the differential diagnosis of thePD patient with abdominal pain, even if the effluent isclear, as a small percentage of patients present in thisfashion. Other causes, such as constipation, renal or bil-iary colic, peptic ulcer disease, pancreatitis, and acuteintestinal perforation, should also be investigated in thePD patient with abdominal pain and clear fluid. Con-versely, while patients with peritonitis most often havesevere pain, some episodes are associated with mild oreven no pain. The degree of pain is somewhat organismspecific (e.g., generally less with CoNS and greater withStreptococcus, gram-negative rods, S. aureus) and canhelp guide the clinician in the decision to admit or treatas an outpatient. Patients with minimal pain can oftenbe treated on an outpatient basis with IP therapy andoral pain medication. Those requiring intravenous (IV)narcotics always require admission for management.

Cloudy effluent will usually represent infectious peri-tonitis but there are other causes (48). The differentialdiagnosis is shown in Table 3. Case reports of sterile peri-tonitis associated with icodextrin-based dialysis solu-tions have been reported from Europe (49). Randomized

TABLE 3Differential Diagnosis of Cloudy Effluent

Culture-positive infectious peritonitis Infectious peritonitis with sterile cultures Chemical peritonitis Eosinophilia of the effluent Hemoperitoneum Malignancy (rare) Chylous effluent (rare) Specimen taken from dry abdomen




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trials comparing icodextrin- to glucose-based dialysissolutions show similar peritonitis risk with the two solu-tions (5052).

The abdomen should be drained and the effluent care-fully inspected and sent for cell count with differential,Gram stain, and culture. An effluent cell count withwhite blood cells (WBC) more than 100/m L (after a dwelltime of at least 2 hours), with at least 50% polymorpho-nuclear neutrophilic cells, indicates the presence of in-flammation, with peritonitis being the most likely cause.To prevent delay in treatment, antibiotic therapy shouldbe initiated as soon as cloudy effluent is seen, withoutwaiting for confirmation of the cell count from the labo-ratory. Patients with cloudy effluent may benefit fromthe addition of heparin (500 units/L) to the dialysateto prevent occlusion of the catheter by fibrin. Heparinis also usually added in cases of hemoperitoneum. Anexperienced observer can differentiate hemoperito-neum from cloudy effluent due to peritonitis. If there isa question, a cell count with differential should beperformed.

The number of cells in the effluent will depend, inpart, on the length of the dwell. For patients on auto-mated PD (APD) who present during their nighttimetreatment, the dwell time is much shorter than with con-tinuous ambulatory PD (CAPD); in this case, the clini-cian should use the percentage of polymorphonuclearcells rather than the absolute number of white cells todiagnose peritonitis. The normal peritoneum has veryfew polymorphonuclear cells; therefore, a proportionabove 50% is strong evidence of peritonitis, even if theabsolute white cell count does not reach 100/ m L. Pa-tients on APD with a day dwell who present during theday generally have cell counts similar to those of CAPDpatients and are not difficult to interpret. However, APDpatients without a daytime exchange who present withabdominal pain may have no fluid to withdraw. In thiscase, 1 L of dialysate should be infused and permittedto dwell a minimum of 1 2 hours, then drained andexamined for turbidity, and sent for cell count with dif-ferential and culture. The differential (with a shorteneddwell time) may be more useful than the absolute WBCcount. In equivocal cases, or in patients with systemicor abdominal symptoms in whom the effluent appearsclear, a second exchange is performed with a dwell timeof at least 2 hours. Clinical judgment should guide ini-tiation of therapy.

Even though the Gram stain is often negative in thepresence of peritonitis, this test should be performedas the Gram stain may indicate the presence of yeast,thus allowing for prompt initiation of antifungal therapyand permitting timely arrangement of catheter removal.

With this exception, empiric therapy should not be basedon the Gram stain but should cover the usual pathogens,as discussed below.

The patient should always be questioned in a non-threatening manner about a break in technique and inparticular whether contamination or disconnection oc-curred recently. Information about recent exit-site in-fections and the last (if any) episode of peritonitis shouldbe obtained. The patient should also be questioned aboutany recent endoscopic or gynecological procedures, aswell as the presence of either constipation or diarrhea.

In peritonitis, abdominal tenderness is typically gen-eralized and is often associated with rebound. Localizedpain or tenderness should raise the suspicion of an un-derlying surgical pathology such as acute appendicitis.The physical examination of the patient presenting withperitonitis should always include a careful inspection ofthe catheter exit site and tunnel. Any drainage from theexit site should be cultured along with the effluent. Ifthe exit site grows the same organism as the effluent(with the exception of CoNS), then it is very likely thatthe origin of the peritonitis is the catheter.

Although an abdominal x-ray image is generally notnecessary, if there is any suspicion of a bowel source,an abdominal film should be obtained. The presence offree air under the diaphragm is suggestive of perfora-tion, although it should be noted that a small amountof IP air is common among PD patients due to inadvert-ent infusion of air by the patient. Routine peripheralblood cultures are unnecessary since they are usuallynegative but they should be obtained if the patient ap-pears septic.

Some PD patients reside in locations that are remotefrom medical facilities and thus cannot be seen expedi-tiously after the onset of symptoms. These patients alsomay not have immediately available microbial and labo-ratory diagnostic services. Since prompt initiation oftherapy for peritonitis is critical, this necessitates reli-ance on immediate patient reporting of symptoms to thecenter, and then initiating IP antibiotics in the homesetting. Such an approach requires that the patients betrained in this technique and that antibiotics be kept inthe home. A delay in treatment could be dangerous.Whenever possible, prior to starting antibiotic, culturesshould be obtained either at a local facility or by havingthe patient keep blood-culture bottles at home for use.Alternatively, the patient may place the cloudy effluentbag in the refrigerator to slow bacterial multiplicationand white cell killing until they are able to bring in thesample. The benefit of self-initiated treatment, however,should be carefully balanced against the potential prob-lems of overdiagnosis and habitual misuse of antibiotics.




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SPECIMEN PROCESSING

Culture-negative peritonitis should not be greaterthan 20% of episodes. Standard culture technique isthe use of blood-culture bottles but a large-volumeculture (e.g., culturing the sediment after centrifug-ing 50 mL of effluent) could further improve the re-covery of micro-organisms (Evidence) (5357).

In the ideal situation (e.g., in specialized academiccenters), one could achieve a less than 10% rate of cul-ture-negative peritonitis. Correct microbiological cultur-ing of peritoneal effluent is of utmost importance toestablish the micro-organism responsible. Identificationof the organism and subsequent antibiotic sensitivitieswill not only help guide antibiotic selection but, in addi-tion, the type of organism can indicate the possiblesource of infection. An optimal culture technique is thecombination of sediment culturing of 50 mL effluent andbedside inoculation of 5 10 mL effluent in two blood-culture bottles. The specimens should arrive within6 hours at the laboratory. If immediate delivery to thelaboratory is not possible, the inoculated culture bottlesshould ideally be incubated at 37C. When the causativemicro-organism has been established, subsequentcultures for monitoring may be performed by only inocu-lating the effluent in blood-culture bottles. Centrifuga-tion of 50 mL peritoneal effluent at 3000g for 15 minutes,followed by re suspension of the sediment in 3 5 mL ofsterile saline, and inoculation of this material both onsolid culture media and into a standard blood-culturemedium, is a sensitive method to identify the causativeorganisms. With this method, less than 5% will be cul-ture negative. The solid media should be incubated inaerobic, microaerophilic, and anaerobic environments.Blood-culture bottles can be directly injected with 5 10 mL of effluent if equipment for centrifuging largeamounts of fluid is not available; this method generallyresults in a culture-negative rate of 20%. If the patient isalready on antibiotics, removal of antibiotics present inthe specimen may increase the isolation rate.

The speed with which bacteriological diagnosis canbe established is very important. Concentration meth-ods not only facilitate correct microbial identificationbut also reduce the time necessary for bacteriologicalcultures. Rapid blood-culture techniques (e.g., BACTEC,Septi-Chek, BacT/Alert; Becton Dickinson) may furtherspeed up isolation and identification and are probablythe best approach. Two recent prospective studies alsosupport the routine use of the broth culture technique(56,57), while the lysiscentrifugation technique needsfurther evaluation. The majority of cultures will become

positive after the first 24 hours and, in over 75% of cases,diagnosis can be established in less than 3 days. Whencultures remain negative after 3 5 days of incubationand clinical suspicion is high, subculture of blood-cul-ture bottles on media with aerobic, anaerobic, and micro-aerophilic incubation conditions for a further 3 4 daysmay help to identify slow-growing bacteria and yeaststhat are undetectable in an automated culture system.

OTHER NOVEL DIAGNOSTIC TECHNIQUES

There is not enough evidence for recommending theuse of novel techniques [such as leukocyte esterase,broad-spectrum polymerase chain reaction (PCR),quantitative bacterial DNA PCR] for the diagnosis ofperitonitis (5864).

A number of novel diagnostic techniques have beenexplored for the early diagnosis of peritonitis. Park et al.(58) and Akman et al. (59) reported that leukocyte es-terase reagent strip has excellent accuracy for the diag-nosis of peritonitis. Various commercially available stripshave been tested to diagnose non-PD peritonitis but theresults vary enormously; more studies are required be-fore this can be applied in a routine setting (60).

Broad-spectrum PCR with RNA sequencing (61) andquantitative bacterial DNA PCR assays (62) may alsocomplement culture methods in the diagnosis of CAPDperitonitis, especially in patients with previous or cur-rent antibiotic use. The latter technique may also helpto identify those patients likely to relapse despite ap-parent clinical improvement with standard antibiotictherapy (62). Another study suggests that the matrixmetalloproteinase-9 test kit may be a reliable methodfor early diagnosis of PD peritonitis (63). The role of rapiddetection of the causative pathogen of peritonitis usingin situ hybridization has also been explored (64).

EMPIRIC ANTIBIOTIC SELECTION

Empiric antibiotics must cover both gram-positive andgram-negative organisms. The Committee recom-mends center-specific selection of empiric therapy,dependent on the local history of sensitivities of or-ganisms causing peritonitis (Opinion). Gram-positiveorganisms may be covered by vancomycin or a cepha-losporin, and gram-negative organisms by a third-generation cephalosporin or aminoglycoside (Evidence)(Figure 1) (65105).

Intraperitoneal administration of antibiotics is supe-rior to IV dosing for treating peritonitis; intermittent and




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continuous dosing of antibiotics are equally efficacious(88).

Therapy is initiated prior to knowledge of the caus-ative organism and should be initiated as soon as pos-sible after appropriate microbiological specimens havebeen obtained. The selection of empiric antibiotics mustbe made in light of both the patients and the programshistory of micro-organisms and sensitivities. It is impor-tant that the protocol cover all serious pathogens thatare likely to be present. For many programs, a first-gen-eration cephalosporin, such as cefazolin or cephalothin,with a second drug for broader gram-negative coverage

(including coverage for Pseudomonas) will prove suit-able. This protocol has been shown to have resultsequivalent to vancomycin plus a second drug for gram-negative coverage (77,87). Many programs, however,have a high rate of methicillin-resistant organisms andthus should use vancomycin for gram-positive coveragewith a second drug for gram-negative coverage (88).

Gram-negative coverage can be provided with anaminoglycoside, ceftazidime, cefepime, or carbapenem.Quinolones should be used for empiric coverage of gram-negative organisms only if local sensitivities support suchuse. For the cephalosporin-allergic patient, aztreonam

Patient Education

Immediately report cloudy effluent,abdominal pain, and/or fever to PD unit

Save drained cloudy dialysate and bringto clinic

Treatment will be adding intraperitonealantibiotics for up to 3 weeks

Report worsening symptoms or persistentcloudiness to PD unit

Schedule retraining for technique issues

Outcomes Evaluation

Collect data to include Date of culture, organism identified, drug therapy used Date infection resolved Recurrent organisms, date of drug therapy Method of interim renal replacement therapy Date of catheter removal Date of new catheter reinsertion Documentation of contributing factors

Break in technique, patient factors, exit-siteinfections, tunnel infections

Date of reeducation/training Enter data into catheter management database

Start intraperitoneal antibiotics as soon as possibleAllow to dwell for at least 6 hours

Ensure gram-positive and gram-negative coverage*Base selection on historical patient and center sensitivity patterns as available

Gram-positive coverage: Gram-negative coverage:Either first-generation Either third-generation

cephalosporin or vancomycin cephalosporin or aminoglycoside

Determine and prescribe ongoing antibiotic treatmentEnsure follow-up arrangements are clear or patient admitted

Await sensitivity results

Figure 1 Initial management of peritonitis: *Continued assessment and modification of therapy based on culture and sensitivityresults; refer to subsequent sections for specific organisms cultured. Dwell time of the exchange for intermittent therapy must bea minimum of 6 hours. Vancomycin may be considered if patient has a history of methicillin-resistant Staphylococcus aureuscolonization/infection, is seriously unwell, or has a history of severe allergy to penicillins and cephalosporins. If the center has anincreased rate of methicillin resistance, vancomycin may also be considered. If the patient is cephalosporin allergic, aztreonamis an alternative to ceftazidime or cefepime. Vancomycin and ceftazidime are compatible when mixed in a dialysis solution volumegreater than 1 L; however, they are incompatible when mixed in the same syringe or empty dialysis solution bag for reinfusion.Aminoglycosides should not be added to the same exchange with penicillins as this results in incompatibility.

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is an alternative to ceftazidime or cefepime for gram-negative coverage if aminoglycosides are not used. An-tibiotic resistance may develop with empiric use ofextended-spectrum cephalosporins and quinolones. Re-sistance should be monitored, especially for enterococci,staphylococci, yeasts, and gram-negative organismssuch as Pseudomonas species, Escherichia coli, Proteusspecies, Providencia species, Serratia species, Klebsiellaspecies, and Enterobacter species, but catheter removalshould not be delayed until the result of antibiotic resis-tance testing is available.

While an extended course of aminoglycoside therapymay increase the risk for both vestibular and ototoxic-ity, short-term use appears to be safe and inexpensiveand provides good gram-negative coverage. Gentamicingiven in once-daily dosing (40 mg IP in 2 L) is as effec-tive as dosing in each exchange (10 mg/2 L, IP, in 4 ex-changes/day) for CAPD peritonitis (89,90). There doesnot appear to be convincing evidence that short coursesof aminoglycosides harm residual renal function (65,91).Repeated or prolonged courses (e.g., longer than2 weeks) of aminoglycoside therapy are probably not ad-visable if an alternative approach is possible. If anaminoglycoside is used for the initial gram-negative cov-erage, intermittent dosing is strongly encouraged andprolonged courses of longer than 3 weeks should beavoided.

Either ceftazidime or cefepime is an appropriate al-ternative for gram-negative coverage. Cefepime is notbroken down by many of the beta-lactamases that arecurrently produced by gram-negative bacilli worldwideso, theoretically, it has better coverage than ceftazidime.

In addition to the above combinations, a variety ofregimens have been tested in prospective trials, withacceptable results (92). In a randomized control studyof 102 patients, IP cefazolin plus netilmicin and cefazolinplus ceftazidime had similar efficacy as empirical treat-ment for CAPD peritonitis (93). In CAPD patients withresidual renal function, significant but reversible reduc-tion in residual renal function and 24-hour urine volumecould occur after an episode of peritonitis, despite suc-cessful treatment by antibiotics. However, the effect ofboth regimens on residual renal function is similar (93).

Other combination therapy may also be effective. Arecent study showed that systemic vancomycin and cipro-floxacin administration might also be an effective first-line antibiotic therapy (94). Lima et al. (95) reportedsatisfactory response rates with ciprofloxacin pluscefazolin as the empirical regimen for peritonitis. Mero-penem plus tobramycin followed by meropenem plus van-comycin is another regimen recently reported to havereasonable success (96), but this combination is too

broad for routine application and should be consideredonly for highly resistant cases. The increased isolationrate of gram-negative rods (Enterobacteriaceae, Acine-tobacter species, and Pseudomonas species) resistant tocarbapenems is of increasing concern (97).

Monotherapy is also possible. In a randomized trial,imipenem/cilastatin (500 mg IP with a dwell of 6 hours,followed by IP 100 mg per 2 L dialysis solution) was aseffective in curing peritonitis as was cefazolin plus cef-tazidime in CAPD patients (98). Cefepime (2 g IP loadwith a dwell time of >6 hours, followed by 1 g/day IP for9 consecutive days) was as effective as vancomycin plusnetilmicin in another randomized trial of CAPD-relatedperitonitis (69).

Quinolones (oral levofloxacin 250 mg daily, or oralpefloxacin 400 mg daily) appear to be an acceptable al-ternative to aminoglycosides for gram-negative cover-age (94,99,100) and do reach adequate levels within theperitoneum, even with cycler PD (101). In another study,oral ofloxacin alone (400 mg, followed by 300 mg daily)was equivalent to cephalothin 250 mg/L for all CAPDexchanges, in combination with tobramycin 8 mg/L(102). However, resolution of S. aureus may prove to beslow with the use of ciprofloxacin alone and it is not theideal drug (103).

In the early days of PD, mild cases of peritonitis suchas those caused by S. epidermidis were treated effectivelywith oral cephalosporin therapy (104). If the organismis sensitive to methicillin and first-generation cepha-losporin, then this approach is still possible if, for somereason, IP or IV antibiotic therapy is not feasible. Oraltherapy is not suitable for more severe cases of perito-nitis. No role has been shown for routine peritoneal lav-age or use of urokinase (88), although one or two rapidexchanges often help to relieve pain, and continuousperitoneal lavage (for 24 48 hours) is often used forpatients with septic shock and grossly turbid PD efflu-ent. In a recent randomized control trial of 88 patients,IP urokinase had no significant benefit as an adjuncttherapy in the treatment of bacterial peritonitis resis-tant to initial antibiotic therapy (105).

DRUG DELIVERY AND STABILITY

Vancomycin, aminoglycosides, and cephalosporinscan be mixed in the same dialysis solution bag withoutloss of bioactivity. However, aminoglycosides should notbe added to the same exchange with penicillins becauseof chemical incompatibility (although aminoglycosideand cephalosporin can be added to the same bag). Forany antibiotics that are to be admixed, separate syringesmust be used for adding the antibiotics. Even though




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vancomycin and ceftazidime are compatible when addedto dialysis solutions (1 L or higher), they are incompat-ible if combined in the same syringe or added to an emptydialysate bag for reinfusion into the patient. This ap-proach is not recommended.

Antibiotics should be added using sterile technique:placing povidone iodine, rubbing with alcohol 70% stripe,or chlorhexidine on the medication port for 5 minutesprior to insertion of the needle through the port. Dwelltime of the exchange must be a minimum of 6 hours.

Data suggest that some antibiotics are stable for vari-able times when added to dextrose-containing dialysissolution. Vancomycin (25 mg/L) is stable for 28 days indialysis solution stored at room temperature, althoughhigh ambient temperatures will reduce the duration ofstability. Gentamicin (8 mg/L) is stable for 14 days butthe duration of stability is reduced by admixture of hep-arin. Cefazolin (500 mg/L) is stable for at least 8 days atroom temperature or for 14 days if refrigerated; addi-tion of heparin has no adverse influence. Ceftazidime isless stable: concentrations of 125 mg/L are stable for4 days at room temperature or 7 days refrigerated, andconcentrations of 200 mg/L are stable for 10 days if re-frigerated. Cefepime is stable in dialysis solution for14 days if the solution is refrigerated (106).

These data are derived from duration of stability stud-ies. It is possible that the agents are stable for longerperiods; more research is needed to identify the optimalstability conditions for antibiotics added to dialysis so-lutions. Icodextrin-containing dialysis solutions arecompatible with vancomycin, cefazolin, ampicillin, clox-acillin, ceftazidime, gentamicin, and amphotericin(107). Nonetheless, data on the stability of individualantibiotics in various new PD solutions are limited. Cli-nicians should remain alert to new studies in this area.

In a recent retrospective study of 613 patients,Blunden et al. (108) confirmed that dosing recommen-dation for vancomycin in CAPD and APD patients pro-duces adequate serum concentrations of the antibioticsin the vast majority (over 85%) of patients. In contrast,the currently recommended dosing regimen of gentami-cin resulted in high levels for more than 50% patients,but switching gentamicin to ceftazidime at day 5 ap-peared safe and limited aminoglycoside exposure. In thisstudy, increasing vancomycin and gentamicin concen-trations did not appear to improve cure rates (108).Since standard microbiological tests [e.g., minimum in-hibitory concentration (MIC) test] do not account forthe unique factors of PD peritonitis, and IP antibioticsact primarily locally, checking of antibiotic levels in pe-ripheral blood should be used for the detection of tox-icity rather than a proof of efficacy.

INTERMITTENT OR CONTINUOUS DOSING OF ANTIBIOTICS:SPECIAL CONSIDERATIONS FOR APD PATIENTS

Little is known about intermittent dosing require-ments in patients treated with APD. The optimal ratio ofantibiotic concentration and MIC value of a bacteriumdepends on various variables, such as bacterial species,presence of postantibiotic effect, and duration of anti-biotic concentration above MIC value. The Committeeagrees that IP dosing of antibiotics for peritonitis is pref-erable to IV dosing in CAPD, since IP dosing results invery high local levels of antibiotics. For example, 20 mg/LIP gentamicin is well above the MIC of sensitive organ-isms. The equivalent dose of gentamicin given IV wouldresult in much lower IP levels. The IP route has the addedadvantage that it can be done by the patient at homeafter appropriate training and it avoids venipuncture.Monitoring of drug levels for aminoglycosides and van-comycin is recommended if toxicity is suspected.

Intraperitoneal antibiotics can be given in each ex-change (i.e., continuous dosing) or once daily (i.e., in-termittent dosing) (109114). In intermittent dosing,the antibiotic-containing dialysis solution must beallowed to dwell for at least 6 hours to allow adequateabsorption of the antibiotic into the systemic circula-tion. Most antibiotics have significantly enhanced ab-sorption during peritonitis (e.g., IP vancomycin is about50% absorbed in the absence of peritonitis but closer to90% in the presence of peritonitis), which permits sub-sequent reentry into the peritoneal cavity during ensu-ing exchanges of fresh dialysis solution. Table 4 providesdoses for both continuous and intermittent administra-tion for CAPD, where there is information available.

There are insufficient data on whether continuousdosing is more efficacious than intermittent for first-generation cephalosporins. A once-daily IP cefazolindose of 500 mg/L results in acceptable 24-hour levels inthe dialysis fluid in CAPD patients (111). An extensivebody of evidence exists for the efficacy of intermittentdosing of aminoglycosides and vancomycin in CAPD butless for APD. Table 5 provides dosing recommendationsfor APD where such data exist or sufficient experiencecan allow a recommendation to be made. A randomizedtrial in children that included both CAPD and APD pa-tients found that intermittent dosing of vancomycin/teicoplanin is as efficacious as continuous dosing (65).Intraperitoneal vancomycin is well absorbed when givenin a long dwell and subsequently crosses again from theblood into the dialysate with fresh exchanges.

Rapid exchanges in APD, however, may lead to inad-equate time to achieve IP levels. There are fewer dataconcerning efficacy of first-generation cephalosporins




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TABLE 4Intraperitoneal Antibiotic Dosing Recommendations for CAPD Patientsa

Intermittent Continuous(per exchange, once daily) (mg/L; all exchanges)

AminoglycosidesAmikacin 2 mg/kg LD 25, MD 12Gentamicin, netilmicin, or tobramycin 0.6 mg/kg LD 8, MD 4

CephalosporinsCefazolin, cephalothin, or cephradine 15 mg/kg LD 500, MD 125Cefepime 1000 mg LD 500, MD 125Ceftazidime 10001500 mg LD 500, MD 125Ceftizoxime 1000 mg LD 250, MD 125

PenicillinsAmoxicillin ND LD 250500, MD 50Ampicillin, oxacillin, or nafcillin ND MD 125Azlocillin ND LD 500, MD 250Penicillin G ND LD 50000 units, MD 25000 units

QuinolonesCiprofloxacin ND LD 50, MD 25

OthersAztreonam ND LD 1000, MD 250Daptomycin (115) ND LD 100, MD 20Linezolid (41) Oral 200300 mg q.d.Teicoplanin 15 mg/kg LD 400, MD 20Vancomycin 1530 mg/kg every 57 days LD 1000, MD 25

AntifungalsAmphotericin NA 1.5Fluconazole 200 mg IP every 2448 hours

CombinationsAmpicillin/sulbactam 2 g every 12 hours LD 1000, MD 100Imipenem/cilastin 1 g b.i.d. LD 250, MD 50Quinupristin/dalfopristin 25 mg/L in alternate bagsb

Trimethoprim/sulfamethoxazole Oral 960 mg b.i.d.

ND = no data; q.d. = every day; NA = not applicable; IP = intraperitoneal; b.i.d. = 2 times per day; LD = loading dose in mg/L; MD =maintenance dose in mg/L.a For dosing of drugs with renal clearance in patients with residual renal function (defined as >100 mL/day urine output), dose

should be empirically increased by 25%.b Given in conjunction with 500 mg intravenous twice daily.

TABLE 5Intermittent Dosing of Antibiotics in Automated Peritoneal Dialysis

Drug IP dose

Cefazolin 20 mg/kg IP every day, in long day dwell (112)

Cefepime 1 g IP in 1 exchange per day

Fluconazole 200 mg IP in 1 exchange per day every 2448 hours

Tobramycin LD 1.5 mg/kg IP in long dwell, then 0.5 mg/kg IP each day in long dwell (112)

Vancomycin LD 30 mg/kg IP in long dwell; repeat dosing 15 mg/kg IP in long dwell every 35 days (aim to keep serum troughlevels above 15 m g/mL)

IP = intraperitoneal; LD = loading dose.




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given intermittently for peritonitis, particularly for thepatient on a cycler. For patients given a daytime ex-change of a cephalosporin only, the nighttime IP levelsare below the MIC of most organisms. This raises a con-cern that biofilm-associated organisms may survive andresult in subsequent relapsing peritonitis. Until a ran-domized trial with large numbers is done, adding first-generation cephalosporin to each exchange wouldappear to be the safest approach.

The Committee agrees that vancomycin can be givenintermittently for patients on APD, even though thereare few studies. However, a randomized European trialin children showed that intermittent dosing of vanco-mycin or teicoplanin (and many of the children were onAPD) was as effective as continuous dosing. Generally, adosing interval of 4 5 days will keep serum trough lev-els above 15 m g/mL but, in view of the variability of lossesdue to residual renal function and peritoneal permeabil-ity, it is best to obtain levels. Intraperitoneal levels ofvancomycin after the initial dose will always be lowerthan serum levels of vancomycin; therefore, the serumlevels need to be kept higher than would be otherwiseindicated (75). Re-dosing is appropriate once serum van-comycin levels go below 15 m g/mL.

Whether or not patients on a cycler need to converttemporarily to CAPD or lengthen the dwell time on thecycler is unclear at present. It is not always practical toswitch patients from APD to CAPD, especially if the pa-tient is treated as an outpatient, since the patient maynot have supplies for CAPD and may not be familiar withthe technique. Resetting the cycler in such cases to per-mit a longer exchange time is an alternative approach;however, it has not been well studied. Further researchis needed in this area.

ADJUNCTIVE TREATMENTS

The majority of fungal peritonitis episodes are pre-ceded by courses of antibiotics (116118). Fungal pro-phylaxis during antibiotic therapy may prevent somecases of Candida peritonitis in programs that have highrates of fungal peritonitis (119124). A number of stud-ies have examined the use of prophylaxis, either oralnystatin or a drug such a fluconazole, given during an-tibiotic therapy to prevent fungal peritonitis, withmixed results. Programs with high baseline rates of fun-gal peritonitis found such an approach to be benefi-cial, while those with low baseline rates did not detecta benefit. In a recent observational study, the fungalperitonitis rate of the nystatin group was slightly lowerthan that of the control group (0.011 vs 0.019/patient-year) but the difference did not reach statistical sig-

nificance (125). There was, however, a significant de-crease in the incidence and proportion of antibiotic-related fungal peritonitis in the nystatin group (125).The Work Group recognizes that nystatin is not avail-able in some countries and that there are few data onthe efficacy and potential problem of fluconazole pro-phylaxis. Each PD program must examine its history offungal peritonitis and decide whether such a protocolmight be beneficial.

Studies of IP urokinase failed to show any benefit ofurokinase over placebo with respect to complete cure inpersistent peritonitis, or primary response to treatmentin the setting of resistant peritonitis (105,126,127).Similarly, catheter removal and relapse rates were notaffected by treatment with urokinase, either in the set-ting of persistent peritonitis or on initiation of fibrino-lytic therapy at the time peritonitis was diagnosed. Incontrast, one randomized control study showed thatsimultaneous catheter removal and replacement wassuperior to urokinase in reducing recurrent episodes ofperitonitis (128).

One, small, randomized control trial reported that theuse of IP immunoglobulin provides significant improve-ment in laboratory parameters (especially dialysate leu-kocyte count), but that there was no effect on the rateof treatment failure or relapse (129).

SUBSEQUENT MANAGEMENT OF PERITONITIS

Once culture results and sensitivities are known, an-tibiotic therapy should be adjusted to narrow-spectrum agents as appropriate. For patients withsubstantial residual renal function (e.g., residual glo-merular filtration rate 5 mL/minute/1.73 m2), thedose of antibiotics that have renal excretion may needto be adjusted accordingly (Opinion).

Few data exist that provide dosing recommendationsfor patients treated with APD. Extrapolation of data fromCAPD to APD may result in significant underdosing of APDpatients for two reasons: First, intermittent administra-tion to any exchange other than a prolonged daytimeexchange would prevent an adequate proportion of thedose from being absorbed into the systemic circulation,but this problem can be avoided by ensuring a minimumof 6 hours dwell during the daytime. Second, data existthat suggest APD may result in higher peritoneal clear-ances of antibiotics than is the case with CAPD (85). Thiswould result in reduced dialysate concentrations, re-duced serum concentrations, and the possibility of pro-longed intervals during a 24-hour period when dialysateconcentrations are less than the MIC for susceptible




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organisms. Table 5 lists the most commonly used antibi-otics that have been studied in APD and provides dosingrecommendations. Patients who are high transportersand those with high dialysate clearances may have a morerapid removal of some antibiotics. Adjustments in dos-ing for such patients are not yet known but the clinicianshould choose the side of higher dosing.

Within 48 hours of initiating therapy, most patientswith PD-related peritonitis will show considerable clini-cal improvement. The effluent should be visually in-spected daily to determine if clearing is occurring. Ifthere is no improvement after 48 hours, cell counts andrepeat cultures should be done. Antibiotic removal tech-niques may be used by the laboratory on the effluent inan attempt to maximize culture yield.

REFRACTORY PERITONITIS

Refractory peritonitis, defined as failure of theeffluent to clear after 5 days of appropriate antibiot-ics, should be managed by removal of the catheter toprotect the peritoneal membrane for future use (Evi-dence) (3,130132).

Refractory peritonitis is the term used for peritonitistreated with appropriate antibiotics without resolutionafter 5 days (see Table 6 for terminology).

A recent retrospective study that had a validationgroup of patients from another center showed that peri-toneal dialysate white cell count 1090/mm3 on day 3was an independent prognostic marker for treatmentfailure after adjustment for conventional risk factors(hazard ratio 9.03) (132). Catheter removal is indicatedto prevent morbidity and mortality due to refractory peri-tonitis and to preserve the peritoneum for future PD(Table 7). If the organism is the same as that of the pre-ceding episode, strong consideration should be given to

replacing the catheter after PD effluent becomes clear.The primary goal in managing peritonitis should alwaysbe the optimal treatment of the patient and protectionof the peritoneum, not saving the catheter. Ideally, at-tempts should be made at the laboratory to identify thecausative micro-organism to the exact species level (e.g.,S. epidermidis, S. hominis, or a species other than CoNS).Prolonged attempts to treat refractory peritonitis areassociated with extended hospital stay, peritoneal mem-brane damage, increased risk of fungal peritonitis, and,in some cases, death. Death related to peritonitis de-fined as death of a patient with active peritonitis, oradmitted with peritonitis, or within 2 weeks of a perito-nitis episode should be a very infrequent event. Therisk of death is highest with peritonitis due to gram-negative bacilli and fungus.

RELAPSING, RECURRENT, AND REPEAT PERITONITIS

Treatments of relapsing, recurrent, or repeat perito-nitis represent distinct clinical entities that portenda worse outcome (particularly for recurrent peritoni-tis). Stronger consideration should be given to timelycatheter removal (Opinion) (133).

TABLE 7Indications for Catheter Removal for Peritoneal

Dialysis-Related Infections

Refractory peritonitis Relapsing peritonitis Refractory exit-site and tunnel infection Fungal peritonitis Catheter removal may also be considered for

Repeat peritonitis Mycobacterial peritonitis Multiple enteric organisms

TABLE 6Terminology for Peritonitis

Recurrent An episode that occurs within 4 weeks of completion of therapy of a prior episode but with a differ-ent organism

Relapsing An episode that occurs within 4 weeks of completion of therapy of a prior episode with the sameorganism or 1 sterile episode

Repeat An episode that occurs more than 4 weeks after completion of therapy of a prior episode with thesame organism

Refractory Failure of the effluent to clear after 5 days of appropriate antibioticsCatheter-related peritonitis Peritonitis in conjunction with an exit-site or tunnel infection with the same organism or 1 site

sterile

Relapsing episodes should not be counted as another peritonitis when calculating peritonitis rates; recurrent and repeat episodesshould be counted.




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A recent retrospective study showed that relapsingand recurrent peritonitis episodes are caused by differ-ent species of bacteria and probably represent two dis-tinct clinical entities (133). Recurrent peritonitisepisodes have a worse prognosis than relapsing episodes.

COAGULASE-NEGATIVE STAPHYLOCOCCUS

Coagulase-negative staphylococcus peritonitis, in-cluding S. epidermidis, is due primarily to touch con-tamination, is generally a mild form of peritonitis,and responds readily to antibiotic therapy but cansometimes lead to relapsing peritonitis due to biofilminvolvement. In such circumstances, catheter replace-ment is advised (Evidence) (Figure 2) (37,134136).

Coagulase-negative staphylococcus, especially S. epi-dermidis, is still a very common organism in many pro-grams, usually denotes touch contamination, generallyresponds well to antibiotic therapy, and is seldom relatedto a catheter infection. Most patients with S. epidermidis

peritonitis have mild pain and often can be managed asoutpatients. In some programs, and depending on theprecise species involved, there is a very high rate of meth-icillin resistance (>50%); therefore, these programs maywish to use vancomycin as empiric therapy. The PD pro-gram should inquire of the laboratory the definition ofresistance based on MIC levels and, ideally, moleculardata (e.g., the presence of the mecA gene). Methicillinresistance of staphylococci is defined as the presence ofthe mecA gene and indicates that the organism is consid-ered resistant to all beta-lactam-related antibiotics, in-cluding penicillins, cephalosporins, and carbapenems.Every effort should be made to avoid inadequate levelsthat may lead to relapsing peritonitis. The Committee feelsthe existing data are inadequate to recommend intermit-tent dosing of first-generation cephalosporins and, untilmore data are available, continuous dosing may be pref-erable. Ideally, repeated cell counts and cultures of theeffluent should guide the therapy but 2 weeks of therapyis generally sufficient. The patients technique should bereviewed to prevent recurrence.

Figure 2 Coagulase-negative staphylococcus (CoNS; Staphylococcus epidermidis): *CoNS can sometimes lead to relapsing peri-tonitis, presumably due to biofilm involvement. The duration of antibiotic therapy following catheter removal and timing ofresumption of peritoneal dialysis may be modified depending on clinical course.

Other Gram-Positive Organisms, Including Coagulase-Negative Staphylococcus, on Culture

Continue gram-positive coverage based on sensitivitiesStop gram-negative coverage

Assess clinical improvement, repeat dialysis effluent cell count and culture at days 35

Clinical improvement(symptoms resolve; bags clear):

Continue antibiotics; Reevaluate for exit-site or occulttunnel infection, intra-abdominal

abscess, catheter colonization, etc.

No clinical improvement(symptoms persist; effluent remains cloudy):

Reculture & evaluate*

No clinical improvement by 5 days onappropriate antibiotics: remove catheter

Duration of therapy: 14 days Peritonitis with exit-site or tunnel infection:Consider catheter removal

Duration of therapy: 1421 days




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Coagulase-negative staphylococci consist of at least20 clinically relevant species that are sometimes diffi-cult to identify by automated systems and therefore re-quire a molecular approach by 16S DNA sequencing. Iffacilities are available, identification to the exact spe-cies level may be useful as some CoNS can cause seriousinfections (e.g., S. schleiferi, S. lugdunensis, S. warneri)and it may help to differentiate contaminated culturesfrom true infections. The introduction of matrix-assistedlaser desorption/ionization-time of flight mass spec-trometry (MALDI-TOF) techniques for routine bacterialidentification in several European countries enables mi-crobiologists to recognize correctly the spectra of vari-ous species of CoNS (137,138). A recently performedcomparative study between MALDI-TOF and two rapididentification automates for identification of 234 CoNSisolates, representing 20 different species, revealed sig-nificantly better performance of MALDI-TOF (139).

Relapsing S. epidermidis peritonitis suggests coloni-zation of the intra-abdominal portion of the catheterwith biofilm and is best treated by replacing the cath-eter (128). This can be done under antibiotic coverageas a single procedure once the effluent clears with anti-biotic therapy. Often, hemodialysis can be avoided byusing either supine PD or low volumes for a short periodof time.

STREPTOCOCCUS AND ENTEROCOCCUS

In general, streptococcal peritonitis is readily curableby antibiotics but enterococcal peritonitis tends to besevere and is best treated with IP ampicillin when theorganism is susceptible (Opinion) (Figure 3) (140,141).

If vancomycin-resistant enterococcus (VRE) is ampi-cillin susceptible, ampicillin remains the drug ofchoice; otherwise, linezolid or quinupristin/dal-fopristin should be used to treat VRE peritonitis(Opinion).

Streptococcal and enterococcal peritonitis generallycause severe pain. Ampicillin 125 mg/L in each exchangeis the preferred antibiotic. An aminoglycoside (givenonce daily IP as 20 mg/L) may be added for synergy forenterococcal peritonitis. Addition of gentamicin is po-tentially useful only if there is no laboratory evidence ofhigh-level resistance to the antibiotic. Since enterococciare frequently derived from the gastrointestinal tract,intra-abdominal pathology must be considered but touchcontamination as a source is also possible. The microbi-ology laboratory should optimize techniques to recog-nize the presence of other bacterial species (e.g.,anaerobic species) that can lead to more suspicion of an

intra-abdominal focus. The patients technique shouldbe reviewed as well.

Peritonitis with enterococci or streptococci may alsoderive from infection of the exit site and tunnel, whichshould be carefully inspected. Some streptococcal spe-cies originate from the mouth; assessment of dental hy-giene could be considered in these cases. Isolatedinfections with viridans streptococci have been reportedto be associated with slower response, poor outcome, andhigher rates of recurrence (142). In contrast, a recentreport from the Australian Registry showed that isolatedstreptococcal peritonitis tends to respond well to antibi-otic therapy (141). A report of 116 episodes of entero-coccal peritonitis from the ANZDATA Registry observedthat this condition was generally more severe and hadworse outcomes than other forms of gram-positive peri-tonitis (143). Moreover, it was reported that other patho-genic organisms were isolated in addition to Enterococcusspecies in approximately half of all cases of enterococcalperitonitis, and that the recovery of other organisms wasassociated with very high rates of catheter removal(52%), permanent transfer to hemodialysis (52%), anddeath (6%). Timely removal of the PD catheter within1 week of the onset of refractory enterococcal peritonitiswas associated with a significant reduction in the risk ofpermanent transfer to hemodialysis (74% vs 100%).

Increased infection rates are reported for amoxicillin-or ampicillin-resistant Enterococcus faecium (ARE) butdata on the incidence in PD infections are lacking (144).VRE has been reported and is seen most often in con-junction with recent hospitalization and prior antibiotictherapy. Vancomycin-resistant E. faecium has been re-ported but remains uncommon in PD patients. Limiteddata are available regarding the appropriate manage-ment of VRE peritonitis (145148). If VRE is ampicillinsusceptible, ampicillin remains the drug of choice.Linezolid or quinupristin/dalfopristin should be used totreat VRE peritonitis. Another recent report on two casesof VRE peritonitis suggests that IP daptomycin may alsobe effective (115) but the dosing and pharmacokineticsneed further studies. Quinupristin/dalfopristin, how-ever, may not be active against E. faecalis isolates. Bonemarrow suppression usually occurs after 10 14 days oflinezolid therapy and more prolonged therapy can alsoresult in neurotoxicity. It is unclear if the catheter mustbe removed for VRE peritonitis but, if the peritonitis doesnot resolve readily, this certainly should be done.

STAPHYLOCOCCUS AUREUS

Staphylococcus aureus causes severe peritonitis. Al-though it may be due to touch contamination, it is




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No clinical improvement(symptoms persist; effluent remains cloudy):

Reculture & evaluate*


Enterococcus/Streptococcus on Culture

Discontinue starting antibiotics*Start continuous ampicillin 125 mg/L each bag; consider adding aminoglycoside for Enterococcus

If ampicillin resistant, start vancomycin;If vancomycin-resistant enterococcus, consider quinupristin/dalfopristin, daptomycin, or linezolid

Assess clinical improvement, repeat dialysis effluent cell count and culture at days 35

often due to catheter infection. Staphylococcal peri-tonitis with concurrent exit-site or tunnel infectionis unlikely to respond to antibiotic therapy withoutcatheter removal (Evidence) (Figure 4) (5,23,149).

Rifampicin could be considered as an adjunct for theprevention of relapse or repeat S. aureus peritonitisbut the enzyme-inducer effect of rifampicin shouldbe considered in patients taking other medications(Opinion) (150).

If the organism is S. aureus, very careful attentionmust be paid to the exit site and tunnel of the catheter,as the mode of entrance of this organism is often via thecatheter, although touch contamination is anothersource. If the episode occurs in conjunction with an exit-

site infection with the same organism, then often theinfection will prove to be refractory and the cathetermust be removed. After a rest period off PD (generally aminimum of 2 weeks), PD can be tried again.

If the strain of S. aureus cultured is methicillin resis-tant then the patient must be treated with vancomycin.Such infections are more difficult to resolve. Comparedwith methicillin-sensitive S. aureus peritonitis, MRSAperitonitis has been reported to be independently pre-dictive of an increased risk of permanent transfer to he-modialysis (odds ratio 2.11) (151). Rifampicin 600 mg/day orally (in single or split dose) can be added to the IPantibiotics but therapy with this adjunctive antibioticshould be limited to 1 week, as resistance often devel-ops with longer courses. If the patient is considered at

Figure 3 Enterococcus or Streptococcus peritonitis: *Choice of therapy should always be guided by sensitivity patterns. If linezolidis used for vancomycin-resistant enterococcus, bone marrow suppression has been noted after 10 14 days. The manufacturersprecaution label states that these antibiotics should not be mixed together in the same solution container. Physicians own judg-ment is necessary. The duration of antibiotic therapy following catheter removal and timing of resumption of peritoneal dialysismay be modified, depending on clinical course.

Clinical improvement(symptoms resolve; bags clear):

Continue antibiotics; Reevaluate for exit-site or occulttunnel infection, intra-abdominal

abscess, catheter colonization, etc.

Duration of therapy: Peritonitis with exit-site or tunnel infection:14 days (Streptococcus) Consider catheter removal21 days (Enterococcus) Duration of therapy: 21 days




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high risk to have asymptomatic tuberculosis, rifampicinshould be used with caution in order to preserve this drugfor treatment of tuberculosis.

Vancomycin may be administered as 15 30 mg/kgbody weight IP, with a maximum dose of 2 g. A typicalprotocol for a patient 50 60 kg is vancomycin 1 g IPevery 5 days. Ideally, the timing of repetitive dosingshould be based on trough levels and is likely to be every3 5 days. The dosing interval is dependent on residualrenal function and patients should receive another doseonce trough serum levels reach 15 mg/mL. Teicoplanin,where available, can be used in a dose of 15 mg/kg bodyweight every 5 7 days. Data for children suggest thatthis approach is successful for both CAPD and APD. Treat-ment should be for 3 weeks (115,148).

In a recent review of 245 cases of S. aureus peritoni-tis, episodes that were treated initially with vancomycinhad a better primary response rate than those that weretreated with cefazolin (98.0% vs 85.2%, p = 0.001) butthe complete cure rate was similar (150). Adjuvantrifampicin treatment for a period of 5 7 days was asso-ciated with a significantly lower risk for relapse or re-peat S. aureus peritonitis than was treatment withoutrifampicin (21.4% vs 42.8%). In this study, recent hos-pitalization was a major risk factor for methicillin resis-tance. However, it should be noted that rifampicin is apotent inducer of drug-metabolizing enzymes and wouldreduce the levels of many medications. Similarly, anevaluation of 503 cases of staphylococcal peritonitis inAustralia found that the initial empiric antibiotic choice

Figure 4 Staphylococcus aureus peritonitis: *If vancomycin-resistant S. aureus, linezolid, daptomycin, or quinupristin/dalfopristinshould be used. Teicoplanin can be used in a dose of 15 mg/kg every 5 7 days. In areas where tuberculosis is endemic, rifampi-cin use for treatment of S. aureus should be restricted. Refractory is defined as failure to respond to appropriate antibioticswithin 5 days. The duration of antibiotic therapy following catheter removal and timing of resumption of peritoneal dialysis maybe modified depending on clinical course. BW = body weight; PD = peritoneal dialysis.

Staphylococcus aureus on Culture

Continue gram-positive coverage based on sensitivities*Stop gram-negative coverage, assess exit site again

If methicillin resistant, adjust coverage to vancomycin or teicoplaninAdd rifampin 600 mg/day orally (in single or split dose) for 57 days (450 mg/day if BW

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between vancomycin and cephazolin was not associatedwith any significant differences in subsequent clinicaloutcomes (151).

Unfortunately, prolonged therapy with vancomycinmay predispose dialysis patients to infections withvancomycin-resistant S. aureus and should be avoidedwhenever possible. If vancomycin-resistant S. aureusperitonitis develops, linezolid, daptomycin, or quinu-pristin/dalfopristin could be considered.

CORYNEBACTERIUM PERITONITIS

Corynebacterium is an uncommon but significantcause of peritonitis and exit-site infection. Completecure with antibiotics alone is possible in many patients(Opinion) (152,153).

Like CoNS, Corynebacterium species belong to thenatural flora of the skin and are therefore difficult torecognize as pathogens. Previously, Corynebacteriumwas thought to have little pathogenic potential in man.However, reporting of infections due to Corynebacteriumhas increased over the past few decades, in large partdue to improved recognition of the clinical relevance ofCorynebacterium species. In a retrospective study, recur-rent Corynebacterium peritonitis was common after a2-week course of antibiotics, but recurrent episodes canusually be cured with a 3-week course of IP vancomycin(152). Another large, retrospective, observational co-hort study of 82 episodes of Corynebacterium peritoni-tis by the ANZDATA Registry (153) demonstrated thatCorynebacterium peritonitis not infrequently resulted inrelapse (18%), repeat peritonitis (15%), hospitalization(70%), catheter removal (21%), permanent transfer tohemodialysis (15%), and death (2%). The overall curerate with antibiotics alone for a median period of 2 weekswas 67%. In individuals requiring catheter removal forrefractory peritonitis, those who had their catheters re-moved more than 1 week after the onset of Corynebac-terium peritonitis had a significantly higher risk ofpermanent transfer to hemodialysis than those who hadtheir catheters removed within 1 week (90% vs 43%).Ideally, coryneform bacteria should be identified to thespecies level. As for CoNS, further attempts should bemade to analyze the exact role of the gingival speciesbecause the group Corynebacterium actually encom-passes at least 46 different species.

CULTURE-NEGATIVE PERITONITIS

If a program has a rate of culture-negative peritoni-tis greater than 20%, then the culture methods should

be reviewed and improved (Opinion) (Figure 5)(154,155).

Cultures may be negative for a variety of technical orclinical reasons. The patient should always be queriedon presentation about use of antibiotics for any reason,as this is a known cause of culture-negative peritonitis(155). If there is no growth by 3 days, repeat cell countwith differential should be obtained. If the repeat cellcount indicates that the infection has not resolved, spe-cial culture techniques should be used for the isolationof potential unusual causes of peritonitis, includinglipid-dependent yeast, mycobacteria, Legionella, slowgrowing bacteria, Campylobacter, fungi, Ureaplasma,Mycoplasma, and enteroviruses. This will require coor-dination with the microbiology laboratory.

In clinical practice, a large proportion of culture-negative peritonitis episodes are caused by gram-posi-tive organisms (e.g., due to touch contamination), whilethe causative organism is not identified for technicalreasons. If the patient is improving clinically, the initialtherapy can be continued. Duration of therapy shouldbe 2 weeks if the effluent clears rapidly. If, on the otherhand, improvement is inadequate by 5 days, catheterremoval should be strongly considered. A recent reviewof 435 episodes of culture-negative peritonitis found thatthis condition was significantly more likely to be curedby antibiotics alone (77% vs 66%) and less likely to becomplicated by hospitalization (60% vs 71%), catheterremoval (12% vs 23%), permanent transfer to hemodi-alysis (10% vs 19%), or death (1% vs 2.5%) comparedwith culture-positive peritonitis (155).

PSEUDOMONAS AERUGINOSA PERITONITIS

Pseudomonas aeruginosa peritonitis, similar to S. aur-eus peritonitis, is often related to a catheter infectionand in such cases catheter removal will be required. Twoantibiotics should always be used to treat P. aerugin-osa peritonitis (Evidence) (Figure 6) (25,156,157).

Pseudomonas aeruginosa peritonitis is generally se-vere and often associated with infection of the catheter.If catheter infection is present or has preceded perito-nitis, catheter removal is necessary. Antibiotics must becontinued for 2 weeks while the patient is on hemodi-alysis. A large retrospective study of 191 episodes ofPseudomonas peritonitis recently conf irmed thatPseudomonas peritonitis is associated with greater fre-quencies of hospitalization, high rates of catheter re-moval, and permanent transfer to hemodialysis but notwith increased death rates. Prompt catheter removal and




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use of two antipseudomonal antibiotics are associatedwith better outcomes (157).

Occasionally, P. aeruginosa peritonitis occurs in theabsence of a catheter infection. An oral quinolone canbe given as one of the antibiotics for P. aeruginosa peri-tonitis. Alternative drugs include ceftazidime, cefepime,tobramycin, or piperacillin. Should piperacillin bepreferred, its dose is 4 g IV every 12 hours in adults. Piper-acillin cannot be added to the dialysis solution in con-junction with aminoglycosides.

Every effort to avoid P. aeruginosa peritonitis shouldbe made by replacing the catheter for recurrent, relaps-ing, or refractory exit-site infections with P. aeruginosaprior to the development of peritonitis. In such cases,the catheter can be replaced as a single procedure;

whereas, if peritonitis develops, the catheter must beremoved and the patient taken off PD for a period of time.In many such cases, permanent peritoneal membranedamage may have occurred.

OTHER SINGLE GRAM-NEGATIVE MICRO-ORGANISMSCULTURED

Single-organism gram-negative peritonitis may bedue to touch contamination, exit-site infection, ortransmural migration from constipation, diverticuli-tis, or colitis (Evidence) (Figure 7) (6,158165).

If a single gram-negative organism, such as E. coli,Klebsiella, or Proteus, is isolated, the antibiotic to be

Figure 5 Culture-negative peritonitis: *The duration of antibiotic therapy following catheter removal and timing or resumptionof peritoneal dialysis (PD) may be modified depending on clinical course.

Culture Negative on Days 1 & 2

Continue initial therapy

Day 3: culture still negativeClinical assessment

Repeat PD fluid white cell count and differential

Infection resolving Infection not resolving:Patient improvement clinically Special culture technique for unusual causes (e.g., viral,

mycoplasma, mycobacteria, Legionella). Consider fungi

Continue initial therapy for 14 days

Now culture positive Still culture negative

Adjust therapy according to Clinical improvement: No clinical improvementsensitivity patterns Continue antibiotic after 5 days:

Duration of therapy based on Duration of therapy:organism identified 14 days Remove catheter*

Continue antibiotics for at least14 days after catheter removal




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used can be chosen based on sensitivities, safety, andconvenience. A fluoroquinolone or cephalosporin maybe indicated based on in vitro sensitivity testing. Unfor-tunately, organisms in the biofilm state may be consid-erably less sensitive than the laboratory indicates (160),which may account for the high proportion of treatmentfailures even when the organism appears to be sensitiveto the antibiotic used (161). A recent retrospective studyof 210 cases suggested that recent antibiotic therapy isthe major risk factor for antibiotic resistance; exit-siteinfection, and probably recent antibiotic therapy, is as-sociated with poor therapeutic response (163). The SPICEorganisms (Serratia, Pseudomonas, and indol-positiveorganisms such as Providencia, Citrobacter, andEnterobacter) seem to have a particularly high risk ofrelapse. One retrospective study suggests that two anti-biotics may reduce the risk of relapse and recurrencecompared to single-agent therapy (163). Outcomes ofthese infections are worse than gram-positive outcomesand are more often associated with catheter loss anddeath. Single-organism gram-negative peritonitis may

be due to touch contamination, exit-site infection, orpossibly a bowel source, such as constipation, colitis, ortransmural migration. Often the etiology is unclear. Re-sponse of gram-negative peritonitis in pediatric PD pa-tients treated with empiric IP ceftazidime is oftensuboptimal (164).

The isolation of a Stenotrophomonas organism,while infrequent, requires special attention since itdisplays sensitivity to only a few antimicrobial agents(158,165). Prior therapy with carbapenems, fluoro-quinolones, and third- or fourth-generation cepha-lospor ins usually precedes Stenotrophomonasinfections. Infection with this organism is generallynot as severe as with Pseudomonas and is usually notassociated with an exit-site infection. Therapy forStenotrophomonas peritonitis is recommended for 3 4 weeks if the patient is clinically improving. Treatmentwith two drugs (chosen based on the sensitivities) isrecommended: the most effective agents are usuallyoral trimethoprim/sulfamethoxazole, IP ticarcillin/clavulanate, and oral minocycline.

Figure 6 Pseudomonas peritonitis. *The duration of antibiotic therapy following catheter removal and timing or resumption ofperitoneal dialysis may be modified depending on clinical course.

Pseudomonas Species on Culture

Without catheter infection (exit-site/tunnel) With catheter infection (exit-site/tunnel) current or prior to peritonitis

Give 2 different antibiotics acting in different waysthat organism is sensitive to, e.g., oral quinolone, Catheter removal*

ceftazidime, cefepime, tobramycin, piperacillin

Continue oral and/or systemicAssess clinical improvement, repeat dialysis antibiotics for at least 2 weekseffluent cell count and culture at days 35

Clinical improvement No clinical improvement(symptoms resolve; bags clear): (symptoms persist; effluent remains cloudy):

Continue antibiotics; Reculture & evaluate* Duration of therapy:

at least 21 days


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POLYMICROBIAL PERITONITIS

If multiple enteric organisms are grown, particularlyin association with anaerobic bacteria, the risk ofdeath is increased and a surgical evaluation shouldbe obtained (Evidence) (Figure 8) (166169).

Peritonitis due to multiple gram-positive organismswill generally respond to antibiotic therapy (Evidence)(4,170173).

In cases of multiple enteric organisms, there is a pos-sibility of intra-abdominal pathology such as diverticu-litis, cholecystitis, ischemic bowel, appendicitis, etc.Presentation with hypotension, sepsis, lactic acidosis,and/or elevation of peritoneal fluid amylase level shouldraise immediate concern for surgical peritonitis (174).A rapid Gram staining of the effluent may lead to therecognition of a mixed bacterial population suggestivefor an intestinal origin. In this setting where the intes-tines are felt to be the source, the therapy of choice ismetronidazole in combination with ampicillin and cef-tazidime or an aminoglycoside in the recommendeddoses. The catheter may need to be removed, particu-larly if laparotomy indicates intra-abdominal pathology

and, in that case, antibiotics should be continued via theIV route. Antibiotics can be tried, however, and in somecases the catheter may not need to be removed. Com-puted tomographic (CT) scan may help identify intra-abdominal pathology but a normal CT scan does noteliminate the possibility of intra-abdominal pathologyas a source.

Polymicrobial peritonitis due to multiple gram-posi-tive organisms more common than that due to entericorganisms has a much better prognosis (175). Thesource is most likely contamination or catheter infec-tion; the patients technique should be reviewed and theexit site carefully examined. Polymicrobial peritonitisdue to contamination generally resolves with antibiot-ics without catheter removal, unless the catheter is thesource of the infection.

FUNGAL PERITONITIS

Fungal peritonitis is a serious complication and shouldbe strongly suspected after recent antibiotic treat-ment for bacterial peritonitis. Catheter removal is in-dicated immediately after fungi are identif ied bymicroscopy or culture (Evidence) (116118,176).

Figure 7 Other single gram-negative organism peritonitis: *Choice of therapy should always be guided by sensitivity patterns.

Single Gram-Negative Organism on Culture*

Other StenotrophomonasE. coli, Proteus, Klebsiella, etc.

Treat with 2 drugs with differing mechanismsAdjust antibiotics to sensitivity pattern. Cephalosporin based on sensitivity pattern (oral trimethoprim/

(ceftazidime or cefepime) may be indicated sulfamethoxazole is preferred)

Assess clinical improvement, repeat dialysis

guias infecciones en dialisis peritoneal

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