RECURRENT INFECTION AND CATHETER LOSS IN PATIENTS ON CONTINUOUS AMBULATORY PERITONEAL DIALYSIS

Peritoneal Dialysis International, Vol. 19, pp. 550 555 Printed in Canada. All rights reserved. 0896-8608/99 $3.00 +.00 Copyright 1999 International Society for Peritoneal Dialysis RECURRENT INFECTION AND CATHETER LOSS IN PATIENTS ON CONTINUOUS AMBULATORY PERITONEAL DIALYSIS Roger Bayston, 1 Mark Andrews, 2 Keith Rigg, 2 and Andrew Shelton 1 Division of Microbiology, 1 University of Nottingham; Renal Unit, 2 City Hospital, Nottingham, United Kingdom Objective: To elucidate the factors leading to catheter loss from recurrent infection in patients on continuous ambulatory peritoneal dialysis (CAPD). Design: All catheters removed from patients were prospectively examined for infection. Setting: CAPD unit in large tertiary-care general hospital. Patients: Sixty-five consecutive patients undergoing catheter removal for whatever cause; 20 catheters rejected because of desiccation or contamination in transit. Interventions: None. Main Outcome Measures: Micro-organisms linked to catheter removal; their locations on removed catheters. Results: Of 45 catheters removed between January 1994 and August 1995, 26 were infected: 13/26 infections were caused by Staphylococcus aureus and 7/26 by Pseudomonas aeruginosa. In only one case was S. epidermidis associated with catheter removal. The most striking finding was that the inner cuff harbored large numbers of the infecting organisms, even when antibiotics had eradicated them from the peritoneal cavity and exit site, where present, and the catheter lumen. Conclusion: The importance of S. aureus and Ps. aeruginosa rather than S. epidermidis in catheter loss due to relapsing infection is confirmed. Persistence of the causative organisms in the inner cuff is a likely explanation for relapse after treatment, and might be due to the predominantly intraperitoneal administration of antibiotics. A clinical trial of the effect on catheter retention of empirical use of systemic or oral agents that give high tissue levels and are active against intracellular microorganisms, along with recommended intraperitoneal regimens, is indicated. Correspondence to: R. Bayston, Biomaterials-Related Infection Group, University of Nottingham Division of Microbiology & Infectious Diseases, City Hospital, Nottingham NG5 1PB United Kingdom. Received 5 February 1999; accepted 21 September 1999. 550 KEY WORDS: Catheter loss; peritonitis; cuff infection; treatment; relapse. Continuous ambulatory peritoneal dialysis (CAPD) is widely accepted as first-line treatment for endstage renal disease, with beneficial impact on quality of life. However, although the number of patients on CAPD is increasing worldwide, there is a better method survival for hemodialysis than CAPD, the difference being due mainly to peritonitis (1). Despite innovations and improvements in CAPD, peritonitis and exit-site infection remain a problem, resulting in significant morbidity and mortality (2,3) and having considerable financial and other resource implications (4). The incidence of peritonitis varies, but a rate of between 1.1 and 1.3 patient-episodes per year has been reported (5). Exit-site infections also vary in incidence: a rate of 0.76 patient-episodes per year has been reported (6). The causative organism is a major factor in determining outcome (7,8). Most infections (40% 60%) are caused by coagulase-negative staphylococci (CoNS), with about 10% each being due to Staphylococcus aureus and gram-negative bacilli, particularly Pseudomonas aeruginosa, and this has led to a concentration of research effort on CoNS. Treatment of CAPD peritonitis usually follows various published guidelines, such as those of the Advisory Committee on Peritonitis Management of the International Society for Peritoneal Dialysis (5,9,10) and the Working Party of the British Society for Antimicrobial Chemotherapy (BSAC) (11), but relapse remains a serious problem that may lead to catheter removal and transfer to hemodialysis. Catheter loss is therefore seen as a major adverse outcome, and the reasons for relapsing infection merit further study. We have therefore prospectively collated clinical data and systematically examined catheters from a consecutive series of patients undergoing catheter removal for any reason in order to elucidate factors leading to relapse of infection and consequent catheter loss. PATIENTS AND METHODS From January 1994 to August 1995, all catheters removed for any reason were examined systematically for infection. The catheters were removed by

PDI NOVEMBER 1999 VOL. 19, NO. 6 INFECTION AND CATHETER LOSS reopening the midline incision and dissecting free the inner cuff. The inner portion of the catheter was then cut from the remainder and removed through the incision. The outer cuff was then released from the subcutaneous tissues from the inside. Complete catheters were sent to the laboratory in sterile sealed double transport bags and refrigerated until examined, which was always within 24 hours and usually within 2 hours. The catheters were examined while still in the transparent inner bags, and to minimize chances of contamination they were sampled through incisions made in the bag after preparation of its outer surface with an isopropanol antiseptic swab. The 2-cm segment bearing the inner cuff was excised using a sterile scalpel and the cuff rolled on the surface of a blood agar plate and then onto a sterile microscope slide before being fixed in buffered glutaraldehyde for scanning electron microscopy (SEM). Slides were stained by Gram s method and examined for neutrophils and organisms. The fluid in the catheter lumen proximal to the cuff was sampled by aseptic flushing and aspiration, and the fluid inoculated onto a blood agar plate and into a brain-heart infusion fluid medium (BHI, Oxoid, Basingstoke, England). One drop of the remaining fluid was placed on a microscope slide and stained and examined as above. All plate cultures were incubated for 48 hours at 37 C. The BHI was subcultured after 24 hours (48 hours if clear) onto a blood agar plate. A segment of unflushed catheter was fixed in glutaraldehyde for SEM. All isolates were identified using API (biomérieux, Basingstoke, England) and their antibiograms determined by disc diffusion. Clinical data relating to infection history (peritonitis and exit-site infection episodes) and treatment prior to catheter removal were recorded. RESULTS During the study period, 65 catheters were received. Twenty of these were not examined because of desiccation or contamination in transit, or because they were incomplete (no inner cuff sent, etc). A total of 45 catheters were therefore examined: 26 had been removed because of recurrent or persistent infection, 8 following successful renal transplantation, 10 for catheter blockage or CAPD failure unrelated to infection, and 1 following a diverticular abscess and perforation. The time elapsed from diagnosis of infection to catheter removal ranged from 16 to 96 days (mean 56 days) for peritonitis due to S. aureus, from 2 to 120 days (mean 78 days) for exit-site infection only, and from 80 to 210 days (mean 128 days) for exitsite infection with peritonitis due to this organism. Pseudomonas exit-site infection in the absence of peritonitis was diagnosed between 6 and 60 days (mean 35 days) prior to catheter removal; there were insufficient pseudomonas infections to allow analysis of cases with peritonitis. Of the 18 catheters removed for reasons other than infection, such as renal transplant, technical or mechanical failure, or noncompliance, 11 grew no organisms from either catheter lumen or cuff and a further 4 gave insignificant growth from one or the other site. Three gave growth that was possibly significant from both sites. In one case (case 24), the catheter was removed because it was blocked, but there was a history of recurrent abdominal pain with insignificant white cell counts on bag fluid examination, and CoNS was isolated sporadically on several occasions over the preceding 6 months. On examination of the removed catheter, while no polymorphs were seen in either the luminal flush fluid or the cuff, both grew 50 colonies of Ps. aeruginosa. In the second case (case 53), the catheter was removed following a renal transplant but the removal was prompted by peritonitis (effluent WBC 8500/mm 3 ) although no organisms were isolated. Vancomycin and flucloxacillin had been given. On examination of the removed catheter, the luminal flush fluid showed many polymorphs and pleomorphic gram-negative bacilli, as did the cuff. Fifteen and five colonies respectively of Ps. aeruginosa were isolated from fluid and cuff. In a third case (case 34) in which the catheter was removed because it had ceased to function, a heavy pure growth of S. simulans was isolated from both lumen and cuff. Many polymorphs were seen in both sites on microscopy. This patient had had Acinetobacter peritonitis 5 months previously, but no infection with S. simulans or any other CoNS had been recorded. Of the 26 patients whose catheters had been removed because of infection (Tables 1 and 2), 11 had exit-site infections only, 7 had peritonitis without exitsite infection, and 8 had exit-site infections followed by peritonitis. None had a clinical tunnel infection. In those patients who had had clinical exit-site infection due to S. aureus or Ps. aeruginosa (17 cases), all had received an appropriate oral antibiotic (usually flucloxacillin for S. aureus and ciprofloxacin for Ps. aeruginosa) for at least 10 days. At the time of catheter removal, the exit-site infection had resolved clinically in 9 of these patients (53%) despite a heavy growth of S. aureus or Ps. aeruginosa from the cuff on removal. Twenty of the 26 cases were caused by either S. aureus (46%) or Ps. aeruginosa (27%). The patient with peritonitis due to Corynebacterium sp also had an inflamed exit site, although no organisms were grown from this site. Similarly, the patient with viridans streptococcus peritonitis also had a clinically infected exit site from which no organisms were isolated. During the 19 months of the study, there were 551

BAYSTON et al. NOVEMBER 1999 VOL. 19, NO. 6 PDI TABLE 1 Clinically Involved Sites in Patients Whose Catheters Were Removed Because of Infection Causative organism N Exit site only Peritonitis only Both Staphylococcus aureus 13 5 2 6 Pseudomonas aeruginosa 7 5 1 1 Corynebacterium sp 2 1 1 Candida albicans 1 1 Viridans streptococcus 1 1 Aspergillus niger 1 1 Staphylococcus epidermidis 1 1 TABLE 2 Results of Catheters Removed Because of Infection Case Organism isolated previously Catheter lumen Cuff 1 Staphylococcus aureus NG 40 colonies, S. aureus 4 S. aureus 3 colonies, S. aureus HPG, S. aureus 9 S. aureus 4 colonies, S. aureus MPG, S. aureus 10 S. aureus NG 28 colonies, S. aureus 12 S. aureus 1 colony, S. aureus HPG, S. aureus 13 S. aureus 3 colonies, S. aureus MPG, S. aureus 26 S. aureus 100 colonies, S. aureus MPG, S. aureus 31 S. aureus 25 colonies, S. aureus MPG, S. aureus 41 S. aureus 2 colonies, S. aureus MPG, S. aureus 48 S. aureus NG NG 50 S. aureus NG NG 61 S. aureus 12 colonies, S. aureus HPG, S. aureus 62 S. aureus NG MPG, S. aureus 2 Pseudomonas aeruginosa NG HPG, Ps. aeruginosa 17 Ps. aeruginosa 3 colonies, Ps. aeruginosa HPG, Ps. aeruginosa 27 Ps. aeruginosa NG NG 29 Ps. aeruginosa NG NG 30 Ps. aeruginosa 25 colonies, Ps. aeruginosa HPG, Ps. aeruginosa 40 Ps. aeruginosa NG NG 58 Ps. aeruginosa HPG, Ps. aeruginosa HPG, Ps. aeruginosa 16 Corynebacterium striatum 12 colonies, C. striatum MPG, C. striatum 49 Corynebacterium sp NG NG 5 Candida albicans MPG, C. albicans MPG, C. albicans 20 Viridans streptococcus NG HPG, Vir Strep 60 Aspergillus niger HPG, A. niger NG 64 S. epidermidis NG NG NG = no growth; HPG = heavy pure growth (approximately 10 7 10 9 colony forming units/ml); MPG = moderate pure growth (approximately 10 5 10 6 cfu/ml). 65 cases of peritonitis due to CoNS, but only 1 patient with persistent S. epidermidis peritonitis had to have his catheter removed. In this case, four relapses had occurred; the patient was an elderly diabetic with poor compliance and he was transferred to hemodialysis. Gram film results were consistent with the culture results. No organisms were seen in lumen fluids from cases 1, 2, 4, 9, 10, 12, 13, 16, 17, 20, 30, 31, 41, 61, and 62 although they were seen in the Gram films of the respective cuffs (Figure 1). Most of the organisms were intracellular. Scanning electron microscopy of the cuffs revealed a mesh of Dacron fibers heavily infiltrated by fibrin (Figure 2). Only very occasional bacteria were detected by this method (Figure 3), presumably because the majority were intracellular as shown by Gram stain. DISCUSSION Significant growth was unexpectedly obtained from both catheter and cuff in 3 patients thought not to be 552

PDI NOVEMBER 1999 VOL. 19, NO. 6 INFECTION AND CATHETER LOSS Figure 1 Gram film of smear of removed inner cuff showing neutrophils and gram-positive cocci (Staphylococcus aureus), mainly intracellular (144 ). Cocci show varying states of cell wall integrity and appear in slightly different focal planes. Figure 2 Scanning electron micrograph of a removed inner cuff showing Dacron fibers and dense host-derived infiltrate (240 ). infected (cases 24, 34, and 53). In cases 24 and 53, peritonitis had been suspected prior to catheter removal for other reasons in one case on the grounds of intermittent abdominal pain and in the other because of a high WBC count in the effluent but no growth was obtained on culture. In the third case infection had not been suspected. In those 26 patients whose catheters were removed because of persistent infection due to S. aureus or Ps. aeruginosa, 17 had had exit-site infections, 9 of which had resolved clinically on treatment before Figure 3 Scanning electron micrograph of a removed inner cuff showing fibrinous infiltrate, red blood cells, phagocytes, and a single extracellular coccus (6000 ). catheter removal. Seven more did not have a recorded exit-site infection but had relapsing peritonitis. While the prognosis of exit-site infections is well known (12), the problem of clinically inapparent infection of the cuff is not well documented. However, Korzets et al. (13) carried out an ultrasound study of patients with CAPD peritonitis without clinical exit-site or tunnel infection in order to determine the relationship between clinically inapparent tunnel infection and peritonitis. In 13 of 16 episodes of peritonitis, extraperitoneal infection was found to be localized to the internal cuff of the Tenckhoff catheter. Of the 26 infections leading to catheter removal, only 1 was due to S. epidermidis. While a great deal of attention has been paid to this group of organisms, and while they account for a high proportion of cases of CAPD peritonitis, they are associated with relatively mild symptoms and generally do not lead to catheter loss. Our findings are consistent with those of other researchers, in that the major problems in CAPD infection in terms of outcome are S. aureus and Ps. aeruginosa. Sixteen of the 26 catheters (62%) removed for infection had significantly greater numbers of bacteria in the cuff than in the catheter lumen, 11 having either no growth or fewer than 5 colonies from the latter site. In two cases (5 and 58) the lumen and the cuff each gave heavy or moderate growth, in one case of Ps. aeruginosa and in the other of Candida albicans. The patient in case 58 had had pseudomonas peritonitis that had not responded to treatment by the time the catheter was removed, and large numbers of bacteria were grown from the effluent preoperatively. In case 5, a variety of antibiotics had been administered 553

BAYSTON et al. NOVEMBER 1999 VOL. 19, NO. 6 PDI 554 over the previous 2 years for a series of CAPD infections due to both gram-positive and gram-negative bacteria. Candida had been isolated intermittently for 8 months prior to catheter removal, and on examination the catheter lumen was almost completely occluded by the fungus. National guidelines for the treatment of CAPD peritonitis have two main aims: to target the most likely bacteria, and to avoid systemic toxicity in the absence of renal excretory function. Both the BSAC guidelines (11) and the updated Advisory Committee recommendations (5) suggest initial empirical treatment that is intended to cover both gram-positive and gram-negative bacteria. In the first of these, administration of a combination of vancomycin and an aminoglycoside, both intraperitoneally, is recommended, while in the second report administration of a first-generation cephalosporin and an aminoglycoside, also intraperitoneally, are suggested in view of concern over vancomycin resistance. In both cases, modification is recommended in the light of culture results. The 1996 Update (5) recommends addition of rifampicin for S. aureus infections if clinical response is less than desired. However, this can be misleading, because eradication of peritonitis, and even also an accompanying exit-site infection, does not necessarily indicate eradication of an undetected inner-cuff infection. In the 1998 Update (10), which deals mainly with exit-site infections, rifampicin is recommended for severe-appearing infections or if there is no improvement on initial therapy. The agents currently recommended by both BSAC (11) and the Advisory Committee (5) for pseudomonas peritonitis are intraperitoneal aminoglycoside and ceftazidime. The patients in our series were treated broadly according to these guidelines except that intraperitoneal vancomycin (50 mg/l in a 2-L bag) was still the preferred treatment for peritonitis due to gram-positive bacteria. Our results show that the two bacteria, S. aureus and Ps. aeruginosa, mainly responsible for CAPD infection leading to catheter loss had been eradicated from the peritoneal cavity and from the catheter lumen, but that they persisted in large numbers in the cuff. The Dacron material from which the cuff is made is designed to encourage ingrowth of fibroblasts in order to anchor the catheter and to prevent migration of bacteria along the tunnel. Unfortunately the infiltrated cuff also provides an ideal environment for these bacteria, consisting of biomaterial with host cells and avascular connective tissue (Figure 2). Large numbers of bacteria have been reported previously in the inner cuff of catheters removed from 3 patients with S. aureus exit-site infections (14). Microbial biofilms in the catheter lumen have also been incriminated (15) although the luminal surfaces were clear of biofilm in our study, possibly because of repeated attempts at intraperitoneal treatment. The treatment regimens for CAPD peritonitis are intended to concentrate antibiotic activity in the catheter lumen and the peritoneal cavity and, if possible, to avoid systemic and therefore tissue levels. Agents such as intraperitoneal cefazolin, one of those recommended by the guidelines, give plasma concentrations many times higher than the minimum inhibitory concentration for S. aureus (16), but they fail to penetrate phagocytic cells, unlike rifampicin which is concentrated within neutrophils and macrophages (17). We consider that the nature and microenvironment of the cuff and the principle of the treatment regimen are responsible for persistence of the bacteria in the cuff, giving rise to relapse, treatment failure, and ultimately to catheter loss. While in some cases a clinical exit-site or tunnel infection would indicate such a problem, this is by no means always evident. The BSAC report does not address exit-site or tunnel infection; indeed it states that, in cases of peritonitis, infection is usually confined to the peritoneal cavity. The 1996 Update does recommend, for patients with S. aureus infection who fail to respond, re-evaluation specifically for an occult tunnel infection. Recommended procedures include ultrasonography, computed tomography scanning, or gallium scanning. In the light of our results we would recommend that, at least in S. aureus and Ps. aeruginosa peritonitis, a cuff infection should be assumed to be present, and oral or systemic agents aimed at achieving therapeutic tissue levels and active against intracellular bacteria should be included in the first-line treatment strategy. On the basis of our findings, we now plan to carry out a clinical trial to determine whether catheter loss can be reduced by treatment aimed at eradication of subclinical internal cuff infection. ACKNOWLEDGMENTS We are grateful to the nursing staff of the CAPD Unit, City Hospital, Nottingham, for their valuable assistance in collection of removed catheters, and to the consultants in renal medicine who allowed us to study their patients. The study was supported financially by the Wade Charitable Trust. REFERENCES 1. Maiorca R, Cancarini GC, Zubani R, Camerini C, Manili L, Brunori G, et al. CAPD viability: a long-term comparison with hemodialysis. Perit Dial Int 1996; 16:276 87. 2. Digenis GE, Abraham G, Savin E, Blake P, Dombros N, Sombolos K, et al. Peritonitis-related deaths in con-

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