pd in the developing world

Peritoneal Dialysis International, Vol. 28, pp. 232–235 Printed in Canada. All rights reserved.

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PD IN THE DEVELOPING WORLD

PERITONITIS IN PERITONEAL DIALYSIS PATIENTS IN URUGUAY

Liliana Gadola,1,2 Lucía Orihuela,1 Daniel Pérez,3 Teresa Gómez,4 Laura Solá,5 Liliana Chifflet,1 Mariela Mautone,6 Eugenia Torres,1 and Grisel Rodriguez2

Uruguay is a South American country (3241003 inhabitants) where renal replacement treatment is universally available. The aim of this study was to analyze the incidence and outcome of peritonitis, and the causative organisms and their sensitivity, in order to recommend an empiric initial antibiotic treatment. A retrospective descriptive study of all peritonitis during the period 2004 – 2005 was performed (144 peritonitis, 44% due to gram-positive bacteria). We conclude that the high prevalence of methicillin-resistant coagulase-negative staphylococci justifies the use of vancomycin in the national empiric initial antibiotic protocols. Perit Dial Int 2008; 28:232–235

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KEY WORDS: Peritonitis; bacteriology; treatment; Uruguay.

U

ruguay is a small South American country that shares borders with Argentina and Brazil, and has a coastline on the Rio de la Plata and the Atlantic Ocean (1). It has an area of 176 215 km2, is divided into 19 departments, and has 3 241003 inhabitants, 13.7% of whom are older than 65 years (1). The ethnic distribution is 93.2% white and 5.9% black (1). In 2001 the gross domestic product per capita was US$8400 and the human development index 0.834. Relative expenditure on health was 10.9% of the gross domestic product (1–3). Correspondence to: L. Gadola, Sociedad Uruguaya de Nefrología – Nefrología, 18 de Julio 2103/802 Montevideo 11200, Uruguay. [email protected] Received 1 July 2007; accepted 10 March 2008. 232

There are public and private healthcare services providing coverage for the total population of the country (around 50% each). Renal replacement therapy in Uruguay expanded rapidly after the creation of the Fondo Nacional de Recursos (The National Resource Fund) in 1980. The National Resource Fund supports treatment with dialysis and renal transplantation for all patients with end-stage renal disease. Since 1981, the Dialysis and Renal Transplant Registry has accumulated data from the entire population on renal replacement therapy programs (4,5). By December 2004, the prevalence of end-stage renal disease had reached 732.2 patients per million population (pmp; 2344 patients). The incidence of end-stage renal disease has experienced progressive growth, from 32 pmp in 1981 to 146 pmp in 2005 (6–8). This incidence is similar to that reported in most developed countries (9) and has not changed significantly during the past 10 years. Renal transplants reached 32 pmp per year in 2004, 89% of which were from deceased donors. During the period 1999 – 2004, the gross mortality rate for dialysis patients varied from 12.3 to 15.9 deaths per 100 patient-years; 34.4% of deaths were due to cardiovascular disease, 18.8% to infectious diseases, 9.7% to cancer, and 11.6% to withdrawal from treatment. During the same period, the 9-year survival rate for patients with a deceased donor transplant was 88% for patients and 53% for grafts. The standardized mortality rate in 2005 was slightly higher on peritoneal dialysis (PD) than on hemodialysis, at 13.3 versus 8.6 deaths per 100 patientyears.

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Department of Nephrology: Hospital de Clínicas,1 CASMU,2 SEINE,3 Uruguayana,4 Hospital Maciel,5 Hospital Americano,6 Montevideo, Uruguay

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Figure 1 — Map of Uruguay.

et al. Composite index of outcome in peritoneal dialysis patients. Presented at the World Congress of Nephrology; April 21–25, 2007; Rio de Janeiro, Brazil). REVIEW OF PERITONITIS IN URUGUAY

Peritonitis is still a severe complication for PD patients in spite of important advances in this technique during past years. Infections are the second most common cause of death among dialysis patients and, in the case of PD, peritonitis is also the principal cause of technique failure. Peritonitis can produce peritoneal membrane failure. The mortality rate among the dialysis population in Uruguay during 2005 was 144 per 1000 patient-years. The global rate of peritonitis was 1 episode every 25 months. The US Renal Data System showed that the mortality rate due to infection for PD patients was 35 per 1000 patient-years (9), and Fried et al. (14) found that peritonitis was an independent risk factor for death. Therefore, prevention and effective treatment of peritonitis in PD patients are important goals. The ISPD has published guidelines for PD-related infections since 1983, with revisions and updates in 1989, 1993, 1996, 2000, and 2005 (13,15). The recommended empiric antibiotic treatment for peritonitis has changed over time according to changes in the sensitivity profiles of the bacteria most frequently cultured. The aim is to cover both gram-positive and gram-negative organisms. Since 1996, an increasing prevalence of vancomycin-resistant micro-organisms has been observed, proving worrisome to the international medical community. Thus, in the 2000 guidelines update, vancomycin was no longer recommended as initial empiric treatment. However, as many PD units had a high prevalence of methicillin-resistant gram-positive organisms, they continued using vancomycin for gram-positive coverage in association with another drug for gram-negative coverage. In the 2005 guidelines, the ISPD Committee switched to recommending a center-specific selection of empiric antibiotic treatment. In 2005, the seven Uruguayan PD units involved in this study used different protocols for empiric initial treatment of peritonitis. The Peritoneal Dialysis Group of the Uruguayan Society of Nephrology decided in 2006 to define a national evidence-based protocol for empiric treatment. The aim of the study was to analyze the incidence and outcome of peritonitis, and the causative organisms and their sensitivity, in order to recommend an empiric antibiotic treatment according to the history of sensitivity of the most frequently cultured organisms. 233


The cost of renal replacement therapy in Uruguay represents almost 3% of the total health budget (one third of the National Resource Fund budget). One hemodialysis treatment costs US$70 (US$900 per patient per month) and 1 month on PD costs US$1200 per patient (10). There are 41 hemodialysis units and 7 PD units distributed across 17 of the 19 departments (Figure 1). In each dialysis unit, there are 4 – 6 nephrologists working and most live in the same area as the unit (11). There are 169 nephrologists in the country: approximately 1 for every 20 000 people population. The dialysis units also have renal nurses, dieticians, social workers, and psychological support. Profits are lower in PD units. International Society for Peritoneal Dialysis (ISPD) guidelines (12,13) are used by all nephrologists to standardize clinical care. As of December 2005, there were 174 patients on PD (7.7% of dialysis patients), 75.8% of them on continuous ambulatory PD (CAPD) and 24.2% on automated PD. The CAPD patients use the Y-system (double bag, UltraBag; Baxter Immuno, Buenos Aires, Argentina). In four PD units studied during the period 2000 – 2006, the cumulative patient survival on PD at 1, 2, and 5 years was 88.1%, 79.5%, and 66.7%, respectively (Gadola L,

PERITONITIS IN PD PATIENTS IN URUGUAY

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METHODS

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TABLE 1 Etiologic Spectrum of Peritonitis

RESULTS During the study period (2004 – 2005), 262 patients were treated with PD in Uruguay; total exposure time was 3552 months, mean age 59 (21 – 93) years, 54.9% were females. Ninety-nine patients suffered 144 episodes of peritonitis. The incidence of peritonitis during this period was 1 episode every 25 months. In the different PD units, the peritonitis rate varied from 1 episode every 11 months to 1 episode every 39 months. Forty-two episodes (29%) were culture-negative peritonitis. The causative organisms were gram positive in 64 episodes (44%), gram negative in 29 episodes (20%), fungus in 2 episodes, and in 3 cases multiple organisms were isolated in PD fluid culture (Table 1). The most common pathogens were coagulase-negative staphylococci (CoNS; 30 episodes), with 57% (17/30) being methicillin resistant (2 of the 17 were also amikacin resistant). Only 1 of the 25 Staphylococcus aureus isolated was methicillin resistant. No vancomycin-resistant gram-positive bacteria were isolated. Two different empirical initial treatment protocols were used at the discretion of the individual centers: (A) vancomycin plus amikacin in 127/144 episodes 234

Gram-positive bacteria Staphylococcus aureus Methicillin sensitive Methicillin resistant Coagulase-negative staphylococci Methicillin sensitive Methicillin resistant Methicillin & amikacin resistant Unknown sensitivity Other gram-positive bacteria Gram-negative bacteria Polymicrobial Fungal Negative culture No data

64 (44%) 24 1 11 15 2 2 9 29 (20%) 3 2 42 (29%) 4

(88%) and (B) cefazolin plus amikacin or ceftazidime (according to residual renal function) in 13/144 (9%). Primary cure with Protocol A was observed in 104/126 episodes (82%) and with Protocol B in 9/13 (69%) (NS). Primary cure of episodes due to gram-positive organisms was significantly more frequent with Protocol A (vancomycin; 49/52) than with Protocol B (cefazolin; 7/11) (p < 0.05). Most methicillin-resistant gram-positive bacteria were isolated in one PD unit (10/18) located in a tertiary level hospital where most patients have serious socioeconomic difficulties. Gram-negative bacteria (29/144 episodes) were cultured less frequently than in recent international reports, and their mortality rate (5/29) was significantly higher than that for peritonitis due to gram-positive organisms (0/64) (p < 0.05). Only 2/23 gram-negative bacteria were amikacin resistant. Ceftazidime was tested in only 13/29 episodes and 3 of the 13 were ceftazidimeresistant bacteria. Ciprofloxacin-resistant bacteria were isolated in 3 of 22 tested. Twenty-two episodes were defined as refractory and the catheters were removed (9 due to gram-positive bacteria). Seven patients died; the causative organisms were gram negative in 5 and the other 2 were due to surgical peritonitis. DISCUSSION Peritonitis is still a common clinical problem among patients on PD and may cause peritoneal membrane damage or even death. The empiric initial antibiotic treatment may have a great impact on the outcome and therefore on peritoneal membrane preservation and patient survival. The choice of the initial antibiotics


A retrospective descriptive study of all PD peritonitis episodes in Uruguay from 1 January 2004 to 31 December 2005 was performed. The Uruguayan Dialysis Register (4) and the medical records of all patients undergoing PD were reviewed in the seven PD units. Peritonitis was defined according to the ISPD recommendations (abdominal pain, cloudy PD fluid, white cell count higher than 100/µL, with at least 50% neutrophils in PD fluid). Culture-negative cases were included in the total number of episodes of PD peritonitis. Patients’ demographic data, time on treatment during the 2004 – 2005 period (exposure time), and, for each episode of peritonitis, the organisms isolated, their sensitivity, the empiric initial treatment, eventual antibiotic changes, and outcome were recorded. The ISPD guidelines antibiotic dose recommendations were used. “Primary cure” was defined as a cure with the initial empiric treatment performed. The empiric antibiotic treatment was changed if necessary according to culture and sensitivity results. If cloudy effluent or any other symptom persisted in spite of adequate antibiotic treatment, the PD catheter was removed. The study protocol was approved by the Ethics Committee of each institution. Statistical analysis was performed using chi-square test. A p value less than 0.05 was considered significant.

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REFERENCES 1. Uruguay. Instituto Nacional de Estadística. Censos de población año 2004. Montevideo - Uruguay. Instituto Nacional de Estadística. Encuesta Continua de Hogares. 1996 – 1997. Montevideo. Available from: http:// www.ine.gub.uy/socio-demograficos/pobhogyviv.htm 2. World Development Reports. Available from: http://wwwwds.worldbank.org 3. United Nations Development Programme. Human Development Report 2003. New York: Oxford University Press;

2003. 4. Registro Uruguayo de Diálisis. Available from: http:// www.nefroprevencion.org.uy/rud/rudialisis.htm 5. Registro Uruguayo de Trasplante Renal. Available from: http://www.nefroprevencion.org.uy/rud/ rtrasplante.htm 6. Mazzuchi N, Schwedt E, Fernández JM, Cusumano HM, Silva Ancao MS, Saldaña-Arèvalo M, et al. Latin American Registry of Dialysis and Renal Transplantation. 1993 annual dialysis data report. Nephrol Dial Transplant 1997; 12: 2521–7. 7. Schwedt E, Fernandez JM, Gonzalez F, Mazzuchi N. Endstage renal disease therapy in Latin America. Nephrology 1998; 4(Suppl 2):s81–3. 8. Fernandez-Cean JM, Gonzalez-Martinez F, Schwedt E, Mazzuchi N, on behalf of the Latin American Registry of Dialysis and Renal Transplantation. Renal replacement therapy in Latin America. Kidney Int Suppl 2000; 74:S55–9. 9. US Renal Data System. USRDS 2005 Annual Data Report. Atlas of End Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2005. 10. Fondo Nacional de Recursos/The National Resource Fund (Uruguay). Available at: http://www.fnr.gub.uy 11. Riella MC, Locatelli A. History of peritoneal dialysis in Latin America. Perit Dial Int 2007; 27:322–7. 12. Lo WK, Bargman JM, Burkart J, Krediet RT, Pollock C, Kawanishi H, et al. Guidelines on targets for solute and fluid removal in adult patients on chronic peritoneal dialysis. Perit Dial Int 2006; 26:520–2. 13. Piraino B, Bailie GR, Bernardini J, Boeschoten E, Gupta A, Holmes C, et al. Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int 2005; 25: 107–31. 14. Fried L, Bernardini J, Johnston JR, Piraino B. Peritonitis influences mortality in peritoneal dialysis patients. J Am Soc Nephrol 1996; 7:2176–82. 15. Kean WF, Bailie GR, Boeschoten E, Gokal R, Golper TA, Holmes CJ, et al. ISPD guidelines/recommendations. Adult peritoneal dialysis-related peritonitis treatment recommendations: 2000 update [Published erratum appears in Perit Dial Int 2000; 20:828–9]. Perit Dial Int 2000; 20: 396–411. 16. Troidle L, Gorban-Brennan M, Kliger A, Finkelstein F. Differing outcomes of gram-positive and gram-negative peritonitis. Am J Kidney Dis 1998; 32:623–8. 17. Yip T, Tse KC, Lam MF, Tang S, Li FK, Choy BY, et al. Risk factors and outcomes of extended-spectrum betalactamase-producing E. coli peritonitis in CAPD patients. Perit Dial Int 2006; 26:191–7.

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should consider both the prevalence of possible causative organisms and their sensitivity, and the risk of inducing growth of antibiotic-resistant bacteria. In the 2005 guidelines, the ISPD Committee recommended center-specific selection of the empiric antibiotic treatment for peritonitis. The peritonitis rate in Uruguay of 1 episode every 25 patient-months is similar to that in other countries and is acceptable according to international guidelines, but there is a broad spectrum among the different PD units. There was a high rate of culture-negative peritonitis. Gram-positive bacteria were the most frequently isolated organisms; most of them were CoNS, with the majority being methicillin resistant. The PD catheter was removed in 22 episodes: 5 due to S. aureus (1 methicillin resistant), 4 CoNS (3 methicillin resistant), 6 gram negatives, 2 fungi, and 5 negative cultures. Only 29 gram-negative bacteria were isolated and these episodes of peritonitis had a high mortality rate (5/29), as has been reported elsewhere (15). No Pseudomonas was isolated. Unfortunately, despite great improvement in connectology that may decrease the incidence of gram-positive peritonitis, gram-negative peritonitis has not been successfully reduced and is associated with more frequent removal of the peritoneal catheter, increased dropout rate, and higher mortality than peritonitis caused by gram-positive organisms (16,17). In conclusion, the high prevalence of methicillinresistant CoNS justifies the use of vancomycin in empiric initial antibiotic protocols. Efforts should be directed at improving culture techniques in order to isolate the causative bacteria and more quickly ascertain their antibiotic sensitivities. Efforts should also be directed at improving patients’ training and their environmental conditions to reduce the incidence of peritonitis.

PERITONITIS IN PD PATIENTS IN URUGUAY