Peritoneal Effluent Markers of Inflammation in Patients Treated with Icodextrin- Based and Glucose-Based Alena Parikova,1 Machteld M

Advances in Peritoneal Dialysis, Vol. 19, 2003

Peritoneal Effluent Markers of Inflammation in Patients Treated with Icodextrin- Based and Glucose-Based Alena Parikova,1 Machteld M. Zweers,1 Dirk G. Struijk,1,2 Raymond T. Krediet1 Dialysis Solutions

Chronic exposure to peritoneal dialysis (PD) solutions Key words is associated with a low-grade local inflammatory Inflammation, leukocyte cell count, leukocyte differ- state of the peritoneum. The occurrence of culture- entiation, icodextrin, glucose/lactate–based dialysis negative peritonitis in some PD patients treated with solution icodextrin focused our interest on subclinical inflammation in icodextrin-treated patients without perito- Introduction nitis. The aim of the present study was to compare In 2001 and 2002, in various European centers, an signs of inflammation in icodextrin-treated patients abnormally high incidence of culture-negative peri- with the same signs in patients using glucose/lactate– tonitis was reported in peritoneal dialysis (PD) pa- based (GL) dialysis solutions only. tients who used icodextrin-based dialysis solution Overnight PD effluents from 19 patients treated (Extraneal: Baxter Healthcare SA, Castlebar, Ireland). with icodextrin and 19 patients treated with GL were Investigations by the producer pointed to high con- investigated for leukocyte count (LC) and differentia- centrations of peptidoglycan as the most likely cause tion (LD), and for dialysate concentrations of cancer of a sterile inflammatory reaction [Personal commu- antigen 125 (CA125, the marker of mesothelial cell nication, Baxter Healthcare; and (1)]. That situation mass) and hyaluronan (marker of inflammation and focused our attention on the lack of published results tissue remodeling in the peritoneal cavity). Blood cell regarding normal values for peritoneal effluent cell counts and serum dextran antibodies (DA) were also counts and differentiation in PD patients without peri- determined. Total LC in the GL group was significantly tonitis who are treated with 7.5% icodextrin for the lower than that in the icodextrin group. The LD was long dwell. not different between the two groups, except for the The objective of the present study was to compare percentage of eosinophils. The blood cell count did signs of local inflammation in stable PD patients treated not differ between the groups. The median value of with icodextrin with the same signs in patients treated DA was similar in both groups. The hyaluronan con- with glucose/lactate–based dialysis solution only. centration was markedly higher in the icodextrin group. No significant difference was found for dialy- Patients and methods sate CA125. Long-dwell effluents (median duration: 11 hours; In conclusion, the higher effluent cell count, higher range: 8 – 16 hours) were obtained from 38 stable PD percentage of eosinophils, and higher effluent patients (26 men, 12 women; median age: 55 years; hyaluronan levels in icodextrin-treated patients are age range: 20 – 83 years). The effluents were investi- consistent with a greater degree of subclinical inflam- gated for leukocyte count and differentiation, and for mation during icodextrin treatment than during GL dialysate concentrations of cancer antigen 125 treatment. (CA125, the marker of mesothelial cell mass) and hyaluronan (a marker of inflammation and tissue re- From: 1Division of Nephrology, Academic Medical Cen- modeling). Blood samples were taken at the same time ter, University of Amsterdam, and 2Dianet Foundation to screen for leukocyte differential cell count and the Amsterdam–Utrecht, Netherlands. presence of dextran antibodies. Parikova et al. 187

Of the 38 patients, 19 (GL group) were treated as a percentage of a serum pool obtained from only with commercially available glucose/lactate– 150 healthy subjects. based dialysis solutions (Dianeal: Baxter Healthcare); the other 19 used 7.5% icodextrin (Extraneal: Baxter Statistical analysis Healthcare) for the long dwell. Of the latter group, Owing to asymmetric distribution, results are ex- 9 patients (icodextrin group 1) used certain batches pressed as medians and ranges. The Mann–Whitney of icodextrin on which other PD patients had devel- test was applied to compare differences between the oped culture-negative peritonitis. The remaining 10 groups. patients (icodextrin group 2) started treatment with icodextrin after delivery of new batches (October Results 2002). Table I presents the dialysate total leukocyte counts, Before inclusion in our study, the patients had been differential cell counts expressed as percentages, and treated with the investigated type of PD solution for percentages of mesothelial cells. The total leukocyte at least 1 month, were showing no signs of infection count and the percentage of eosinophils were lower at the time of examination, and had been peritonitis- in the GL group than in the two icodextrin groups free for 4 weeks prior to the investigation. The pa- (p = 0.01). The icodextrin groups were not different tients in the GL group had been treated with PD for a from one another. The percentages of other cells were median period of 23 months (range: 3 – 168 months); similar among the groups. The absolute counts for all those in icodextrin group 1, for a median of 14 months leukocyte types, except basophils, were higher in ico- (range: 12 – 32 months); and those in icodextrin dextrin group 1 (p < 0.03) than in the GL group; only group 2, for a median of 15 months (range: 1 – the eosinophil and monocyte counts were higher in 59 months). icodextrin group 2 (p < 0.01) than in the GL group The effluents were cultured using our normal pro- (Table II). Table III gives the total leukocyte counts cedures (2), and leukocytes were counted in a Bürker and differentiations for blood. No difference was counting chamber. The differential cell counts were significant. performed on cytospin effluents after Jenee–Giemsa The median dialysate CA125 concentration was staining. The procedure was this: centrifugation for 35 U/mL (range: 7 – 163 U/mL) in the GL group, 20 minutes at 1500 rpm, removal of the supernatant, 36 U/mL (range: 17 – 73 U/mL) in icodextrin group 1, and mixing of the final pellet with 1 mL phosphate- and 21 U/mL (range: 8 – 54 U/mL) in icodextrin buffered saline. Cytospins of the pellets were prepared group 2 (p = nonsignificant). using 60 µL of the suspension. The median level of serum dextran antibodies was A microparticle enzyme immunoassay, in combi- 25% (range: 6% – 630%) in the glucose group, 23% nation with a monoclonal antibody against CA125 (range: 2% – 376%) in icodextrin group 1, and 23% (Abbott Laboratories, Abbott Park, IL, U.S.A.), was (range: 5% – 450%) in icodextrin group 2. The dif- used to measure CA125. A radioimmunoassay (Kabi ferences were not significant. Pharmacia Diagnostics AB, Uppsala, Sweden) was The dialysate hyaluronan level was related to the used to determine the peritoneal hyaluronan concen- dialysate total leukocyte count (r = 0.51, p = 0.01, tration. The total leukocyte count and differential cell Figure 1). The hyaluronan concentration was 355 µg/L counts in blood were determined by flow cytometry (range: 117 – 256 µg/L) in the GL group and 682 µg/L (Technicon H1: Technicon Instruments, Tarrytown, (range: 499 – 1298 µg/L) in icodextrin group 1 (p < NY, U.S.A.) in blood anticoagulated with ethylene- 0.01). diaminetetraacetic acid (EDTA). Dextran antibodies were measured in serum by an enzyme-linked Discussion immunosorbent assay (ELISA) using the dextran Chronic exposure to PD solutions is associated with 500,000 antigen (Pharmacia, Uppsala, Sweden), anti– impairment of peritoneal host defense. Alterations of human immunoglobulin G antibodies (Dako Corpo- cellular components within the peritoneal cavity lead ration, Glostrup, Denmark) and O-phenylenediamine to disturbances in the release of pro- and anti-inflam- dihydrochloride (Sigma, Steinheim, Germany) as sub- matory mediators (3,4). Normal values for effluent cell strate. The quantity of dextran antibodies is expressed counts and differentiation have been published for 188 Signs of Inflammation in ICO-Treated vs. GLU-Treated Patients

TABLE I Dialysate leukocyte counts and differential cell counts in effluent from the long dwell in patients treated with 7.5% icodextrin solution as compared with counts in effluent from patients treated only with glucose/lactate–based solutions

Glucose/lactatea Icodextrin 1b Icodextrin 2c (n=19) (n=9) (n=10)

Total leukocyte count (∞106/L) 5 (0–80) 25 (10–85)d 30 (0–70)d Macrophages (%) 86 (5–100) 70 (61–90) 76 (56–86) Lymphocytes (%) 5 (0–90) 9 (0–26) 4 (0–11) Neutrophils (%) 6 (0–50) 10 (1–13) 12 (6–14) Eosinophils (%) 1 (0–6) 6 (1–8)d 6(3–22)d Basophils (%) 0 (0–1) 0 (0–0) 0 (0–0) Mesothelial cells (%) 2 (1–6) 2 (2–3) 2 (1–4) a Patients who used glucose/lactate–based dialysis solution only. b Stable patients who used certain batches of 7.5% icodextrin on which other peritoneal dialysis patients developed culture-negative peritonitis. c Patients who started icodextrin treatment after omission of the potential causative agent for culture-negative peritonitis. d p = 0.01 versus glucose/lactate group.

TABLE II Absolute counts of the peritoneal leukocyte population in effluent from the long dwell in patients treated with 7.5% icodextrin or only with glucose/lactate–based dialysis solutions

Glucose/lactatea Icodextrin 1b Icodextrin 2c (n=19) (n=9) (n=10)

Macrophages (∞106/L) 4.7 (0–69.9) 18.3 (14.0–75.9)d 23.9 (0–56)d Lymphocytes (∞106/L) 0.1 (0–20.9) 3.6 (0.6–11.4)d 1.1 (0–7.8) Neutrophils (∞106/L) 0.2 (0–27.2) 2.1 (0.2–8.3)e 2.9 (0–7.8) Eosinophils (∞106/L) 0.1 (0–4.2) 1.8 (0.2–5.6)d 2.0 (0–15.6)d Basophils (∞106/L) 0 (0–0.1) 0 (0–0) 0 (0–0) Mesothelial cells (∞106/L) 0.2 (0.1–2.5) 0.5 (0.3–0.6) 0.6 (0.4–1.1) a Patients who used glucose/lactate–based dialysis solution only. b Stable patients who used certain batches of 7.5% icodextrin on which other peritoneal dialysis patients developed culture-negative peritonitis. c Patients who started icodextrin treatment after omission of the potential causative agent for culture-negative peritonitis. d p < 0.01. e p = 0.03 versus glucose/lactate group.

TABLE III Comparison of blood leukocyte populations between patients treated with 7.5% icodextrin and patients treated with glucose/ lactate–based dialysis solution for the long dwell

Glucose/lactatea Icodextrin 1b Icodextrin 2c (n=19) (n=9) (n=10)

Total leukocyte count (∞106/L) 8 (5–20) 8 (7–9) 8 (6–9) Macrophages (%) 7 (5–13) 8 (5–14) 8 (6–14) Lymphocytes (%) 19 (7–45) 21 (9–23) 20 (12–27) Neutrophils (%) 68 (41–87) 68 (64–83) 66 (60–79) Eosinophils (%) 3 (0–17) 4 (0–5) 4 (0–9) Basophils (%) 0 (0–1) 0 (0–1) 0 (0–1) a Patients who used glucose/lactate–based dialysis solution only. b Stable patients who used certain batches of 7.5% icodextrin on which other peritoneal dialysis patients developed culture-negative peritonitis. c Patients who started icodextrin treatment after omission of the potential causative agent for culture-negative peritonitis. Parikova et al. 189

the three patient groups, time on PD is excluded as a cause for the differences found. Dialysate hyaluronan, which is considered a marker of peritoneal inflammation (10), was significantly higher in the icodextrin-treated patients than in patients treated only with glucose solution. Moreover, a correlation was present between effluent hyaluronan and leukocyte count. The osmotic effectiveness of icodextrin is well established, but the biocompatibility of the solution is controversial. Some studies detected a less injuri- ous impact on membrane function and host defense (11–15); other studies have not observed differences between icodextrin-based and glucose/lactate–based FIGURE 1 A positive correlation was present between dialysate solutions (16–18). hyaluronan concentration and peritoneal total leukocyte count (r = Our data indicate that icodextrin might induce a 0.51, p = 0.01). somewhat greater local inflammatory reaction than does glucose-based solution. However, no differences glucose-based dialysis solutions (5–7). In the present in effluent concentration of CA125 (the mesothelial study, we investigated those parameters for 7.5% ico- cell mass marker) were present among the three dextrin. In addition, we analyzed dialysate concen- groups. Dialysate CA125 is increased during perito- trations of the mesothelial cell mass marker CA125 nitis (19). Our results therefore indicate that the en- and the inflammatory marker hyaluronan. hancement of the inflammatory response under Leukocyte numbers and differentiation in glucose icodextrin does not lead to mesothelial cell damage. effluents were similar to those reported previously That finding may explain the results of in vitro stud- by our group (6). Icodextrin effluents contained sig- ies that show better host defense with icodextrin (11– nificantly more leukocytes. Also, the percentage of 15). However, differences in the incidence of microbial eosinophils was markedly higher in icodextrin efflu- peritonitis between icodextrin-treated and glucose- ent than in glucose effluent. Nevertheless, the values only patients have not been reported. found for icodextrin were still within the normal Effluent hyaluronan could not be determined in ranges reported in previous studies for glucose solu- icodextrin group 2 because production of the relevant tions (6–9). radioimmunoassay kits had been discontinued. Nev- Icodextrin group 1 was investigated at the time ertheless, based on the similarity between icodextrin of a culture-negative peritonitis epidemic in ico- group 1 and icodextrin group 2, we assume that the dextrin patients. We therefore could not exclude results in icodextrin group 2 would have been similar. the possibility that the values obtained might have Comparison of blood dextran antibodies revealed been influenced by high dialysate peptidoglycan no difference between the GL group and the two ico- levels. For that reason, we investigated icodextrin dextrin groups. That finding agrees with previous data group 2, which was studied after the peptidogly- (20), in which no relationship was found between dex- can was removed from the icodextrin dialysis so- tran antibodies and chronic exposure to icodextrin lution. However, the results obtained in icodextrin solution. group 2 were not different from those obtained in icodextrin group 1. That finding makes it unlikely Conclusion that the cell counts we found were a subclinical Based on higher cell counts and higher hyaluronan manifestation of peptidoglycan-induced culture- concentrations, we conclude that icodextrin shows negative peritonitis. some enhancement of the local inflammatory response. Effluent cell counts are generally lower in long- That finding was not associated with signs of mesothe- term PD patients than in patients in their first few years lial damage. Our findings are unrelated to peptidogly- of PD (6). Because the duration of PD was similar in can-induced culture-negative peritonitis. 190 Signs of Inflammation in ICO-Treated vs. GLU-Treated Patients

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Severe Peritoneal Mononucleosis Associated with Icodextrin Use in

Juan Martín, Gabriela Sansone, Antonio Cirugeda, José A. Continuous Ambulatory Sánchez–Tomero, Cecilia Muñoz, Rafael Selgas on behalf of Grupo Centro de Diálisis Peritoneal* Peritoneal Dialysis

Icodextrin is a glucose polymer obtained from starch 80% (mean: 70.6%) of the cells. Microbiology cul- hydrolysis. It is used as an osmotic agent at 7.5% for tures were always negative. A rechallenge with the peritoneal dialysis (PD). Its use in PD has been asso- same batches of PD fluid was tried. In 100% of the ciated with several side effects separate from the one patients, the clinical and cellular patterns relapsed. reported here, the most frequent being sterile perito- No short-term changes in peritoneal function have nitis. Recently, three mechanisms have been proposed been observed. The manufacturer informed us that the to explain the occurrence of sterile peritonitis: allergy icodextrin was contaminated with a peptidoglycan. to dextrin, production of anti-dextran antibodies, and In this sterile peritonitis outbreak with a simulta- impurities introduced during manufacture. Here, we neous, similar clinical presentation in a group of pa- report a peritoneal mononucleosis outbreak that is tients treated with icodextrin solution (presumably highly suggestive of being a consequence of the last- contaminated with peptidoglycan), clinical outcome mentioned mechanism. was, for the most part, mild-to-moderate. Symptoms During the period December 2001 to May 2002, disappeared immediately after icodextrin withdrawal a group of 8 Spanish hospitals whose individual PD and relapsed after rechallenge with the relevant fluid programs regularly share information and activity re- batches. Monocyte cell counts predominated during ported 29 cases of sterile peritonitis associated with the episode. Although we cannot rule out an allergic icodextrin use in continuous ambulatory peritoneal cause, the massive peritoneal mononuclear cell re- dialysis (CAPD) patients [mean age: 60.7 ± cruitment suggests a particular mechanism. This is a 14.47 years; 8 women (27.59%), 21 men (72.41%); new mechanism for peritoneal cell recruitment in PD. mean time on PD: 25.21 ± 35.31 months; mean time on icodextrin: 15.17 ± 11.03 months]. Of the 29 pa- Key words tients, 51.8% showed no symptoms. The remainder Mononucleosis, icodextrin, dialysate contamination, presented with mild abdominal discomfort and anor- peptidoglycan exia. Only 2 patients showed general malaise, severe nausea, fever, and abdominal pain. The initial white Introduction cell count in peritoneal effluent was 512 ± 386 cells/ Icodextrin is a glucose polymer obtained from starch mL (45.0% ± 28% neutrophils, 44.92% ± 32.6% mono- hydrolysis. It is used as an osmotic agent nuclear cells, 7.75% ± 12% eosinophils). In 5 of the (282 mOsm/kg) at 7.5% for peritoneal dialysis (PD), patients, we performed an immunophenotype (CD14) being very useful for long-dwell exchanges. Icodex- study, demonstrating the monocyte nature of 60% – trin use reduces the need for glucose-containing dialysate, potentially favoring the status of the peritoneal From: Servicio de Nefrología, Hospital Universitario de La membrane. Princesa, Madrid, Spain. The icodextrin molecule is variable in size, with a range of subunits from 4 to 250 (molecular weight: * Alberto Ortiz, Guadalupe Caparrós, M. Auxiliadora 1,638 Da – 45,000 Da; mean: 16,200 Da; median: Bajo, Elisa Ruiz, Inés Castellanos, Patricia Sequera, Fran- 5,800 Da). The molecule structure branches variably cisco Coronel. by mean of α linkages (less than 10% 1♦4, and more 192 Martín et al. than 85% 1♦6) in varying quantities and proportions. some methods are manual, with direct observation Dextrans are composed only of α linkages (1♦6) and (and unable to separate mononuclear cells from one have a limited catabolic capacity (1). another). Icodextrin PD solution is generally well tolerated, but several side effects separate from the one reported Results here have been described. The first side effects re- The mean age of the affected patients was 60.7 ± ported were psoriasis-like skin reactions, epidermoly- 14.47 years (range: 25 – 85 years). Eight (27.59%) sis, and blistering, which were suggested to be were female, and 21 (72.41%) were male. Mean time cross-reactivity with dextran (2–4). Interference with on dialysis was 25.21 ± 35.31 months (range: 1 – plasma determinations of glucose and amylase have 145 months), and the mean time on icodextrin was also been found. But the most frequent side effect is 15.17 ± 11.03 months (range: 1 – 52 months). Of the so-called sterile peritonitis. Recently, three mecha- 29 patients, 28 were being treated with CAPD, and 1 nisms have been proposed to explain that condition: with optimized continuous peritoneal dialysis allergy to dextrin, production of anti-dextran antibod- (OCPD), with a diurnal icodextrin exchange of the ies, and impurities introduced during fluid manufac- CAPD type. The icodextrin batches involved were ture (5). R25JI7G40, O2AI0G40, O2A31G42, R29K29G42. In the present article, we report a peritoneal mono- Clinical manifestations (mild abdominal pain and nucleosis outbreak, manifested as sterile peritonitis anorexia) were present in 14 of 29 patients (48.2%). episodes, that is highly suggestive of being a conse- Two patients presented with peritoneal rebound, fe- quence of the last-mentioned mechanism. ver, and nausea. The other patients showed no symptoms at all. The manifestations were independent of Patients and methods hospital, dialysate batch, demographic characteristics, During the first meeting of Grupo Centro de Diálisis and initial cell count. Peritoneal (GCDP) in 2002, the existence of several With regard to the peritoneal effluent cell count, cases of icodextrin-related sterile peritonitis were re- the cell count during the initial outbreak showed vary- ported. A decision was taken to collect all of those ing results, according to the methodology used. (The episodes when they appeared in any of the 26 hospi- automated device used in one of the hospitals revealed tals in the group. To that purpose, an episode was de- that most of the cells were mononuclear. As a result fined as any increase in peritoneal cell count > of the varying approaches, the mean results reported 100/mL, whether or not accompanied by abdominal here have the potential for misinterpretation.) A mean or general symptoms, with no microbiological growth of 512 ± 386 cells/mL (45.4% ± 28% neutrophils, from effluent sampled in appropriate conditions (no 44.92% ± 36% mononuclear cells, 7.75% ± 12% eosi- antibiotics) from patients using icodextrin. nophils) were detected. An initial mononuclear pre- Nephrologists were alerted to observe (independently dominance was present in 20 of 29 patients (69%); of their own requirements) patients using icodextrin. 1 patient later changed to eosinophil predominance. The following 8 hospitals reported a total of 29 epi- The other 9 patients (31%) started with neutrophil pre- sodes: 4 in Fundación Jiménez–Díaz (Madrid), 4 in dominance (>60% of the count); 3 later changed to Hospital Alarcos (Ciudad Real), 3 in Hospital La Paz mononuclear cell predominance. (Madrid), 1 in Hospital del Aire (Madrid), 1 in Hos- In 29.1% of patients, the syndrome resolved in pital San Pedro de Alcántara (Cáceres), 1 in Hospital less than 24 hours after icodextrin withdrawal. In Príncipe de Asturias (Alcalá de Henares), 2 in Hospi- 29.1% of patients, resolution came in 1 – 3 days; and tal San Carlos (Madrid), and 13 in Hospital La Princesa in 29.1%, in 4 – 7 days. In 12.5% of the cases, the (Madrid). All of the episodes were reported to the syndrome lasted for more than 7 days. For 5 patients, Spanish health authorities. we have no information about outcome. Half of the The methodology for peritoneal effluent culture patients received empiric intraperitoneal antibiotics is similar in all of the hospitals. However, the cell (most of them before the outbreak was recognized). count methodology is different: some methods are After the second meeting of the GCDP, antibiotic treat- automated (and distinguish lymphocytes from mono- ment was restricted to doubtful cases, so that the rest cytes, all of them referred to as “mononuclear”) and of the patients did not receive empiric antibiotics. Severe Peritoneal Mononucleosis with ICO in CAPD 193

The 13 cases at our center (all of them at a mild Monocyte chemoattraction is mediated by specific grade of severity, and most of them undetected by the molecules, mainly monocyte chemoattractant protein- patient) represented 100% of our icodextrin users. To 1 (MCP-1) (6). That molecule may mediate the par- clarify the peritoneal effluent cell count, we asked ticular monocyte migration related to peptidoglycan 6 patients to reintroduce an isolated icodextrin ex- contamination of icodextrin. The mechanism goes change from the same batch that provoked the phe- beyond our initial aim, which was simply to describe nomenon. A similar clinical picture unequivocally a new model in peritoneal cell recruitment. That model followed re-instillation of icodextrin. Immuno- was previously observed after addition of intraperito- phenotypic characterization by flow cytometry con- neal granulocyte macrophage–colony stimulating fac- firmed the monocytic nature of the cells in 5 of 6 cases tor (GM-CSF) in vivo (7). The characteristic that the (60% – 80% CD14+; mean: 70.6%; Figure 1). model has in common with the present situation is the The manufacturer (Baxter Healthcare SA, maintenance of cell integrity, which preserves perito- Castlebar, Ireland) found that the icodextrin batches neal tissue from the catastrophic consequences of rup- involved were contaminated by a peptidoglycan. ture of white cells. In other words, we can consider monocyte recruit- Discussion ment induced by peptidoglycan to be a chemotactic In the present article, we describe an outbreak of ster- phenomenon instead of an inflammatory condition. ile peritonitis caused by contamination of several However, the data revealed by a peritoneal biopsy batches of icodextrin fluid for CAPD. The principal study in an identical situation might question the be- peritoneal reaction was mononuclear cell infiltration. nignity of the process (8). Denudated mesothelium, This occurrence should be added to the previously submesothelial edema, and monocyte infiltration con- known causes of sterile peritonitis in PD. firm that the process has some anatomic repercussions. We were not able to establish a cause–effect rela- Because the biopsy was taken after brief use of ico- tionship between the contaminant (peptidoglycan) and dextrin, we may not have been able to observe more the particular peritoneal cell recruitment. What we profound changes. The process is defined immuno- observed is that, in the cases in which polymorpho- logically as type IV hypersensitivity reaction, medi- nuclear neutrophilic granulocytes (PMNs) were not ated by dendritic cells. involved, the reaction seemed to be self-limiting. It In clinical terms, most of our patients showed a disappeared, leaving no markers of damage, after ico- transitory reaction, totally dependent on the presence dextrin withdrawal. of the contaminated icodextrin, with no functional repercussions at medium term. In contrast, prolonged use of the contaminated fluid was associated with a severe reaction in 2 cases. In those cases, the peritoneal polymorphonuclear cell recruitment and systemic repercussions are suggestive of a classical inflammatory process. To summarize, the extended use of contaminated icodextrin may generate a change in the initial response to the contaminant, changing into a true peritonitis process with all of its potential sequelae. We strongly recommend using a cytology diagnosis to differenti- ate peritoneal mononucleosis in its early stage, con- sidering that removing icodextrin at that stage assures a benign and quiet outcome.

Conclusions In the present article, we describe a sterile peritonitis FIGURE 1 Phenotypic expression of CD14 in the cells released into peritoneal effluent of a patient included in the icodextrin outbreak with simultaneous, similar clinical presen- rechallenge. tation in a group of patients treated with icodextrin 194 Martín et al. presumably contaminated with peptidoglycan. Clini- 4 Goldsmith D, Jayawardene S, Sabharwal N, Cooney cal outcome was mild-to-moderate in most of the pa- K. Allergic reactions to the polymeric glucose-based tients, with immediate disappearance of the symptoms peritoneal dialysis fluid icodextrin in patients with after icodextrin withdrawal. Symptoms relapsed upon renal failure. Lancet 2000; 355:897. rechallenge with batches of the fluid involved, and 5 Gokal R. Icodextrin-associated sterile peritonitis. Perit Dial Int 2002; 22:445–8. monocytes predominated in the cell counts during the 6 Tekstra J, Visser CE, Tuk CW, et al. Identification of episodes. Although we cannot rule out an allergic re- the major chemokines that regulate cell infiltration in action, the massive recruitment of peritoneal mono- peritoneal dialysis patients. J Am Soc Nephrol 1996; nuclear cells suggests a particular mechanism. This is 7:2379–84. a new mechanism for peritoneal cell recruitment in PD. 7 Selgas R, Fernández de Castro M, Jiménez C, et al. Immunomodulation of peritoneal macrophages by References granulocyte-macrophage colony-stimulating factor. 1 Moberly JB, Mujais S, Gehr T, et al. Pharmacokinet- Kidney Int 1996; 50:2070–8. ics of icodextrin in peritoneal dialysis patients. Kid- 8 Goffin E, Tintillier M, Cosyns JP, Devuyst O. Sterile ney Int 2002; 62(Suppl 81):S23–33. chemical peritonitis secondary to icodextrin: 2 Valance A, Lebrun–Vignes B, Descamps V, immunohistopathological description. Perit Dial Int Queffeulou G, Crickx B. Icodextrin cutaneous hyper- 2002; 22:723–6. sensitivity: report of 3 psoriasiform cases. Arch Dermatol 2001; 137:309–10. Corresponding author: 3 Queffeulou G, Lebrun–Vignes B, Wheatley P, Rafael Selgas, MD, Servicio de Nefrología, Hospital Montagnac R, Mignon F. Allergy to icodextrin. Universitario de La Princesa, Diego de León 62, Lancet 2000; 356:75. Madrid E-28006 Spain. Advances in Peritoneal Dialysis, Vol. 19, 2003

Strategies for Intervention in and Prevention of Biofilm- Related Infection in

Mrinal K. Dasgupta Peritoneal Dialysis Patients

Bacteria from the exit site of the peritoneal dialysis • Use proper exit-site care and prophylactic antibi- (PD) catheter and from contaminated dialysis fluids otics (for example, mupirocin) locally at the exit can grow into microcolonies in biofilm. Those bacte- site (2,3) ria are implicated in recurrent peritonitis in patients • Screen for Staphylococcus carrier state in patients undergoing treatment with PD. The present article with recurrent catheter infections, and use prophy- highlights new strategies that are designed to alter lactic antibiotics for carriers (4,5) the major factors regulating biofilm formation and • Avoid touch contamination of PD fluid by using that thereby reduce biofilm-related infections in PD disconnect systems such as the twin-bag system patients. (6,7) • Use the Moncrief–Popovich catheter implantation Key words procedure when possible in PD (8). Use of the Biofilm bacteria, peritonitis, catheter biomaterials, Moncrief–Popovich procedure reduces biofilm antibiotic lock growth on catheter surfaces and exit-site infection (randomized study) in PD (8). The procedure is Introduction widely used even with routine catheters and has Biofilm formation on peritoneal catheters is common been termed the “AV [arteriovenous] fistula of PD (1). The primary factors that regulate biofilm forma- treatment” (8). tion in peritoneal dialysis (PD) are (A) skin bacteria that colonize PD catheters, gaining entrance to the ster- Biofilm culture and antibiotic sensitivity ile peritoneal cavity from the exit site and or from Early removal of a biofilm-colonized dialysis catheter touch contamination of PD fluid during daily dialysis and subsequent replacement with a new catheter is re- exchange procedures; (B) catheter biomaterials that quired to cure recurrent catheter-related infection in allow skin bacteria to adhere and to grow in biofilm PD and to protect the peritoneum of the PD patient. microcolonies; and (C) a PD environment that pro- The procedure is often arbitrarily done without proper vides optimum conditions for growth, proliferation, culture of biofilm growth from PD effluents. Over time, and dissemination of biofilm bacterial microcolonies biofilms develop antibiotic resistance as they develop from the catheter surface. The subject has recently a mature biofilm matrix, and, in those cases, catheter been reviewed in detail (1). removal is indicated. But early biofilms are sensitive to antibiotics (9), and the catheter can be salvaged by Discussion proper antibiotic treatment. For that reason, it is pref- The strategies outlined below are useful for interven- erable to perform a parallel culture of PD effluent with ing in and preventing biofilm-related infection in PD the routine microbiologic (planktonic) culture, together patients. with a biofilm culture in the same clinical materials and a comparison of antibiotic sensitivities [minimal Reduce access by skin bacteria inhibitory concentrations (MICs)] between the two The primary strategy is to minimize access by skin cultures. If the biofilm MIC is less than two dilutions bacteria to catheter surfaces: different from the routine (planktonic) culture, early biofilm formation with mild antibiotic resistance is in- From: University of Alberta, Edmonton, Alberta, Canada. dicated. Antibiotic treatment should be continued, and 196 Dasgupta catheter removal will not be required. However, if the otic lock”) into the catheter lumen (16). According to biofilm MIC is significantly different from the plank- the study protocol, the antibiotic solution was instilled tonic culture (>2 dilution difference), mature biofilm into the catheter lumen at the end of each consecutive formation with high antibiotic resistance is present. dialysis session. The solution was left to dwell until Patients whose catheter-related infections show such the beginning of the next dialysis session. A protocol a result are at high risk of treatment failure with con- for the use of antibiotic lock in conjunction with sys- tinuation of routine doses of antibiotics. Catheter re- temic antibiotics has recently been described for suc- moval and replacement by a new catheter is appropriate cessful management of HD catheter-related infections in that subgroup (10). (16). The concentration of the antibiotics in the lumen The same strategy can be applied to determine the reached a level 100-fold higher than the correspond- treatment end-point for antibiotic use in catheter-re- ing systemic therapeutic concentration in plasma (16). lated infections in hemodialysis (HD) and PD patients The protocol permits eradication of biofilms and alike. Several assays to culture biofilm growth from achievement of a bacteriologic cure without replace- dialysis and other biologic fluids have been described ment of the catheter (16). in the literature, but neither the nephrology commu- nity nor the dialysis industry has used them to man- New catheter biomaterials age biofilm-related infections in dialysis patients (1). Silastic catheter materials are prone to biofilm formation. Research is in progress to develop new bio- Drugs that penetrate biofilm layers materials that would prevent bacterial colonization. In recent literature, the use of certain antibiotics (such Among the new materials tested, hydroxyapatite-coated as rifampin) and thrombolytic agents (such as strep- and silver-coated catheters seem to be promising (17). tokinase or urokinase, which penetrate biofilm ma- Clinical data for hydroxyapatite-coated catheters are trix and allow antibiotics to act on biofilm bacteria) still lacking. Silver-coated PD catheters are biocom- have been described for successful treatment of bio- patible, prevent bacterial colonization, and have anti- film-related infections in dialysis patients. bacterial activity as well (17). However, silver is Rifampin exhibits exceptional antimicrobial ac- released from the catheter into the pericatheter tissues tivity against staphylococcal biofilms, with a syner- and adjoining blood vessels (17), raising concern that gistic effect by addition of other antibiotics (11). toxicity (argyria) could develop with long-term use. Rifampin is therefore already recommended as a part The release of silver from the coated catheters may of the antibiotic protocol for treatment of recurrent indicate technical problems in laser-coating the silver peritonitis in PD (12,13). However, use of rifampin is onto Silastic catheters. Clinical use of silver-coated PD sometimes restricted, because it interacts with hep- catheters cannot be considered safe pending further arin, insulin, and several other drugs that are com- technical refinement in the quality of the coating (17). monly used in patients on maintenance dialysis. Thrombolytic agents such as streptokinase and Alterations in the dialysis environment urokinase also lyse biofilms and allow antibiotic pen- Clinical and research data indicate that biofilm growth etration into biofilms. Those agents have been suc- and dissemination from PD catheters occur easily in a cessfully used for recurrent peritonitis (14) and for PD environment of conventional glucose-based dialy- catheter salvage in PD patients who develop two or sis solutions. No information is available about the more peritonitis episodes and cannot tolerate hemo- influence of new PD solutions (for example, poly- dialysis. Both drugs have similar efficacy. Drawbacks glucose and amino-acid solutions) on biofilm include adverse drug reactions with streptokinase. growth (1). Also, urokinase is not always commercially available because of manufacturing problems. To circumvent Future research those limitations, recombinant tissue plasminogen New treatment strategies for recurrent biofilm-related activator (tPA) has been used successfully in patients infections are under investigation in animal models. with relapsing peritonitis (15). Those strategies include use of liposomal ciprofloxacin Biofilms can also be eradicated by instilling a hydrogel-coated silicone in a rat model of persistent highly concentrated solution of antibiotics (“antibi- Pseudomonas peritonitis (18); use of a heparin-coated Biofilm-Related Infection in PD 197

PD catheter, which improved exit-site healing in an- 10 Dasgupta MK, Kowalewaska–Grochowska K, other rat model of PD (19); and use of a heptapeptide, Costerton JW. Biofilm and peritonitis in peritoneal RNAIII-inhibiting peptide, which slows the growth dialysis. Perit Dial Int 1993; 13(Suppl 2):S322–5. of staphylococcal biofilms on silicone and polyure- 11 Obst G, Gagnon RF, Harris A, Prentis J, Richards thane dialysis catheters (20). GK. The activity of rifampin and analogs against Staphylococcus epidermidis biofilms in a CAPD en- Adsorption of host proteins or other host molecules vironment model. Am J Nephrol 1989; 9:414–20. from blood plasma or serum can activate adhesion of 12 Keane WF, Bailie GR, Boeschoten E, et al. Adult bacteria on catheter surfaces to form heterogeneous peritoneal dialysis-related peritonitis treatment rec- biofilms with fibrin clots and other eukaryotic cells ommendations: 2000 update. Perit Dial Int 2000; (1). Subsequent dislodgment of those biofilms may 20:396–411. [Erratum in: Perit Dial Int 2000; 20: induce chronic and distant tissue infections. That area 828–9.] of research needs to be explored. 13 de Fijter CW, ter Wee PM, Oe LP, Verbrugh HA. Intraperitoneal ciprofloxacin and rifampicin versus References cephradine as initial treatment of (C)APD-related 1 Dasgupta MK. Biofilms and infection in dialysis pa- peritonitis: a prospective randomized multicenter tients. Semin Dial 2002; 15:338–46. comparison (CIPPER trial). Perit Dial Int 2001; 21: 2 Bernardini J, Piraino B, Holley J, Johnston JR, Lutes 480–6. R. A randomized trial of Staphylococcus aureus pro- 14 Dasgupta MK. Use of streptokinase or urokinase in phylaxis in peritoneal dialysis patients: mupirocin recurrent CAPD peritonitis. Adv Perit Dial 1989; calcium ointment 2% applied to the exit site versus 7:169–72. cyclic oral rifampin. Am J Kidney Dis 1996; 27: 15 Duch JM, Yee J. Successful use of recombinant tis- 695–700. sue plasminogen activator in a patient with relapsing 3 Thodis E, Bhaskaran S, Passadakis P, Bargman JM, peritonitis. Am J Kidney Dis 2001; 37:149–53. Vas SI, Oreopoulos DG. Decrease in Staphylococcus 16 Krishnasami Z, Carlton D, Bimbo L, et al. Manage- aureus exit-site infections and peritonitis in CAPD ment of hemodialysis catheter-related bacteremia patients by local application of mupirocin ointment at with an adjunctive antibiotic lock solution. Kidney the catheter exit site. Perit Dial Int 1998; 18:261–70. Int 2002; 61:1136–42. 4 Mupirocin Study Group. Nasal mupirocin prevents 17 Dasgupta MK. Exit-site and catheter-related infection Staphylococcus aureus exit-site infection during peri- in peritoneal dialysis: problems and progress. toneal dialysis. J Am Soc Nephrol 1996; 7:2403–8. Nephrology 2000; 5:17–25. 5 Perez–Fontán M, Garcia–Falcon T, Rosales M, et al. 18 Finelli A, Burrows LL, DiCosmo FA, et al. Coloniza- Treatment of Staphylococcus aureus nasal carriers in tion-resistant antimicrobial-coated peritoneal dialysis continuous ambulatory peritoneal dialysis with catheters: evaluation in a newly developed rat model mupirocin: long-term results. Am J Kidney Dis 1993; of persistent Pseudomonas aeruginosa peritonitis. 22:708–12. Perit Dial Int 2002; 22:27–31. 6 Dasgupta MK, Fox S, Gagnon D, Bettcher K, Ulan 19 Kim YL, Cho S, Kim JC, et al. Effect in a rat model RA. Significant reduction of peritonitis rate by the of heparinized peritoneal dialysis catheters on bacte- use of twin-bag system in a Canadian regional CAPD rial colonization and the healing of exit site. Perit program. Adv Perit Dial 1992; 8:223–6. Dial Int 2001; 21(Suppl 3):S357–8. 7 Harris DC, Yuill EJ, Byth K, Chapman JR, Hunt C. 20 Balaban N, Giacometti A, Cirioni O, et al. Use of the Twin- versus single-bag disconnect systems: infec- quorum-sensing inhibitor RNAIII-inhibiting peptide tion rates and cost of continuous ambulatory perito- to prevent biofilm formation in vivo by drug-resistant neal dialysis. J Am Soc Nephrol 1996; 7:2392–8. Staphylococcus epidermidis. J Infect Dis 2003; 15: 8 Dasgupta MK. Moncrief–Popovich catheter and im- 625–30. plantation technique: the AV fistula of peritoneal dialysis. Adv Ren Replace Ther 2002; 9:116–24. Corresponding author: 9 Anwar H, Dasgupta M, Lam K, Costerton JW. Mrinal K. Dasgupta, MD, Room 2E3 22 WMC, Uni- Tobramycin resistance of mucoid Pseudomonas versity of Alberta, Edmonton, Alberta T6G 2B7 aeruginosa biofilm grown under iron limitation. Canada. J Antimicrob Chemother 1989; 24:647–55. E-mail: [email protected] Advances in Peritoneal Dialysis, Vol. 19, 2003

The Effects of Weekly Mupirocin Application on Infections in Continuous Ambulatory Peritoneal Müjdat Zeybel, Ayse Özder, Canan Sanlidag, Serkan Yildiz, Caner Cavdar, Rifki Ersoy, Ali Celik, Taner Camsari Dialysis Patients

Application of mupirocin to the nares or catheter exit Introduction site and frequency of mupirocin administration in Infections are of great concern in the management of continuous ambulatory peritoneal dialysis (CAPD) peritoneal dialysis (PD). Introduction of new deliv- patients remain controversial. The objective of our ery systems and advances in connection technology study was to evaluate, using a historical control have resulted in a reduction in the rate of catheter- group, the efficacy on CAPD-related infections of related infections. Although many infections are once-weekly application of mupirocin at the cath- treated successfully with antibiotics, some still com- eter exit site. We instructed 18 CAPD patients, who plicate PD and cause technical failure. Recurrent and did not initially use prophylactic antibiotic treatment, severe peritonitis can also result in sclerosing perito- about once-weekly application of mupirocin ointment nitis and a switch from PD to hemodialysis. to the exit site as part of their exit-site care. We re- The micro-organism that most commonly causes corded the incidence of catheter-related infections, catheter-related infections in continuous ambulatory the causative micro-organisms, and the rate of cath- peritoneal dialysis (CAPD) patients is Staphylococ- eter loss. cus aureus. That bacterium is commonly isolated from We observed 17 acute exit-site infections (AESIs: hands, groin, and (particularly) the nares of patients. 0.45 episodes/patient–year) before mupirocin treat- Carriage of S. aureus is related to infections in CAPD ment and 2 AESIs (0.06 episodes/patient–year) after patients. Prophylactic antibiotics (neomycin sulfate, treatment. The relative rate of AESI reduction was mupirocin, rifampin, trimethoprim/sulfamethoxazole, 86%. Before application of mupirocin, 52% of AESIs and ciprofloxacin) have been administered to eradi- were attributable to Staphylococcus aureus; after cate S. aureus colonization and to prevent catheter- mupirocin administration, no AESIs were staphylo- related infections (1,2). Reductions in infection rates coccal. Peritonitis episodes were also reduced from have been achieved by nearly all antibiotics; however, 21 before mupirocin treatment (0.56 episodes/pa- because of side effects and the potential for develop- tient–year), to 9 after mupirocin administration ment of antibiotic resistance, topical antibiotics (0.29 episodes/patient–year). The relative rate of (mupirocin) have been substituted for systemic ones peritonitis reduction was 48%. Once-weekly appli- in the past decade (3,4). cation of mupirocin to the exit site resulted in a re- Mupirocin binds to bacterial isoleucyl transfer duction in exit-site infections and peritonitis episodes RNA synthetase and inhibits bacterial protein synthe- comparable to those obtained with daily application. sis. At low concentrations, mupirocin is bacteriostatic; topical administration has a bacteriocidal effect for Key words S. aureus. Mupirocin, exit-site care, exit-site infections, perito- Several investigators have evaluated the effect of nitis, Staphylococcus aureus administration of mupirocin ointment to the exit site and nares, either daily or 2 – 5 times per week, in From: Department of Internal Medicine and Department of CAPD patients. They showed a statistically signifi- Nephrology, Dokuz Eylul University Medical Faculty, cant reduction in acute exit-site infections (AESIs) and Izmir, Turkey. peritonitis rates (1–6). However, to date, outcome from Zeybel et al. 199 regular once-weekly application of mupirocin to the TABLE I Demographic data for the study patients exit site in CAPD patients is unknown. The objective of our study was to evaluate, using Age (years) 54.2±7.4 (range: 41–70) Sex (M/F) 13/5 a historical control group, the efficacy on CAPD-re- Cause of renal failure lated infections of once-weekly application of mupir- Hypertension 7 ocin at the catheter exit site. Tubulointerstitial nephritis 3 Diabetes mellitus 2 Patients and methods Pyelonephritis 2 Amyloidosis obstruction 2 The study population included 18 patients receiving Unknown 2 CAPD treatment between November 1996 and Au- Dialysis duration (months) 24.8±18.9 (range: 4–72) gust 2002. We instructed those patients about once- weekly application of mupirocin ointment to their exit sites as part of exit-site care. The patients had not ini- tive rate of reduction in AESIs was 86%. Before tially used that treatment. They now were asked to mupirocin application, 52% of AESIs were attrib- apply, by themselves, mupirocin 2% ointment utable to S. aureus. After mupirocin administration (Bactroban: GlaxoSmithKline, Istanbul, Turkey) as a was started, no AESI was staphylococcal. Episodes thin film to the exit site. of peritonitis were also reduced from 21 before Evaluation of exit sites occurred at the time of the mupirocin treatment (0.56 episodes/patient–year) monthly outpatient visit, according to the classifica- to 9 after mupirocin administration (0.29 episodes/ tion described by Twardowski et al. (7). Diagnosis of patient–year). The relative rate of peritonitis re- peritonitis was made according to the presence of two duction was 48%. Table II and Figure 1 show the of the following three findings: abdominal pain, number and the percentages of AESIs and perito- cloudy dialysate, and demonstration of micro-organ- nitis episodes by micro-organisms isolated before isms upon dialysate culture. The incidence of exit- and after treatment with mupirocin. site infections and peritonitis before the mupirocin treatment period, the organisms isolated at those times, Discussion and the causes of transfer to other renal replacement Previous reports showed that prophylactic adminis- therapies were retrospectively investigated. tration of mupirocin ointment reduces catheter-related After mupirocin prophylaxis was started, we re- infections in CAPD patients. However, how frequently corded the incidence of catheter-related infections, the mupirocin should be applied and whether it should be causative micro-organisms, and the rate of catheter applied to the exit site or nares, to all patients or only loss. Patients were followed up for occurrence of side to S. aureus carriers, remain controversial. Bernardini effects related to mupirocin application (burning, itch- et al. (2) showed that daily administration of mupiro- ing, erythema). cin ointment to the exit site is as effectual as cyclic Statistical analysis was carried out using descrip- oral rifampin in reducing staphylococcal peritonitis tive statistics. and exit-site infections: peritonitis and exit-site infections respectively declined by 33% and 55% relative Results to historical controls. Better success rates (69% and Table I shows the demographic data (age, sex, du- 91% respectively) were obtained by Thodis et al. (5), ration of CAPD therapy, and cause of renal fail- who compared daily or thrice-weekly applications of ure) for the study population. The average period mupirocin to the exit site with a historical control of follow-up was 20 ± 12 months from the start of group. In a prospective, historically-controlled study, mupirocin application. No patient was lost to fol- Casey et al. (6) demonstrated that daily administra- low-up or transferred to another renal replacement tion of mupirocin to the exit site reduces rates of peri- modality during study period. We encountered no tonitis and AESIs (31% and 49%, respectively). side effects related to mupirocin use.We observed The present study obtained results comparable to 17 AESIs (0.45 AESI episodes/patient–year) be- those of Thodis and colleagues. Our results suggest fore the start of mupirocin treatment, and 2 AESIs that once-weekly application of mupirocin to the exit (0.06 AESI episodes/patient–year) after. The rela- site produced a 48% reduction in the rate of peritonitis 200 Weekly Mupirocin Application in CAPD Patients

TABLE II Absolute numbers and rates of infection for the duration of the study

Staphylococcus aureus All other organisms AESI Peritonitis AESI Peritonitis (n) Ratea (n) Ratea (n) Ratea (n) Ratea

Before mupirocin 9 0.24 2 0.05 8 0.21 19 0.51 After mupirocin 0 0 1 0.03 2 0.06 8 0.26 Reduction (%) 100 50 71 49 a Expressed as episodes per patient–year. AESI = acute exit-site infection.

mupirocin in CAPD patients means that the question of whether frequency of mupirocin administration af- fects the emergence of mupirocin resistance remains speculation. In recent years, Perez–Fontán et al. (9) have reported higher rates of mupirocin resistance (0% – 12.4%) and an associated increase in the risk of exit- site infection in CAPD patients. In our department, we isolated a mupirocin-resistant S. aureus strain in only 1 of 36 CAPD patients who used the antibiotic once weekly for 2 years (Unpublished data).

Conclusions Once-weekly application of mupirocin to the exit site

FIGURE 1 Effect of mupirocin on acute exit-site infections (AESIs) in CAPD patients causes reductions in AESIs and peri- and peritonitis due to Staphylococcus aureus and all other tonitis episodes comparable to those seen with daily organisms. application. Application of mupirocin to the exit site may also reduce the rate of non staphylococcal infec- and an 86% reduction in the rate of AESIs. According tions. Future studies concerning mupirocin prophylaxis to our study, once-weekly administration seems to be are likely to be related to mupirocin resistance. equivalent to daily or thrice-weekly application. Another finding of the present study is a reduc- References tion in infections attributable to micro-organisms other 1 Perez–Fontán M, Rosales M, Rodriguez–Carmona A, than S. aureus (including culture-negative infections). et al. Treatment of Staphylococcus aureus nasal car- Although mupirocin has antibacterial activity against riers in CAPD with mupirocin. Adv Perit Dial 1992; other bacteria in vitro, the finding of activity in vivo is 8:242–5. an uncommon finding shared only with the study from 2 Bernardini J, Piraino B, Holley J, Johnston JR, Lutes Thodis et al. (5). R. A randomized trial of Staphylococcus aureus pro- Administration of mupirocin has beneficial effects phylaxis in peritoneal dialysis patients: mupirocin on catheter-related infections, but long-term therapy calcium ointment 2% applied to the exit site versus cyclic oral rifampin. Am J Kidney Dis 1996; 27: with mupirocin can lead to the emergence of resistant 695–700. staphylococci. In a study by Annigeri and colleagues, 3 Mupirocin Study Group. Nasal mupirocin prevents resistance rates after 4 years of mupirocin use were Staphylococcus aureus exit-site infection during peri- reported to be only 3% (8). All of the patients in whom toneal dialysis. J Am Soc Nephrol 1996; 7:2403–8. resistance occurred were treated with intermittent (1– 4 Thodis E, Passadakis P, Panagoutsos S, Bacharaki D, 4 times weekly) mupirocin. No mupirocin resistance Euthimiadou A, Vargemezis V. The effectiveness of was seen in daily (5–7 times weekly) users (8). But mupirocin preventing Staphylococcus aureus in cath- the limited number of studies analyzing resistance to eter-related infections in peritoneal dialysis. Adv Zeybel et al. 201

Perit Dial 2000; 16:257–61. mupirocin-resistant Staphylococcus aureus in chronic 5 Thodis E, Bhaskaran S, Passadakis P, Bargman JM, peritoneal dialysis patients using mupirocin prophy- Vas SI, Oreopoulos DG. Decrease in Staphylococcus laxis to prevent exit-site infection. Perit Dial Int aureus exit-site infections and peritonitis in CAPD 2001; 21:554–9. patients by local application of mupirocin ointment at 9 Perez–Fontán M, Rosales M, Rodriguez–Carmona A, the catheter exit site. Perit Dial Int 1998; 18:261–70. Falcon TG, Valdes F. Mupirocin resistance after 6 Casey M, Taylor J, Clinard P, et al. Application of long-term use for Staphylococcus aureus coloniza- mupirocin cream at the catheter exit site reduces exit- tion in patients undergoing chronic peritoneal dialy- site infections and peritonitis in peritoneal dialysis sis. Am J Kidney Dis 2002; 39:337–41. patients. Perit Dial Int 2000; 20:566–8. 7 Twardowski ZJ, Prowant BF. Classification of normal Corresponding author: and diseased exit sites. Perit Dial Int 1996; 16(Suppl Müjdat Zeybel, MD, Dokuz Eylül Üniversitesi Tip 3):S71–6. Fakültesi Hastanesi, Ic Hastaliklari ABD, Izmir 35340 8 Annigeri R, Conly J, Vas SI, et al. Emergence of Turkey.