Correspondence to: W.F. Keane, Department of Medicine, Division of Nephrology, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, Minnesota 55415 U.S.A.

Copyright Multimed Inc. 1996

OVERVIEW

Peritonitis is a common clinical problem that occurs in patients with end-stage renal disease treated by peritoneal dialysis (PD). Although the incidence of continuous ambulatory peritoneal dialysis (CAPD) peritonitis varies from center to center, during the 1980s and 1990s an overall average of approximately 1.1 to 1.3 episodes/patient/year has been reported. The more recent introduction of automated peritoneal dialysis (APD) has also contributed to the growth of PD, particularly in children, but it is also complicated by episodes of peritonitis. The development of disconnect systems has had a modest effect on the overall reduction of the incidence of peritonitis, particularly those due to skin organisms. The incidence of peritonitis in pediatric patients is higher than that seen in adults, and is highest in infants and younger children (Warady et al., 1996). A variety of microorganisms may cause PD peritonitis. Gram-positive organisms, particularly Staphylococcus aureus and S. epidermidis, have been the most frequent pathogens. However, in patients utilizing the disconnect systems, with the reduction in the incidence of gram-positive peritonitis, the relative probability of gram-negative infection has increased. Many different antimicrobial agents have been used to treat PD peritonitis, and the attempt by this committee during the past has been to review experiences reported in the literature and to formulate recommendations based upon these assessments. Over the years, a variety of different regimens have been proposed based upon experience. Antibiotics were administered either intraperitoneally (IP) or intravenously (IV), and a number of different dosing regimens have been utilized. Unfortunately, no single regimen has been shown to be the most efficacious in appropriate clinical trials.

A diagnostic and therapeutic approach to the patient with presumptive PD peritonitis was published in 1987, and revised in 1989 and 1993. These latter recommendations contained a number of new recommendations based upon intermittent dosing with both vancomycin and aminoglycosides. These recommendations reflected the changing approach to the treatment of serious infections. In the current review, these approaches are reevaluated in light of the data that have emerged in the last few years. Specifically, the emergence of vancomycin resistance has created a therapeutic dilemma of international proportions (Initiation of Therapy section). As a result, major modifications in our recommendations have been proposed this year. As always, individual clinical situations and variability in patient populations may necessitate modification of these recommendations. We do not suggest that the recommendations outlined in this report represent the only acceptable ways to manage peritoneal dialysis patients with peritonitis; nonetheless, the purpose of this document is to present a systematic approach reflecting a changing microbial environment. In addition, this year we have expanded our sections dealing with exit-site infections and have added some additional recommendations for the pediatric patient. It is recognized that only a few studies are available in the pediatric patient; however, reported experiences have increased over the past few years and have provided a stimulus for us to incorporate this information. For the purpose of this report, pediatric patients are considered to be patients <19 years of age. In addition to these therapeutic recommendations, an important clinical management tool is the development and utilization of techniques in each center for monitoring the incidence of peritonitis, exit-site infections, and tunnel infections in the peritoneal dialysis population. This epidemiologic approach should allow program directors to assess whether a change in the frequency and incidence of peritonitis has occurred in their patient population and, thus, provide an index of quality of care. Importantly, attention to changing microbial biograms within a center is also of major importance in the setting of increasing prevalence of vancomycin-resistant staphylococcus and enterococcus organisms.

CLINICAL PRESENTATION

Diagnosis of Peritonitis in CAPD Patients: In patients with cloudy fluid and/or abdominal pain and/or fever, a sample of the dialysate effluent should be obtained for laboratory evaluation, including a cell count with differential, Gram stain, and culture. An elevated dialysate cell count of white blood cells (WBC) > 100/mm3, of which at least 50% are polymorphonuclear neutrophils (PMN), is supportive of the diagnosis of peritonitis and calls for immediate initiation of therapy. In asymptomatic patients with only cloudy fluid, it is reasonable to delay initiation of therapy until the results of the cell count and differential and Gram stain are available, as long as these studies can be performed expeditiously (i.e., within 2 to 3 hours). If there is no increase in the peritoneal WBC count, the differential does not show a predominance of PMN, and no bacteria are seen on Gram stain, immediate therapy is not indicated. Similarly, if >10% of peritoneal leukocytes are eosinophils and the Gram stain is negative, immediate antimicrobial therapy is usually unnecessary. Patients with cloudy fluid accompanied by abdominal pain and/or fever require prompt initiation of empiric therapy that should be delayed no more than one hour for cell count, differential, and Gram stain results. Neither the differential nor the magnitude of the WBC elevation has been shown to be helpful in predicting the causative organism. A Gram stain is positive in 9% to 40% of peritonitis episodes, and, when positive, is predictive of eventual culture results in approximately 85% of cases. A Gram stain is particularly useful in the early recognition of fungal peritonitis. Culture of dialysate effluent should always be performed prior to initiation of therapy, but treatment should not be delayed while waiting for culture results.

Diagnosis of Peritonitis in APD Patients: Patients on various forms of APD require a modified approach to diagnosis and treatment of peritonitis. These patients receive a period of consecutive, relatively short exchanges during the night and may have only a partial exchange or a dry abdomen during the day. Peritonitis diagnostic criteria were established based on clinical experience with CAPD patients whose dwell times are 4 ­ 6 hours long. Concerns have been raised that the shorter dwell times of APD patients with suspected peritonitis could result in misleadingly low dialysate cell counts and falsely negative cultures. In pediatric patients, 70% of whom are treated with APD, this has not been the case. For more than a decade, CAPD peritonitis diagnostic and treatment criteria and methods have been successfully applied to the management of pediatric patients receiving APD, with only minor modifications (see Kuizon et al., 1995). The following recommendations are based on this pediatric experience, and may prove useful in the management of adults on APD. Data on peritonitis diagnosis and treatment in adults on APD are not available. Cloudy fluid remains the hallmark of peritonitis in APD-treated patients. Occasionally, the initial drain of the "stagnant" fluid that has been present in the abdomen all day in patients with only partial or dry daytime exchanges will appear cloudy in the absence of peritonitis. The WBC may exceed 100/mm3, but mononuclear cells will predominate. More important, dialysate rapidly clears with initiation of peritoneal dialysis. If cloudy fluid and/or abdominal pain and/or fever is/are observed at any point in the daily APD treatment cycle, a sample of dialysate effluent should be obtained for cell count and differential, Gram stain, and culture, as with CAPD patients. If the fluid is very turbid, the initial sample is sufficient for study, regardless of the length of the dwell time that produced it. In equivocal cases, or in patients with systemic or abdominal symptoms in whom dialysate appears to be clear, a second exchange is performed with a dwell time of at least one hour. Longer exchanges, approximating the four- to six-hour exchanges of CAPD, have not been necessary to establish the diagnosis of peritonitis in pediatric APD patients. Using this technique, the incidence of culture-negative peritonitis has remained approximately 20%, similar to that reported in pediatric CAPD patients.

Diagnosis of Peritonitis in Pediatric Patients: The clinical presentation of peritonitis in pediatric patients is similar to that in adult patients, with cloudy fluid the predominant initial finding (see Fine et al., 1983; Warady et al., 1984; and Watson et al., 1986). Fever is common in infants and young children with peritonitis; occasionally a febrile child will have clear dialysate effluent, only to have the following drained exchange appear cloudy. Infants may become anorexic or vomit during the early stages of developing peritonitis, but this is usually only appreciated in retrospect.

As with adults, pediatric patients with suspected peritonitis, including all febrile pediatric patients, should have cell count with differential, Gram stain, and culture performed on dialysate. In addition, febrile infants <24 months of age with apparent peritonitis should have a peripheral blood culture obtained; infants appear to be less capable of keeping bacterial infections sequestered within the peritoneal cavity than older patients, and a positive blood culture will dictate more extensive therapy. Although early reports suggested that a peritoneal WBC count of 50/mm3 was sufficient to support the diagnosis of peritonitis in children, common practice now is to require the same supportive laboratory criteria as are used in adult patients.

INITIATION OF THERAPY

Emergence of Vancomycin Resistance: In the last few years, the increasing prevalence of vancomycin-resistant microorganisms has been noted. Initially, vancomycin resistance was confined to enterococci isolated from patients who were critically ill in intensive care units. Subsequently, it has been documented that similar organisms could be isolated from patients with chronic illnesses treated with multiple antibiotics who frequently had prolonged hospital stays. The prevalence of vancomycin-resistant organisms has dramatically increased from approximately 0.4% to nearly 14% and has been particularly evident in larger hospitals that are university affiliated. Vancomycin resistance has been associated with resis-tance to other penicillins and aminoglycosides, thus presenting a treatment dilemma, since many of the second-line antimicrobial agents that could be used have not been proven in therapeutic trials. This change in vancomycin sensitivity has prompted a number of worldwide agencies to discourage routine use of vancomycin for prophylaxis, for empiric therapy, or for oral (po) use for Clostridium difficile enterocolitis. The major concern is that the vancomycin resis-tance gene is transmitted to staphylococcal strains creating an issue of major epidemiological importance. While a great deal of concern has been raised regarding vancomycin, it is still an important part of our antimicrobial armamentarium. Indeed, it is recommended for use in methicillin-resistant Staphylococcus aureus (MRSA) infections and treatment of infections due to beta lactam­resistant organisms, as well as for treatment of infections in patients with serious gram-positive infections who are allergic to other agents, and the treatment of C. difficile enterocolitis that is not responding to metronidazole. Clinical Utility of Gram Stain: If, on initial evaluation, the Gram stain reveals a gram-positive organism, therapy with a single antibiotic with activity against gram-positive organisms should be initiated. However, identification of a single species by Gram stain does not preclude the presence of other species present in lesser concentrations. Thus, the Gram stain results must be considered as preliminary. In rare cases the Gram stain may indicate gram-negative organisms, and the selection of an antimicrobial agent with activity against gram-negative bacteria is appropriate. The Gram stain may also be useful in revealing the presence of yeast and thus allow for prompt initiation of antifungal therapy. The finding of gram-positive cocci and gram-negative rods together suggests the possibility of a perforated abdominal viscus, and prompt surgical evaluation is warranted. Unfortunately, on many occasions the Gram stain is unavailable, delayed, or negative for any specific organisms. Empiric therapy is indicated in these conditions (Figure 1). There are some clinical clues that may be helpful. There is a slight statistical likelihood that the causative pathogen will be the same as the most recent infection. If the exit site is infected with pseudomonas or S. aureus when peritonitis presents, there is a high probability that the peritonitis is caused by the same organism. If the patient is having frequent peritonitis episodes, then relapse or recurrence with the same organism is likely. It is recognized that many patients treated with CAPD reside in locations that are remote from medical facilities and, thus, may not be seen expeditiously after the onset of symptoms. In addition, these CAPD patients may not have immediately available microbial and laboratory diagnostic services. Since most experts agree that prompt initiation of therapy for peritonitis is critical, this necessitates reliance on immediate patient reporting of symptomatology to the center. Prompt initiation of therapy by these patients remote from the center is of obvious importance and requires the availability of antimicrobials in the patientıs home. This approach has been broadly accepted by medical care providers worldwide and has demonstrated efficacy. Instructions for the reporting of symptomatology and the utilization of home antimicrobial therapy should be considered part of CAPD patient training.

INITIAL EMPIRIC ANTIBIOTIC SELECTION

If the effluent sediment Gram stain suggests gram-positive bacteria, a gram-negative organism, or is unavailable, delayed, or negative for any specific organisms, empiric therapy is indicated (Figure 1). To prevent unnecessary exposure to vancomycin and thus prevent emergence of resistant organisms, it is recommended that a first-generation cephalosporin, for example, cefazolin or cephalothin, with an aminoglycoside be initiated. These antibiotics can be mixed in the same dialysate bag either as loading or maintenance doses, without significant loss of bioactivity. The loading dose for either cefazolin or cephalothin is 500 mg/L, and maintenance is 125 mg/L. The rationale for this dosing regimen is in large part because of the possibility that gram-positive organisms such as enterococcus will require an aminoglycoside for this regimen to be effective. In addition, aminoglycosides have synergistic activity against staphylococci and streptococci. Limited experience with once-daily dosing of cefazolin 1.5 g has suggested that this regimen may be an effective alternative, however, no studies have been reported, and further experiences with this approach must be gained before it can be routinely accepted. Alternatives to cefazolin and cephalothin in this combination regimen include nafcillin, clindamycin, vancomycin, and ciprofloxacin, in that order of preference (Table 1). This strategy is consistent with the desire to preserve vancomycin for true methicillin-resistant organisms. Many of the S. epidermidis-like organisms that have been reported to be resistant to cefazolin or cephalothin are, in fact, sensitive to the drug because the levels achieved at the site of the infection (peritoneal cavity) are so high as a result of the intraperitoneal dosing strategies recommended. The cephalosporins were selected as empiric therapy because of their activity against both gram-positive and gram-negative organisms. Once a single gram-positive organism is cultured, an agent with a more narrow antimicrobial activity, such as nafcillin, can be selected. However, many clinicians may prefer to continue use of the cephalosporins because of convenience and ease of use. This is further discussed in detail, in the section, Modification of Treatment Regimen Once Culture and Sensitivity Results Are Known. Gentamicin, tobramycin, and netilmicin are dosed at 0.6 mg/kg body weight in only one exchange per day. Amikacin is dosed at 2.0 mg/kg body weight, also in only one exchange per day (Figure 1). New insights into the pharmacodynamic principles governing the activity as well as the toxicity of aminoglycosides have led to the development of alternative dosing regimens that may be used for the treatment of peritoneal dialysis­related peritonitis. A single daily dose of these agents has been shown to be efficacious and may be less toxic in other patient populations with severe systemic infections. Increased bacterial killing rates associated with prolonged postantibiotic effect are obtained using once-daily dosing, while toxic drug accumulation in renal and cochlear tissue may be minimized. In limited numbers of patients with pseudomonas peritonitis, once-daily therapy has also been effective. In contrast, continuous administration results in sustained, but low, serum levels, which are bactericidal but may favor toxic accumulation of these agents in renal and cochlear tissue. The aminoglycoside dosing regimen recommended provides once-a-day intraperitoneal concentrations that are at least ten times higher than the minimal inhibitory concentration of susceptible bacteria (20 mg/L), although the exact duration of the postantibiotic effect is unclear, particularly in patients with some degree of residual renal function (see Low et al., 1996). Loading doses aimed at filling body compartments other than the peritoneal cavity and its surrounding membrane are no longer recommended, since they contribute little to the antimicrobial effect at the infection site, but do lead to sustained serum levels that are potentially toxic after repeated or prolonged exposure (see Bailie and Eisele, 1995). Thus, whether prolonged or closely spaced, repetitive courses with aminoglycosides should be avoided. Finally, it should be recognized that, in patients with residual renal function, increased dosages or more frequent dosing intervals, particularly when using intermittent regimens, are required (Figure 1). Gram Stain Reveals Yeast: If yeast is seen on Gram stain, prompt initiation of antifungal therapy should be initiated. Although the mainstay of therapy in the past has been amphotericin B, its toxicity has frequently precluded its effective use. Experiences with the newer imidazoles/triazoles and flucytosine have suggested that these agents are well tolerated and are efficacious. When used in combination, these agents appear to have a synergistic effect and have demonstrated cure rates similar to those reported with amphotericin B (see Millikin et al., 1991). Initial Antibiotic Dosing in Pediatric Patients: Continuous intraperitoneal cephalosporin and aminoglycoside therapy in pediatric patients is possible using the same dosing guidelines as for adult patients because exchange volumes in children are roughly proportional to body size. However, it must be remembered that the typical pediatric exchange volume is 40 mL/kg body weight, whereas a 2-L exchange in a 70-kg adult corresponds to only 28 mL/kg body weight. Thus, when antibiotics are given in fixed concentrations in dialysate, the administered IP dose may be 25% higher in children than in adults. For loading doses and continuous maintenance therapy with cephalosporins, this potential difference in delivered dose poses no problems for children and allows the use of the same dosing recommendations for children as for adults. Similarly, continuous therapy with fixed dialysate concentrations of aminoglycosides (without a loading dose) has been shown to be effective in pediatric patients and to result in serum concentrations of aminoglycosides that are "nontoxic." Limited studies in children who have received continuous IP aminoglycosides for peritonitis have failed to show a convincing increase in the incidence of ototoxicity, although these studies have been retrospective and uncontrolled for other preexisting or comorbid conditions. While, in theory, the use of once-daily aminoglycoside IP dosing to treat peritonitis is attractive, this regimen has not been studied in children, and questions remain about its safety. Until the results of studies of once-daily aminoglycoside dosing in pediatric patients become available, clinicians should either use continuous therapy (see Table 1) or closely monitor serum aminoglycoside levels throughout the course of treatment.

MODIFICATION OF TREATMENT REGIMEN ONCE CULTURE AND SENSITIVITY RESULTS ARE KNOWN

Gram-Positive Microorganisms Cultured: Within 24 to 48 hours after the appropriate culture of dial-ysate fluid, 70% ­ 90% of these samples yield a specific microorganism (Figure 2). If the organism is an enterococcus, the cephalosporin is replaced with ampicillin 125 mg/L in each exchange, and the aminoglycoside may be continued in one exchange per day if necessary, based on sensitivity. A factor to consider in deciding whether or not to continue the aminoglycoside is the recognition of the high ampicillin level that will be achieved at the site of infection. As previousy discussed, we urge restraint in immediately utilizing vancomycin for enterococci without considering all the implications. Since enterococci are frequently derived from the gastrointestinal tract, intra-abdominal pathology must be considered. More-over, care should be exercised in evaluating the dialysate culture since other more fastidious and slow-growing organisms from the bowel may be present in conjunction with the enterococci.

Preliminary results of a controlled trial of once-weekly IP vancomycin in pediatric patients show a trend toward lower cure rates with intermittent compared to continuous vancomycin, although the difference was not statistically significant (see Klaus et al., 1995). Problems with intermittent vancomycin therapy in pediatric patients appear to correlate with higher levels of residual renal function. When vancomycin is used in children, it should be given either continuously (see Table 1) or more often than every seven days. In the absence of specific data on different intermittent vancomycin regimens in children, it seems reasonable to recommend an IP dose of 30 mg/kg body weight, given in a single exchange every four to five days. Teicoplanin has also been used in children in a dose of 15 mg/kg body weight every five to seven days. If the organism is identified as a gram-positive organism other than enterococcus, or S. aureus, cephalosporin can be continued or replaced with nafcillin, and the aminoglycoside should be stopped. S. epidermidis is the most frequently identified organism in this situation. Often an S. epidermidis sensitivity profile will state resistance to first-generation cephalosporins. This "resistance" is relative, and is usually defined by minimal inhibitory concentration between 16 and 32 mg/L. Since the antibiotic level in dialysate and thus in peritoneal tissue exceeds 100 mg/L, this "resistance" is often easily overcome. This is the justification for using high doses of cephalothin or cefazolin for S. epidermidis peritonitis. However, peritonitis caused by coagulase-negative staphylococci that are "resistant" to cephalosporins may not resolve with cephalosporins, despite the high levels achieved. In this setting of methicillin-resistant S. epidermidis not responding to therapy, consideration should be given to the use of clindamycin or vancomycin. Also, if clear improvement is not observed within 48 hours, or if the current peritonitis episode is a recurrence or relapse, switching to an alternative agent such as clindamycin or vancomycin is warranted. Lastly, for uncomplicated infections, an oral first-generation cephalosporin (e.g., cephradine 250 mg four times a day or cephalexin 500 mg four times a day) may be utilized to complete the second week of therapy.

Cultures Are Negative: Occasionally (less than 20%), cultures may be negative for a variety of technical or clinical reasons. Experience would indicate that, if the patient is clinically improving after four to five days, and there is no suggestion of gram-negative organisms on Gram stain, only the cephalosporin should be continued, and aminoglycoside antibiotic can be discontinued (Figure 3). Duration of therapy should be for two weeks. If, on the other hand, no clinical improvement occurs, repeat evaluation is mandatory with consideration of mycobacteria, and catheter replacement or removal should be contemplated. Gram-Negative Microorganisms Cultured: If a single cephalosporin-sensitive gram-negative organism, such as Escherichia coli, klebsiella, or proteus, is isolated, it is not necessary to continue the aminoglycoside. The goal is to narrow the spectrum of antibiotic to specifically cover the infecting pathogen, minimizing the exposure to broad-spectrum antibiotics. Thus, the first-generation cephalosporin may suffice for many common gram-negative infections. Utilization of the cephalosporin of choice must be guided by in vitro sensitivity testing. If the culture report reveals multiple gram-negative organisms, it is imperative to consider the possibility of intra-abdominal pathology necessitating surgical exploration (Figure 4). In addition, if anaerobic gram-negative bacteria are isolated, either alone or in combination with other gram-negative organisms, serious consideration should be given to surgical intervention because of the likelihood of bowel perforation. In this setting, metronidazole, in combination with a cephalosporin and aminoglycoside in the recommended doses, is the therapy of choice. Metronidazole is administered intravenously, orally or rectally, in a dose of 500 mg every eight hours in adults and 15 mg/kg body weight every eight hours in children.

The isolation of a xanthomonas organism, while infrequent, requires special attention since it displays sensitivity only to a few antimicrobial agents (see Figure 4). Infection with this organism is generally not as severe as with pseudomonas and is usually not associated with an exit-site infection. Therapy for pseudomonas/xanthomonas peritonitis is recommended for three to four weeks if the patient is clinically improving. The consequences of persistent gram-negative peritonitis, particularly pseudomonas, on peritoneal membrane integrity over the long term are poorly understood. However, it is thought that this could lead to loss of peritoneal transport function. Therefore, consideration of early catheter removal is important to preserve peritoneal function and avoid repeated long-term treatment with potentially toxic antibiotics. Fungal Organisms Cultured: Many clinicians still feel that catheter removal is indicated immediately after fungi are identified by Gram stain or culture. As indicated above (in the section, Gram Stain Reveals Yeast), recent experience with the newer imidazoles/triazoles and flucytosine (po or, if available, IP) has suggested that these agents can also be efficaciously administered. Although prospective clinical trials of peritoneal dialysis­related fungal peritonitis comparing amphotericin B to the imidazole/triazole-flucytosine combinations have not been performed, a retrospective analysis of published data suggests this latter combination is as efficacious as amphotericin B, particularly for the nonfilamentous fungi. However, emergence of resistance to the imidazoles has occurred, thus raising some concerns. Where available, fungal sensitivities should be obtained. It is reasonable that successful therapy should be continued for four to six weeks (Figure 5). However, if clinical improvement does not occur after four to seven days of therapy, the catheter should be removed. Therapy with these agents should be continued after catheter removal, orally with flucytosine 1000 mg (25 ­ 50 mg/kg body weight in children) and fluconazole 100 ­ 200 mg daily (3 mg/kg body weight in children) for an additional ten days (Table 1). Oral flucytosine has recently been withdrawn from some markets (e.g., Canada), and this will influence local protocols.

TREATMENT OF PERITONITIS IN APD PATIENTS

When peritonitis is present in an APD patient, after a sample is obtained for laboratory studies, up to three in-and-out exchanges may be performed for reduction of abdominal pain and clearance of some fibrin. Antibiotic therapy is then initiated according to the guidelines presented above for CAPD patients. For APD patients, the dialysis prescription is adjusted to provide round-the-clock exchanges with dwell times of three to four hours. Exchanges every three to four hours are continued until the fluid clears, which occurs in most cases in 24 to 72 hours. During this time the patient must remain connected to the cycler, or may disconnect for one dwell/24 hours, as long as a full exchange is maintained. When the fluid has cleared, the patient may return to a more typical APD regimen, with short nightly cycles and a prolonged daytime dwell. The daytime dwell, which contains antibiotics, must be a full exchange for as long as treatment is continued. As with CAPD, adjustments of the APD prescription may be needed in patients who experience altered ultrafiltration during episodes of peritonitis.

In all other respects, the foregoing guidelines for diagnosis and treatment of peritonitis in CAPD patients may be used in APD patients. Studies of peritonitis in APD patients are needed to refine these recommendations. In adults on APD, some centers change patients to a CAPD regimen during peritonitis and treat as described above.

ASSESSMENT OF PATIENTS WHO FAIL TO DEMONSTRATE CLINICAL IMPROVEMENT

Within 48 hours of initiating therapy, most patients with peritoneal dialysis­related peritonitis will show considerable clinical improvement. Occasionally, symptoms may persist beyond 48 to 96 hours. At 96 hours, if patients have not shown definitive clinical improvement, a reevaluation of the clinical status is essential. Specifically, cell counts, Gram stain, and cultures should be repeated. Antibiotic removal techniques may be used in an attempt to maximize culture yield.

Among the paramount clinical concerns in patients with persistent symptomatology is the presence of intra-abdominal or gynecological pathology requiring surgical intervention, or the presence of unusual organisms, such as mycobacteria, fungi, or fastidious organisms. Identification of these latter organisms will often require special culture techniques and must be coordinated with the microbiology laboratory. In patients with S. aureus infections that have not shown significant improvement, the possibility of an underlying tunnel infection must be considered. In addition, in the reevaluation of the patientıs medical status, the antimicrobial regimen should be reassessed. Patients with S. aureus peritonitis treated with cephalosporin to which rifampin has already been added to the regimen who demonstrate failure to clinically improve should be reevaluated. Specifically, evaluation for an occult tunnel infection should be considered. Ultrasonography, computed tomography scanning, or, less often, gallium scanning may be performed to assess the presence of an occult abscess within the tunnel of the peritoneal catheter. If a coagulase-negative staphylococcus (S. epidermidis) has been cultured from the dialysate effluent and the patient has failed to respond to the initial therapy, rifampin may also be added in the doses recommended. Alternatively, in the setting of methicillin-resistant staphylococcus, clindamycin or vancomycin could be used.

If anaerobic bacteria have been identified by culture, and the patient has not clinically improved by 96 hours, the catheter should be removed, surgical exploration considered, the antibiotic regimen reevaluated, and therapy should be continued intravenously for five to seven additional days after catheter removal. Similarly, if more than one gram-negative organism other than pseudomonas has been identified, catheter removal is warranted and intravenous antibiotics should be continued for five to seven days. In those patients with anaerobic bacteria or gram-negative organisms, exclusive of pseudomonas, the possibility of an intra-abdominal pro-cess necessitating surgical exploration should be considered. Finally, if pseudomonas has been identified and, clinically, the patient has failed to demonstrate any significant improvement within 48 to 72 hours after initiating therapy, the catheter should be removed. As described above, two antibiotics with antipseudomonal activity should be continued intravenously for at least five to seven days. The suggested duration of antibiotic therapy after removal of the catheter may be modified depending upon the clinical course. There are no studies that have established the appropriate duration of antimicrobial therapy after catheter removal. If therapy for fungal peritonitis was initially instituted but no clinical improvement is seen, the catheter should be removed. Finally, for those patients in whom the original cultures were negative, and who are still demonstrating persistence of symptomatology at 96 hours, the catheter should be removed and cultured, and intravenous antibiotics should be continued for five to seven days.

DURATION OF ANTIBIOTIC THERAPY

Patients Demonstrating Clinical Improvement: In patients with gram-positive peritonitis, antibiotic treatment for 14 days after initiating an effective regimen is usually adequate. However, there are no carefully conducted trials to define the optimal length of treatment. In patients with S. aureus peritonitis the recommended duration of treatment is 21 days. In patients with gram-negative infections, exclusive of the pseudomonas/xanthomonas or culture-negative peritonitis, 14 days of antimicrobial therapy has been recommended. However, emerging data from a recent outcome study have suggested that single gram-negative organism peritonitis other than pseudomonal infection may require longer therapy (21 days). Until this issue is resolved, clinical judgment should be used in these patients. If effective, therapy for pseudomonas/xanthomonas should be at least 21 days in duration.

Patients Who Fail to Demonstrate Clinical Improvement: In patients with gram-positive infections in whom a change in the antibiotic regimen has been made, an additional 96 hours of treatment is needed in order to assess clinical response. In those patients with persistent symptomatology after antibiotic modification, one should remove the catheter. If clinical improvement does not occur, an intra-abdominal abscess should be considered.

Antibiotic Toxicities: The intermittent dosing recommendation for aminoglycosides (amikacin, tobramycin, gentamicin, and netilmicin) can be expected to reduce the risk of ototoxicity and cochlear toxicity associated with their use. However, some risk for such toxicity will remain, especially if therapeutic courses are extended beyond two to three weeks, particularly if patients are anuric. Thus, prolonged treatment with these agents should be limited to the rare occasion when no alternative, less toxic agents are likely to be effective. Similarly, repeated use of aminoglycosides within four to six weeks, for example, for relapsing peritonitis, should be avoided. A meta-analysis of the literature has suggested that netilmicin may be less ototoxic and nephrotoxic than tobramycin (see Buring et al., 1988). This claim is supported by observations made in laboratory animals showing netilmicin to have less intrinsic vestibulo-cochlear toxicity compared to other commonly used aminoglycosides (see Govaerts et al., 1990). Although the monitoring of aminoglycoside serum levels in CAPD peritonitis has not been performed routinely, its use is recommended only to identify potentially toxic accumulation of aminoglycosides. However, a safe serum level has not been established in this patient population.

TUBERCULOUS PERITONITIS

Tuberculous (TB) peritonitis is a rare complication of peritoneal dialysis (see Vas, PDI, 1994). It should be considered in patients with peritonitis, who are not responding to appropriate antibiotic treatment, whether it is a culture-negative peritonitis or proven bacterial peritonitis. In general, TB peritonitis is due to reactivation of a latent peritoneal focus rather than a primary infection through the catheter. Most of the patients present with fever and abdominal pain. Peritoneal fluid differential leukocyte count, gallium scanning, and other methods of imaging are not usually helpful in diagnosis of this entity. Smears of the peritoneal effluent often fail to reveal acid-fast bacilli and thus, diagnosis must rely on TB cultures. Since peritoneal fluid culture for acid-fast organisms usually takes six weeks, the diagnosis is frequently delayed in the majority of patients. In order to make an earlier diagnosis in patients not responding to therapy, invasive procedures such as exploratory laparotomy or laparoscopy with biopsy of the peritoneum or omentum should be considered. Detection of microbacterial deoxyribonucleic acid (DNA) amplified by polymerase chain reaction techniques from peritoneal effluent holds the greatest promise for rapid detection of TB. No data exist for the optimal choice and duration of chemotherapy of TB peritonitis. Based on the usual conservative approach to extrapulmonary tuberculosis, most reported cases have been treated with three drugs (isoniazid 300 mg po q.d., rifampicin 600 mg po q.d., and pyrazinamide 1.5 g po q.d.) usually for 12 months (Table 1). Since streptomycin, even in reduced doses, may cause ototoxicity after prolonged use, it should not be administered in the end-stage renal disease patient. Similarly, ethambutol, because of the high risk of optic neuritis, is not recommended.

Catheter removal appears not to be mandatory in all cases, provided prompt diagnosis and chemotherapy are carried out. Long-term ultrafiltration failure may develop as a late complication after TB peritonitis if peritoneal dialysis is continued during chemotherapy. It occurs most frequently in patients in whom antituberculous therapy has been delayed for more than five weeks after apparent onset of TB peritonitis. Thus, early diagnosis and chemotherapy for this unusual infection are crucial.

PROPHYLACTIC ANTIBIOTIC USE

Extended Use of Prophylactic Antibiotics: Prophylactic use of antibiotics does not prevent peritonitis. This has been shown for penicillins and the sulfamethoxazole trimethoprim combinations. In patients with chronic exit-site infections, there are no data to show whether long-term antibiotic therapy for chronic exit-site infections decreases peritonitis risk. However, the regular use of intranasal mupirocin for nasal carriage has a definitive advantage in decreasing S. aureus exit-site infections. Recently, it has been suggested that use of oral prophylaxis with nystatin (500 U ƒ 3) during antibiotic therapy for various infections reduced the incidence of subsequent fungal peritonitis (see Záruba et al., 1991). Additional studies of this approach will be of great interest.

Short-Term Antibiotic Prophylaxis: Invasive procedures associated with transient bacteremia have not been frequently reported to cause peritonitis in PD patients. In some patients undergoing colonoscopy polypectomy, ampicillin plus aminoglycoside with or without metronidazole prescribed as a three-dose antibiotic course (three exchanges) started immediately prior to the procedure may be of potential benefit. However, a randomized prospective study in PD patients has not been performed.

Prophylactic Antibiotics and Catheter Placement: There is some evidence now that prophylactic antibiotics before catheter placement will prevent subsequent infection. The experience in general surgical practice indicates that perioperative antibiotics, especially in the presence of a foreign body, diminish the incidence of wound infection. A first-generation cephalosporin has been most frequently used in this context. In this setting routine use of vancomycin should be avoided.

Use of Prophylactic Antibiotics after a Technique Break: There are no data to support or refute the suggestion that the use of prophylactic antibiotics after a break in sterile technique is effective in preventing peritonitis. Thus, no specific recommendation for antibiotic use can be made in this setting, although many nephrologists give a short three- to five-day course of antibiotics after a break in sterile technique. Exit-Site Infections and Prophylactic Antibiotics: S. aureus nasal carriage is associated with an increased risk of S. aureus exit-site/tunnel infections and peritonitis (see Luzar et al., 1990). Prophylaxis with intranasal mupirocin, exit-site mupirocin, or oral rifampin is effective in reducing S. aureus exit-site infection in adults (see Zimmerman et al., 1991; Bernardini et al., 1996; and Coles et al., 1994). Rifampin, 300 mg b.i.d. for five days every 12 weeks, effectively reduced the incidence of S. aureus exit-site infections to one third of the rate in the controls, but 12% of the patients could not tolerate the drug (see Figure 6). Mupirocin applied daily to the exit site after routine exit-site care was as effective as oral rifampin in reducing exit-site infection rates. The use of mupirocin at the exit site, however, should be avoided in patients with polyurethane catheters (Cruz catheter), as structural damage to the catheter has been reported. Intranasal mupirocin b.i.d. for five days every four weeks to S. aureus carriers was also effective in reducing S. aureus exit-site infections to 0.12 episodes/year compared to 0.43 episodes/year in the placebo group. Patients with three negative nose cultures are at minimal risk for S. aureus infections. Therefore, in this group of patients prophylaxis is unnecessary.

TREATMENT OF EXIT-SITE INFECTIONS

An exit-site infection is defined by the presence of purulent drainage with or without erythema of the skin at the catheter-epidermal interface (Figure 7). A culture of the purulent drainage should be obtained. Empiric antibiotic therapy may be initiated immediately, if the clinical appearance warrants early intervention, or delayed until the results of the culture are available. Gram-positive organisms are treated with an oral penicillinase-resistant penicillin, cephalexin or sulfamethoxazole trimethoprim (see Flanigan et al., 1994). To prevent unnecessary exposure to vancomycin and, thus, emergence of resistant organisms, vancomycin should be avoided in the routine treatment of gram-positive exit-site and tunnel infections. In slowly resolving or particularly severe-appearing S. aureus exit-site infections, rifampin 300 mg b.i.d. in adults (5 ­ 10 mg/kg body weight b.i.d. in children) may be added. Gram-negative organisms may be treated in adults with oral quinolones such as ciprofloxacin 500 mg b.i.d. Chelation interactions may occur between fluoroquinolones and concomitantly administered mutivalent cations. Calcium salts, oral iron supplements, zinc preparations, sucralfate, magnesium-aluminum antacids, and milk may reduce oral ciprofloxacin absorption by 75% ­ 91%, with a possible significant reduction in antimicrobial activity. It is suggested that the administration of the preparations be staggered as much as possible. A minimum spacing of two hours between preparations is recommended, with the ciprofloxacin administered first (see Lomaestro and Bailie, 1995). In growing children, ciprofloxacin cannot be recommended for routine use. Alternative therapy based on sensitivity patterns should be selected. If the organism is P. aeruginosa, and resolution is slow or recurrence occurs, intraperitoneal ceftazidime may be added. Therapy should be continued until the exit site appears completely normal. Prolonged antibiotics may be necessary. If three to four weeks of antibiotics fail to resolve the infection, the catheter may be replaced. Alternatively, revision of the tunnel may be performed in conjunction with continued antibiotic therapy. This procedure, however, may result in peritonitis, in which case the catheter should be promptly removed.

RELAPSING PERITONITIS

Relapsing peritonitis is defined arbitrarily as another episode of peritonitis caused by the same genus/species that caused the immediately preceding episode, occurring within four weeks of completion of the antibiotic course. Clinically, these patients will have signs and symptoms similar to those described in patients with sporadic peritonitis. Relapsing infections with coagulase-positive or -negative staphylococci should be treated with cephalosporins and rifampin for approximately four weeks. However, in the setting of relapsing peritonitis with methicillin-resis-tant S. aureus or S. epidermidis, clindamycin or vancomycin should be considered for therapy. In the presence of coagulase-positive staphylococcus infection, a search for an occult tunnel infection should also be made. If enterococci are recultured, ampicillin and an aminoglycoside should be used in the recommended doses. Consideration should also be given to the possibility of an intra-abdominal abscess. If no clinical response is noted after 96 hours of therapy for relapsing peritonitis, catheter removal is indicated. If the patient responds clinically, but subsequently relapses an additional time, catheter removal and replacement are recommended. In relapsing peritonitis caused by gram-negative organisms, one should clinically evaluate for an intra-abdominal abscess. Catheter removal and surgical exploration should be strongly considered in these patients. Treatment with ceftazidime or aminoglyco-side alone can be used, once culture results are known. If pseudomonas or xanthomonas organisms are identified again on culture, the catheter should be removed. Finally, in those patients with relapsing peritonitis, short-term interruption of peritoneal dialysis may be of value. However, the availability of supportive hemodialysis will dictate whether this option can be considered.

CATHETER INSERTION AFTER REMOVAL FOR CAPD PERITONITIS

The optimal time period between catheter removal for infection and reinsertion of a new catheter is not known. Empirically, a minimum of three weeks between catheter removal and reinsertion of a new catheter is recommended. However, recent experiences have suggested that a shorter interval may be acceptable (see Swartz et al., 1991). Indeed, removal of the old catheter and insertion of a new one during the same operation has been used successfully in the setting of persistent or recurrent peritonitis. Since a peritoneal dialysis­free interval (with or without a catheter in place) may also be helpful in resolving peritonitis, the timing of catheter reinsertion should be individualized. The availability of operative time, backup hemodialysis capabilities, the presence of an intra-abdominal abscess, exit or tunnel infections, and patient and physician preference are all factors involved in this decision.

USE OF ADJUNCTIVE THERAPY IN TREATMENT OF CAPD PERITONITIS

The performance of two to three rapid exchanges of peritoneal dialysis solution immediately after diagnosis of peritonitis is reported to be of symptomatic benefit but does not appear to offer any other specific therapeutic benefits. Continuous lavage in the treatment of CAPD peritonitis has been shown to be inferior to a continuation of CAPD therapy. This may be related to the adverse effect on phagocytic cell function related to the low pH and high osmolality of the peritoneal dialysis solution, a phenomenon very clearly shown in vitro. A few rapid exchanges of dialysis solution every 20 minutes are advocated only for severe symptomatic peritonitis at the start of therapy. Heparin (500 ­ 1000 U/L) may be added to the regular regimen until dialysate effluent clears. This usually occurs within 48 to 72 hours. Thrombolytic therapy should be reserved for those infections for which no other cause or complication is evident, and probably should be limited to coagulase-negative staphylococcal or culture-negative infections. Temporary discontinuation of peritoneal dialysis with continuation of the antibiotic therapy may be a reasonable adjunctive therapy for recurring or relapsing infections. Although the duration of this approach has not been clearly established, durations of seven to 21 days have been advocated in uncomplicated and clinically mild cases of peritonitis (see Pagniez et al., 1988). A number of variations of this approach have also been proposed and include hyperconcentrated antibiotics or fibrinolytics added within the catheter lumen at the time of peritoneal resting. Several small studies have reported some benefit using peritoneal rest with or without intracatheter agents. Overall, the role of thrombolytic therapy, as well as temporary discontinuation of PD, is limited. Furthermore, pain, fever, and peritoni-tislike syndromes may be common with intraperitoneal injection of streptokinase. In a recent report evaluating the treatment of refractory and recurring peritonitis, including patients with associated tunnel infections, simultaneous removal and replacement of the catheter was shown to be of benefit to patients with refractory peritonitis (see Innes et al., 1994). It should be noted that the organisms involved in these failures included mycobacteria, fungi, and/or pseudomonas.

TECHNIQUE FOR SAMPLING AND CULTURING OF PERITONEAL DIALYSIS EFFLUENT

Specimen Processing: Several recent studies have dealt with the conditions necessary for improved diagnosis in CAPD peritonitis. In order to establish accurate microbiological diagnosis of peritonitis, the following points are important:

1. Cultures should be taken as early as possible from suspected cases of peritonitis; the first cloudy bag is the best specimen. A delay of several hours from the time of collection to the time of culture does not seem to decrease the accuracy of bacteriological diagnosis

2. Large volumes should be cultured or concentrated to maximize bacterial recovery rates

3. Washing the specimen sediment with sterile saline or using antibiotic removing resin may be necessary in patients already receiving antibiotic therapy

4. Identification and sensitivity testing should be done as soon as possible to achieve rational antibiotic therapy

FUTURE DIRECTIONS

There have been a considerable number of therapeutic developments during the past decade. We are now faced with an increasing incidence of vancomycin-resistant gram-positive organisms, which has created substantial concern worldwide. Because of the increasing economic pressures in the health-care delivery system, considerable effort has been directed towards the development of an international study group in order that our community can begin to maximize the utilization of antibiotics in the treatment of PD peritonitis and related infections. Thus, the Committee recommends that we develop, under the auspices of the International Society for Peritoneal Dialysis, a multicentered infection study project. In this way, new protocols and therapies can be prospectively designed and evaluated to maximize the benefits for our patients. An area of continued investigation must be related to the improvement of catheter technology and the early detection and therapy of catheter-related infections. Additional insights into catheter management should be developed, particularly as they pertain to exit and tunnel infections. The optimal interval before catheter insertion can be safely performed must be defined, and improvement in catheter design and materials should be supported. The opportunity to do so in an international, collaborative way is a potentially important and exciting road for us to embark upon.

SUMMARY

The recommendations provided in this document represent a distillation of various experiences, as well as data obtained from published studies in the setting of substantial changes in antibiotic sensitivity. It is hoped that this revised compilation will provide a basis upon which future developments and advances can be made in the therapeutic approach to infectious complications of peritoneal dialysis.

ACKNOWLEDGMENTS

The authors wish to express their thanks to Baxter Healthcare, Inc., McGaw Park, Illinois, which provided support for the meeting, and to David Woodburn, who helped with meeting logistics. Special thanks to Deanna Gunderson, who coordinated all aspects of manuscript preparation. In addition, the International Society for Peritoneal Dialysis has formally endorsed this Advisory Committee on Peritonitis Management and has established an official subcommittee of this organization to address this important issue. In preparing this document a bibliography of over 500 references has been established, and this is available (including the full article) for review through the Download Options for this article on the PDI Website.