A reevaluation of empiric therapy for peritoneal dialysis-related peritonitis

Abstract

PERITONITIS is a common and potentially serious infection in patients undergoing peritoneal dialysis (PD). Significant complications include hospitalization, protracted or recurrent infections, catheter removal, and an attributable mortality rate approaching 10%.1Canada USA (CANUSA) Peritoneal Dialysis Study GroupAdequacy of dialysis and nutrition in continuous peritoneal dialysis Association with clinical outcomes.J Am Soc Nephrol. 1996; 7: 198-207PubMed Google Scholar, 2Fried L. Abidi S. Bernardini J. Johnston J.R. Piraino B. Hospitalization in peritoneal dialysis patients.Am J Kidney Dis. 1999; 33: 927-933Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 3Fried L.F. Bernardini J. Johnston J.R. Piraino B. Peritonitis influences mortality in peritoneal dialysis patients.J Am Soc Nephrol. 1996; 7: 2176-2182PubMed Google Scholar The incidence of PD-related peritonitis is approximately 0.5 episodes per patient-year with two thirds representing Gram-positive infections.4Zelenitsky S. Barns L. Findlay I. et al.Analysis of microbiological trends in peritoneal dialysis-related peritonitis from 1991 to 1998.Am J Kidney Dis. 2000; 36: 1009-1013Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Infectious peritonitis usually is suspected based on signs and symptoms including cloudy dianeal effluent, abdominal pain, and fever. Therefore, most, if not all, patients receive initial empiric therapy, while awaiting microbiologic results. Antibiotic therapy for PD-related peritonitis is complicated by unique administration (ie, intraperitoneal), variable pharmacokinetics, frequent use of combinations, and effects of dialysate on activity. The clinical study of antibiotics is largely based on small trials with insufficient power to detect significant differences between treatments. Furthermore, the antibiotic pharmacodynamics or relationship between antibiotic and concentration, organism susceptibility, and clinical outcome for PD-related peritonitis are poorly understood.5Troidle L. Gorban-Brennan N. Kliger A. Finkelstein F.O. Continuous peritoneal dialysis-associated peritonitis A review and current concepts.Semin Dial. 2003; 16: 428-437Crossref PubMed Scopus (64) Google Scholar Recent reports indicate that standard antibiotic dosing may not provide adequate intraperitoneal drug concentrations for the treatment of infection.6Manley H.J. Bailie G.R. Frye R. Hess L.D. McGoldrick M.D. Pharmacokinetics of intermittent intravenous cefazolin and tobramycin in patients treated with automated peritoneal dialysis.J Am Soc Nephrol. 2000; 11 (1310–1306)PubMed Google Scholar, 7Manley H.J. Bailie G.R. Frye R.F. McGoldrick M.D: . Intravenous vancomycin pharmacokinetics in automated peritoneal dialysis patients.Perit Dial Int. 2001; 21: 378-385PubMed Google ScholarThe International Society for Peritoneal Dialysis (ISPD) provides comprehensive treatment guidelines for the management of PD-related peritonitis.8Keane W.F. Bailie G.R. Boeschoten E. et al.Adult peritoneal dialysis-related peritonitis treatment recommendations: 2000 update..Perit Dial Int. 2000; 20: 396-411PubMed Google Scholar Importantly, the recommendations are updated with new findings relevant to the microbiology and treatment of these complex infections. The threat of vancomycin resistance was addressed in the 1996 update, which suggested empiric therapy with a first-generation cephalosporin plus an aminoglycoside (AG) instead of the previously recommended vancomycin.9Keane W.F. Alexander S.R. Bailie G.R. et al.Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update..Perit Dial Int. 1996; 16: 557-573PubMed Google Scholar Undoubtedly, this response reduced unnecessary vancomycin use in a population susceptible to colonization and infection with multidrug-resistant organisms.The most recent 2000 ISPD update recommends empiric therapy with a first-generation cephalosporin in combination with ceftazidime (instead of an AG) in patients with residual urine output greater than 100 mL/d.8Keane W.F. Bailie G.R. Boeschoten E. et al.Adult peritoneal dialysis-related peritonitis treatment recommendations: 2000 update..Perit Dial Int. 2000; 20: 396-411PubMed Google Scholar This change was prompted by concerns that AGs may lead to greater declines in residual renal function. Our review of the literature at the time found 1 relatively small study with such findings. Shemin et al10Shemin D. Maaz D. St Pierre D. Kahn S.I. Chazan J.A: . Effect of aminoglycoside use on residual renal function in peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 14-20Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar observed 29 PD patients without peritonitis (group I), 26 with peritonitis not treated with an AG (group II), and 17 with peritonitis treated with at least 3 doses of an AG (group III). Creatinine clearances and daily urine volumes were extremely variable with overall reductions over time in all groups. Patients receiving AGs had a significantly greater decline in renal clearance than group I and II, but a greater reduction in daily urine volume compared with group II only. This inconsistency highlights the need for cautious interpretation of small studies with outcomes that are intrinsically variable. In this case, results in group III could have been influenced significantly by few cases such as the 5 with 14 days and 1 with 36 days of AG therapy. Furthermore, the apparent analysis using multiple t-tests without correction could have overstated statistical significance compared with more appropriate tests. More recently, Baker et al11Baker R.J. Senior H. Clemenger M. Brown E.A: . Empirical aminoglycosides for peritonitis do not affect residual renal function.Am J Kidney Dis. 2003; 41: 670-675Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar assessed renal function in 70 patients without peritonitis, 61 patients with peritonitis not treated with an AG, and 70 patients with peritonitis treated with an AG. Changes in mean glomerular filtration rate and urine output were not different among groups. In addition, AG-associated risk was not observed in patients with more than 5 days of therapy or residual urine output greater than 250 mL/d. Current evidence does not appear to support an association between AG use for PD-related peritonitis and increased loss of residual renal function. The expected risk with abbreviated courses for empiric therapy would be extremely small. However, the effect of AG exposure repeatedly in patients with recurrent or multiple infections is unknown.Another issue that warrants discussion but has received less attention is AG-associated otovestibular toxicity. Drug uptake and saturation of inner-ear tissues may damage hair cells leading to auditory and vestibular impairment.12Minor L.B: . Gentamicin-induced bilateral vestibular hypofunction.JAMA. 1998; 279: 541-544Crossref PubMed Scopus (81) Google Scholar Similar incidences of toxicity with traditional and high-dose AG regimens support the theory that toxicity is not associated with transiently high peak levels.13Ferriols-Lisart R. Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: A meta-analysis..Am J Health Syst Pharm. 1996; 53: 1141-1150PubMed Google Scholar Although numerous risk factors, including renal dysfunction, have been suggested, compelling clinical evidence is lacking. In a risk factor analysis by Gatell et al,14Gatell J.M. Ferran F. Araujo V. et al.Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides.Antimicrob Agents Chemother. 1987; 31: 1383-1387Crossref PubMed Scopus (86) Google Scholar age was the only variable independently associated with auditory toxicity in 18 of 187 patients receiving AGs. A few small studies in PD patients have reported no statistically significant difference in audiogram readings before and after AG therapy.15Mars R.L. Moles K. Pope K. Hargrove P. Use of bolus intraperitoneal aminoglycosides for treating peritonitis in end-stage renal disease patients receiving continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis.Adv Perit Dial. 2000; 16: 280-284PubMed Google Scholar, 16Nikolaidis P. Vas S. Lawson V. et al.Is intraperitoneal tobramycin ototoxic in CAPD patients?.Perit Dial Int. 1991; 11: 156-161PubMed Google Scholar However, another study of patients receiving multiple 10-day courses of gentamicin found significant signs of vestibular impairment by the third and fourth treatments.17Gendeh B.S. Said H. Gibb A.G. Aziz N.S. Kong N. Zahir Z.M. Gentamicin ototoxicity in continuous ambulatory peritoneal dialysis.J Laryngol Otol. 1993; 107: 681-685Crossref PubMed Scopus (21) Google ScholarFinally, the selection of ceftazidime to replace AGs as empiric therapy for PD-related peritonitis warrants some scrutiny. Ceftazidime also adds Gram-negative (eg, Pseuodmonas aeruginosa) coverage to the spectrum of cefazolin. However, cefazolin-ceftazidime may be less active than the potentially synergistic combination of cefazolin and an AG against organisms such as methicillin-resistant Staphylococcus epidermidis.18Ariano R.E. Franczuk C. Fine A. Harding G.K. Zelenitsky S.A. Challenging the current treatment paradigm for methicillin-resistant Staphylococcus epidermidis peritonitis in peritoneal dialysis patients.Perit Dial Int. 2002; 22: 335-338PubMed Google Scholar Most notable, however, are the well-established associations between extended-spectrum cephalosporin use and β-lactamase-mediated resistance especially in the family Enterobacteriaceae (eg, Enterobacter spp).19Lee S.O. Kim Y.S. Kim B.N. Kim M.N. Woo J.H. Ryu J. Impact of previous use of antibiotics on development of resistance to extended-spectrum cephalosporins in patients with enterobacter bacteremia.Eur J Clin Microbiol Infect Dis. 2002; 21: 577-581Crossref PubMed Scopus (31) Google Scholar In a report by Mebis et al,20Mebis J. Goossens H. Bruyneel P. et al.Decreasing antibiotic resistance of Enterobacteriaceae by introducing a new antibiotic combination therapy for neutropenic fever patients.Leukemia. 1998; 12: 1627-1629Crossref PubMed Scopus (53) Google Scholar the empiric use of ceftazidime for febrile neutropenia corresponded to significant increases in inducible Enterobacteriaceae and 75% reduction in ceftazidime susceptibility. The removal of ceftazidime from the initial empiric protocol was accompanied by dramatic reductions in cephalosporin resistance rates. Similar concerns apply to the management of PD-related peritonitis. The empiric use of ceftazidime equates to broad systemic antibiotic exposure with significant potential for the induction and selection of resistance. The potential consequences are more serious and difficult-to-treat infections in an already high-risk patient population.Peritonitis is a serious complication that accounts for significant antibiotic use in PD patients. The ISPD treatment guidelines, last updated in 2000, are a valuable resource that broadly impact clinical practice and patient care. New information and practical issues highlighted in this report warrant consideration in future decisions and recommendations regarding empiric therapy for PD-related peritonitis. PERITONITIS is a common and potentially serious infection in patients undergoing peritoneal dialysis (PD). Significant complications include hospitalization, protracted or recurrent infections, catheter removal, and an attributable mortality rate approaching 10%.1Canada USA (CANUSA) Peritoneal Dialysis Study GroupAdequacy of dialysis and nutrition in continuous peritoneal dialysis Association with clinical outcomes.J Am Soc Nephrol. 1996; 7: 198-207PubMed Google Scholar, 2Fried L. Abidi S. Bernardini J. Johnston J.R. Piraino B. Hospitalization in peritoneal dialysis patients.Am J Kidney Dis. 1999; 33: 927-933Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 3Fried L.F. Bernardini J. Johnston J.R. Piraino B. Peritonitis influences mortality in peritoneal dialysis patients.J Am Soc Nephrol. 1996; 7: 2176-2182PubMed Google Scholar The incidence of PD-related peritonitis is approximately 0.5 episodes per patient-year with two thirds representing Gram-positive infections.4Zelenitsky S. Barns L. Findlay I. et al.Analysis of microbiological trends in peritoneal dialysis-related peritonitis from 1991 to 1998.Am J Kidney Dis. 2000; 36: 1009-1013Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Infectious peritonitis usually is suspected based on signs and symptoms including cloudy dianeal effluent, abdominal pain, and fever. Therefore, most, if not all, patients receive initial empiric therapy, while awaiting microbiologic results. Antibiotic therapy for PD-related peritonitis is complicated by unique administration (ie, intraperitoneal), variable pharmacokinetics, frequent use of combinations, and effects of dialysate on activity. The clinical study of antibiotics is largely based on small trials with insufficient power to detect significant differences between treatments. Furthermore, the antibiotic pharmacodynamics or relationship between antibiotic and concentration, organism susceptibility, and clinical outcome for PD-related peritonitis are poorly understood.5Troidle L. Gorban-Brennan N. Kliger A. Finkelstein F.O. Continuous peritoneal dialysis-associated peritonitis A review and current concepts.Semin Dial. 2003; 16: 428-437Crossref PubMed Scopus (64) Google Scholar Recent reports indicate that standard antibiotic dosing may not provide adequate intraperitoneal drug concentrations for the treatment of infection.6Manley H.J. Bailie G.R. Frye R. Hess L.D. McGoldrick M.D. Pharmacokinetics of intermittent intravenous cefazolin and tobramycin in patients treated with automated peritoneal dialysis.J Am Soc Nephrol. 2000; 11 (1310–1306)PubMed Google Scholar, 7Manley H.J. Bailie G.R. Frye R.F. McGoldrick M.D: . Intravenous vancomycin pharmacokinetics in automated peritoneal dialysis patients.Perit Dial Int. 2001; 21: 378-385PubMed Google Scholar The International Society for Peritoneal Dialysis (ISPD) provides comprehensive treatment guidelines for the management of PD-related peritonitis.8Keane W.F. Bailie G.R. Boeschoten E. et al.Adult peritoneal dialysis-related peritonitis treatment recommendations: 2000 update..Perit Dial Int. 2000; 20: 396-411PubMed Google Scholar Importantly, the recommendations are updated with new findings relevant to the microbiology and treatment of these complex infections. The threat of vancomycin resistance was addressed in the 1996 update, which suggested empiric therapy with a first-generation cephalosporin plus an aminoglycoside (AG) instead of the previously recommended vancomycin.9Keane W.F. Alexander S.R. Bailie G.R. et al.Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update..Perit Dial Int. 1996; 16: 557-573PubMed Google Scholar Undoubtedly, this response reduced unnecessary vancomycin use in a population susceptible to colonization and infection with multidrug-resistant organisms. The most recent 2000 ISPD update recommends empiric therapy with a first-generation cephalosporin in combination with ceftazidime (instead of an AG) in patients with residual urine output greater than 100 mL/d.8Keane W.F. Bailie G.R. Boeschoten E. et al.Adult peritoneal dialysis-related peritonitis treatment recommendations: 2000 update..Perit Dial Int. 2000; 20: 396-411PubMed Google Scholar This change was prompted by concerns that AGs may lead to greater declines in residual renal function. Our review of the literature at the time found 1 relatively small study with such findings. Shemin et al10Shemin D. Maaz D. St Pierre D. Kahn S.I. Chazan J.A: . Effect of aminoglycoside use on residual renal function in peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 14-20Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar observed 29 PD patients without peritonitis (group I), 26 with peritonitis not treated with an AG (group II), and 17 with peritonitis treated with at least 3 doses of an AG (group III). Creatinine clearances and daily urine volumes were extremely variable with overall reductions over time in all groups. Patients receiving AGs had a significantly greater decline in renal clearance than group I and II, but a greater reduction in daily urine volume compared with group II only. This inconsistency highlights the need for cautious interpretation of small studies with outcomes that are intrinsically variable. In this case, results in group III could have been influenced significantly by few cases such as the 5 with 14 days and 1 with 36 days of AG therapy. Furthermore, the apparent analysis using multiple t-tests without correction could have overstated statistical significance compared with more appropriate tests. More recently, Baker et al11Baker R.J. Senior H. Clemenger M. Brown E.A: . Empirical aminoglycosides for peritonitis do not affect residual renal function.Am J Kidney Dis. 2003; 41: 670-675Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar assessed renal function in 70 patients without peritonitis, 61 patients with peritonitis not treated with an AG, and 70 patients with peritonitis treated with an AG. Changes in mean glomerular filtration rate and urine output were not different among groups. In addition, AG-associated risk was not observed in patients with more than 5 days of therapy or residual urine output greater than 250 mL/d. Current evidence does not appear to support an association between AG use for PD-related peritonitis and increased loss of residual renal function. The expected risk with abbreviated courses for empiric therapy would be extremely small. However, the effect of AG exposure repeatedly in patients with recurrent or multiple infections is unknown. Another issue that warrants discussion but has received less attention is AG-associated otovestibular toxicity. Drug uptake and saturation of inner-ear tissues may damage hair cells leading to auditory and vestibular impairment.12Minor L.B: . Gentamicin-induced bilateral vestibular hypofunction.JAMA. 1998; 279: 541-544Crossref PubMed Scopus (81) Google Scholar Similar incidences of toxicity with traditional and high-dose AG regimens support the theory that toxicity is not associated with transiently high peak levels.13Ferriols-Lisart R. Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: A meta-analysis..Am J Health Syst Pharm. 1996; 53: 1141-1150PubMed Google Scholar Although numerous risk factors, including renal dysfunction, have been suggested, compelling clinical evidence is lacking. In a risk factor analysis by Gatell et al,14Gatell J.M. Ferran F. Araujo V. et al.Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides.Antimicrob Agents Chemother. 1987; 31: 1383-1387Crossref PubMed Scopus (86) Google Scholar age was the only variable independently associated with auditory toxicity in 18 of 187 patients receiving AGs. A few small studies in PD patients have reported no statistically significant difference in audiogram readings before and after AG therapy.15Mars R.L. Moles K. Pope K. Hargrove P. Use of bolus intraperitoneal aminoglycosides for treating peritonitis in end-stage renal disease patients receiving continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis.Adv Perit Dial. 2000; 16: 280-284PubMed Google Scholar, 16Nikolaidis P. Vas S. Lawson V. et al.Is intraperitoneal tobramycin ototoxic in CAPD patients?.Perit Dial Int. 1991; 11: 156-161PubMed Google Scholar However, another study of patients receiving multiple 10-day courses of gentamicin found significant signs of vestibular impairment by the third and fourth treatments.17Gendeh B.S. Said H. Gibb A.G. Aziz N.S. Kong N. Zahir Z.M. Gentamicin ototoxicity in continuous ambulatory peritoneal dialysis.J Laryngol Otol. 1993; 107: 681-685Crossref PubMed Scopus (21) Google Scholar Finally, the selection of ceftazidime to replace AGs as empiric therapy for PD-related peritonitis warrants some scrutiny. Ceftazidime also adds Gram-negative (eg, Pseuodmonas aeruginosa) coverage to the spectrum of cefazolin. However, cefazolin-ceftazidime may be less active than the potentially synergistic combination of cefazolin and an AG against organisms such as methicillin-resistant Staphylococcus epidermidis.18Ariano R.E. Franczuk C. Fine A. Harding G.K. Zelenitsky S.A. Challenging the current treatment paradigm for methicillin-resistant Staphylococcus epidermidis peritonitis in peritoneal dialysis patients.Perit Dial Int. 2002; 22: 335-338PubMed Google Scholar Most notable, however, are the well-established associations between extended-spectrum cephalosporin use and β-lactamase-mediated resistance especially in the family Enterobacteriaceae (eg, Enterobacter spp).19Lee S.O. Kim Y.S. Kim B.N. Kim M.N. Woo J.H. Ryu J. Impact of previous use of antibiotics on development of resistance to extended-spectrum cephalosporins in patients with enterobacter bacteremia.Eur J Clin Microbiol Infect Dis. 2002; 21: 577-581Crossref PubMed Scopus (31) Google Scholar In a report by Mebis et al,20Mebis J. Goossens H. Bruyneel P. et al.Decreasing antibiotic resistance of Enterobacteriaceae by introducing a new antibiotic combination therapy for neutropenic fever patients.Leukemia. 1998; 12: 1627-1629Crossref PubMed Scopus (53) Google Scholar the empiric use of ceftazidime for febrile neutropenia corresponded to significant increases in inducible Enterobacteriaceae and 75% reduction in ceftazidime susceptibility. The removal of ceftazidime from the initial empiric protocol was accompanied by dramatic reductions in cephalosporin resistance rates. Similar concerns apply to the management of PD-related peritonitis. The empiric use of ceftazidime equates to broad systemic antibiotic exposure with significant potential for the induction and selection of resistance. The potential consequences are more serious and difficult-to-treat infections in an already high-risk patient population. Peritonitis is a serious complication that accounts for significant antibiotic use in PD patients. The ISPD treatment guidelines, last updated in 2000, are a valuable resource that broadly impact clinical practice and patient care. New information and practical issues highlighted in this report warrant consideration in future decisions and recommendations regarding empiric therapy for PD-related peritonitis.