Treatment of Peritoneal Dialysis–Associated Peritonitis: A Systematic Review of Randomized Controlled Trials Kathryn J. Wiggins, MBBS,1 David W. Johnson, PhD, MBBS,1 Jonathan C. Craig, PhD, MBChB,2 and Giovanni F.M. Strippoli, MD, MPH, MM(Epi)2,3 Background: Peritonitis frequently complicates peritoneal dialysis. Appropriate treatment is essential to reduce adverse outcomes. Available trial evidence about peritoneal dialysis peritonitis treatment was evaluated. Selection Criteria for Studies: The Cochrane CENTRAL Registry (2005 issue), MEDLINE (1966 to February 2006), EMBASE (1985 to February 2006), and reference lists were searched to identify randomized trials of treatments for patients with peritoneal dialysis peritonitis. Interventions: Trials of antibiotics (comparisons of routes, agents, and dosing regimens), fibrinolytic agents, peritoneal lavage, and intraperitoneal immunoglobulin. Outcomes: Treatment failure, relapse, catheter removal, microbiological eradication, hospitalization, all-cause mortality, and adverse reactions. Results: 36 eligible trials were identified: 30 trials (1,800 patients) of antibiotics; 4 trials (229 patients) of urokinase; 1 trial of peritoneal lavage (36 patients); and 1 trial of intraperitoneal immunoglobulin (24 patients). No superior antimicrobial class was identified. In particular, glycopeptides and first-generation cephalosporins were equivalent (3 trials, 387 patients; relative risk [RR], 1.84; 95% confidence interval [CI], 0.95 to 3.58). Simultaneous catheter removal/replacement was superior to urokinase at decreasing treatment failures (1 trial, 37 patients; RR, 2.35; 95% CI, 1.13 to 4.91). Continuous and intermittent intraperitoneal antibiotic dosing were equivalent regarding treatment failure (4 trials, 338 patients; RR, 0.69; 95% CI, 0.37 to 1.30) and relapse (4 trials, 324 patients; RR, 0.93; 95% CI, 0.63 to 1.39). One trial showed superiority of intraperitoneal antibiotics over intravenous therapy. Limitations: The method quality of trials generally was suboptimal and outcome definitions were inconsistent. Small patient numbers led to inadequate power to show an effect. Interventions, such as optimal duration of antibiotic therapy, were not evaluated. Conclusions: Trials did not identify superior antibiotic regimens. Intermittent and continuous antibiotic dosing are equivalent treatment strategies. Am J Kidney Dis 50:967-988. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Antimicrobial agents; peritoneal dialysis; peritoneal lavage; peritonitis; urokinase.
P
eritoneal dialysis (PD) is an effective form of renal replacement therapy. However, it continues to be complicated by peritonitis1 despite the introduction of such preventative strategies as disconnect and double-bag systems.2-4 The incidence of peritonitis varies from 1 episode/9 to 53 patient-months.5,6 Risk factors for its development include diabetes mellitus,7 race,8,9 obesity,10 temperate climate,11,12 and depression.13 Additionally, some studies showed PD modality to influence peritonitis rates, although other studies did not confirm this.14,15 PD-associated peritonitis results in significant morbidity and, not uncommonly, catheter removal. Ultrafiltration failure can occur both acutely16,17 and in the longer term, resulting in technique failure.18,19 Peritonitis is prevalent in patients with encapsulating sclerosing peritonitis and may be a causal factor.20,21 In some patient groups, peritonitis increases overall mortality rates.22
Early and effective management of peritonitis decreases the risk of adverse outcomes, including catheter removal,23 and increases the use of PD.24 The mainstay of treatment is antimicrobial therapy, although adjunctive therapies, including fibrinolytic agents,25,26 peritoneal lavage,27 and routine early catheter removal, have been used. From the 1Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane; 2 Centre for Kidney Research, NHMRC Centre for Clinical Research Excellence in Renal Medicine, Cochrane Renal Group, Children’s Hospital at Westmead, School of Public Health, University of Sydney, Australia; and 3Mario Negri Sud Consortium, Santa Maria Imbaro (Ch), Italy. Received April 10, 2007. Accepted in revised form August 23, 2007. Address correspondence to Kathryn J. Wiggins, MBBS(Hons), Department of Nephrology, St Vincent’s Hospital, PO Box 2900, Fitzroy, Victoria 3065, Australia. E-mail:
[email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/5006-0010$32.00/0 doi:10.1053/j.ajkd.2007.08.015
American Journal of Kidney Diseases, Vol 50, No 6 (December), 2007: pp 967-988
967
968
Wiggins et al
Current guidelines recommend the use of antibiotics that cover gram-positive and gramnegative organisms in patients with peritonitis.28,29 However, several questions about the optimal treatment of patients with PD-associated peritonitis are unanswered. In particular, the choice, route of administration,30 and duration of antimicrobial therapy are debated. Many treatment regimens are based on continuous ambulatory PD (CAPD), and their applicability to automated PD (APD) is uncertain.31 To explore existing uncertainties in this area, we performed a systematic review of randomized controlled trial (RCT) evidence examining the effectiveness of all treatment options that were the subject of RCTs and are currently used for PD-associated peritonitis.
Validity Assessment Results of searches were analyzed in title and abstract form by 2 authors according to the inclusion criteria (K.W., G.F.M.S.). Reference lists from identified articles, reviews, and guidelines then were searched. Any differences and problems in data extraction were resolved by discussion among authors. When data were missing or incomplete, the investigators of the trial were contacted for clarification. The method quality of included trials was assessed by using standard criteria (allocation concealment; blinding of participants, investigators, and outcome assessors; analysis by intention to treat; and completeness of follow-up).
Data Abstraction Each trial was assessed by 2 independent reviewers (K.W., G.F.M.S.). From all included trials, data were extracted about characteristics of the study sample, type of peritonitis treatment, methods and characteristics of the trial, and outcomes.
Study Characteristics METHODS Searches Electronic searches were performed in MEDLINE (1966 to January 2006), EMBASE (1988 to January 2006), and the Cochrane Renal Group Specialist Register of RCTs (2005 issue) using optimally sensitive search strategies for the identification of RCTs developed by the Cochrane Collaboration. The Cochrane Renal Group’s Specialised Register contains hand-searched results performed by trial search coordinators of the Cochrane Renal Group and Renal Health Library of conference proceedings from general and specialty meetings from 1995 onward. Therefore, conference proceedings were not specifically searched manually. Reference lists from guidelines, review articles, and relevant trials also were searched. For unpublished studies, additional information was sought from the investigators. The following medical subject terms and text words were used: peritoneal dialysis, PD, CAPD, continuous cycling peritoneal dialysis, peritonitis, peritoneum, infection, bacterial infections, and mycoses. Trials were considered without language restriction.
Selection All available RCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by predictable methods, including alternation, use of alternate medical records, date of birth, or other) comparing the effects of any interventions for the treatment of patients with PD-associated peritonitis were considered. Specifically, RCTs of the following subjects were included: administration of an antibiotic(s) by different routes; comparisons of different classes and combinations of antibiotics; high versus low dose of an antibiotic(s); different frequencies of antibiotic administration; and any other intervention, including fibrinolytic agents and peritoneal lavage; intraperitoneal (IP) immunoglobulin, and early catheter removal.
The following outcomes were considered: peritonitis treatment failure (failure to achieve a clinical response, defined as resolution of symptoms and signs), relapse (recurrence of peritonitis caused by the same organism with the same antibiotic sensitivities within 28 days of completing treatment), time to peritonitis relapse (days from completion of treatment), death from peritonitis, all-cause mortality, need to change antibiotic(s) after culture results, catheter removal and/or replacement, hospitalization duration and rate (number of patients hospitalized per episode of peritonitis), technique failure (transfer from PD to hemodialysis therapy because of peritonitis), and treatment toxicity.
Quantitative Data Synthesis Results of individual trials are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for all categorical outcomes. Data were pooled using a Der Simonian-Laird random-effects model, but the fixed-effects model was also evaluated to ensure robustness of the model chosen and susceptibility to outliers. When continuous scales of measurement were used to assess effects of treatment, weighted mean difference was used. Heterogeneity was analyzed by using a -square test with N ⫺ 1 df (Cochran Q statistic), with ␣ of 0.05 used for statistical significance and the I2 statistic.32 Subgroup analysis was planned to explore how possible sources of heterogeneity (pediatric versus adult population, age, sex, cause of end-stage renal disease, body mass index, duration of dialysis, PD modality [CAPD versus APD], previous peritonitis episodes, type of dialysate, and microorganism isolated) might influence treatment effect.
RESULTS
Trial Flow
Overall, 1,681 reports were retrieved electronically, of which 1,617 were excluded at title and abstract assessment stage. Analysis of the remaining 67 studies by full text identified 36 trials
Treatments for Peritoneal Dialysis–Associated Peritonitis
969
Figure 1. Flow chart summarizes results of the literature review, included studies, and excluded studies. Abbreviation: RCT, randomized controlled trial.
(2,089 patients) published in 42 articles that were included in this review. Search results are shown in Fig 1.
229 patients), peritoneal lavage27 (1 study, 36 patients), and IP immunoglobulin66 (1 study, 24 patients; Table 4).
Study Characteristics
Method Quality
Thirty studies (1,800 patients, 2,191 peritonitis episodes) considered the use of antibiotic agents. Twelve studies compared different routes of administration: IP versus intravenous (IV; 2 trials, 100 patients)33,34 and IP versus oral (10 trials, 535 patients).35-44 Study populations and interventions of these trials are listed in Table 1. Different IP antibiotic classes and/or combinations were tested head to head in 15 trials45-59 (Table 2). These included 3 trials (234 patients) comparing glycopeptides with first-generation cephalosporins.51,55,59 Four trials (274 patients) compared intermittent and continuous dosing53,60-62 (Table 3). There were 6 studies of adjunctive therapies, namely urokinase versus placebo63,64,26 or simultaneous catheter removal/replacement65 (4 trials,
Trial allocation methods and allocation concealment generally were incompletely reported and therefore difficult to assess. Allocation concealment was adequate in 7 trials (20%), only 4 trials (11%) blinded participants and investigators, and an intention-to-treat analysis was used in 14 trials (40%). Patients lost to follow-up ranged from 0% to 64.5%. Quality metrics of included studies are listed in Table 5. Quantitative Data Synthesis
Treatment Failure and Peritonitis Relapse IP Versus IV Antimicrobial Agents There was a statistically significant increase in the treatment failure rate for IV compared with IP vancomycin/
970
Wiggins et al
Table 1. Characteristics of Trials Comparing Different Routes of Antimicrobial Administration in the Treatment of Peritoneal Dialysis–Associated Peritonitis Study Population Demographics
Reference
Year
IV v IP (same antibiotic) 1987 Bailie et al34 Bennet-Jones et al33
1987
Location
Control Intervention
Sex (men:women)
Age (y)
Antibiotic
Dose
United Kingdom
NS
11:9
IP vancomycin
United Kingdom
NS
NS
IP vancomycin
LD, 1 g; MD, 25 mg/L dialysate 20 mg/L dialysate qid
IP tobramycin
4 mg/L dialysate qid
Discontinuation of 1 antibiotic after d 4 depending on culture and sensitivity results Oral v IP (same antibiotic) Boeschoten 1985 et al44 Cheng et al37
1993
The Netherlands
47 (21-66)
20:19
IP cephradine
LD, 500 mg; MD, 250 mg qid
Hong Kong
NS
NS
IP
LD, 200 mg; MD, 25 mg/L dialysate qid
ciprofloxacin
Cheng et al36
1997
Oral v IP (different antibiotic) Bennet-Jones 1990 et al35
Chan et al42
Cheng et al41
Cheng et al43
Gucek et al38 Lye et al
39
Tapson et al40
1990
1991
1998
Hong Kong multicenter
Control group, 51 (36-80) Treatment group, 51.5 (26-71)
Control group, 6:11 Treatment group, 11:7
IP ofloxacin
LD, 100 mg/L dialysate; MD, 25 mg/L dialysate qid
United Kingdom
NS
NS
IP vancomycin IP gentamicin
Hong Kong
Control group, 53 ⫾ 14 (SEM) Treatment group 1, 44 ⫾ 15 (SEM) Treatment group 2, 49 ⫾ 13 (SEM) NS
Control group, 21:15 Treatment group 1, 18:16 Treatment group 2, 22:14 NS
IP cephalothin
25 mg/L dialysate LD, 8 mg/L dialysate (48 h); MD, 4 mg/L dialysate 250 mg/L dialysate
IP tobramycin
8 mg/L dialysate
IP vancomycin
IP aztreonam
LD, 500 mg/L dialysate; MD, 30 mg/L dialysate 250 mg/L dialysate
IP vancomycin
500 mg-1 g d 1 and 7
IP netromycin
20 mg/L dialysate od
IP cephazolin
LD, 100 mg; MD, 250 mg qid LD, 1 g
Hong Kong multicenter
Hong Kong multicenter
1994
Slovenia
1993
Singapore
1990
United Kingdom
Control group, 56.6 ⫾ 11.0 Treatment group, 56.5 ⫾ 13.2 53.5 ⫾ 11
Control group, 29:25 Treatment group, 25:22 15:8
Control group, 59.0 ⫾ 12.0 (SEM) Treatment group, 61.6 ⫾ 8.5 (SEM) Control group, 55.3 (30-76) Treatment group, 58.8 (30-76)
Control group, 9:21 Treatment group, 11:19 NS
(Continued)
IP vancomycin IP gentamicin IP vancomycin IP netilmycin
LD, 80 mg; MD, 15 mg/2L dialysate qid 30 mg qid 30 mg to alternate exchanges
Treatments for Peritoneal Dialysis–Associated Peritonitis
971
Table 1 (Cont’d). Characteristics of Trials Comparing Different Routes of Antimicrobial Administration in the Treatment of Peritoneal Dialysis–Associated Peritonitis Experimental Intervention Antibiotic
Dose
IV vancomyin
No. of Patients/ No. of Peritonitis Episodes
Duration of Treatment (d)
Follow-Up (d)
Outcomes Reported
LD, 1 g IV; MD, 25 mg/L dialysate IP IV vancomycin LD, 0.5 g (BSA ⬍1.73 m2) or 1.0 g (BSA ⬎ 1.73 m2); MD, 0.5 g d 6 IV tobramycin LD, 1.0 mg/kg; MD, 20-60 mg d 2, 4, or 6 depending on serum levels PO therapy d 4 depending on culture and sensitivity results
20/20
14
NS
Treatment failure Adverse effects Treatment failure Adverse effects
80/80
10
NS
PO cephradine
LD, 500 mg; MD, 250 mg qid
39/84
PO ciprofloxacin
750 mg bd
46/54
Until 1 wk after dialysate WCC ⬍ 100/L & negative culture 10
2 wk after completion of treatment NS
PO ofloxacin
LD, 400 mg; MD, 300 mg od
35/36
10
28
PO ciprofloxacin
LD, 750 mg tds (24 h); MD, 750 mg bd
51/51
10
28
Treatment failure Relapse Adverse effects
PO ofloxacin PO rifampicin (n ⫽ 36 only)
LD, 400 mg; MD, 300 mg od 300 mg od
106/117
10
28
Treatment failure Catheter removal Adverse effects
PO ofloxacin
LD, 400 mg; MD, 300 mg od
46/46
10
28
IP vancomycin PO levofloxacin
500 mg-1 g d 1 and 7 300 mg od
101/101
10
28
Treatment failure Relapse Hospitalization rate and duration All-cause mortality Adverse effects Treatment failure Relapse
PO ofloxacin
LD, 300 mg; MD, 200 mg od
23/23
10
NS
Treatment failure
IP vancomycin
1gd1
60/60
14
14
PO pefloxacin
400 mg bd
PO ciprofloxacin
500 mg qid
50/50
10
28
Treatment failure Relapse Catheter removal Adverse effects Treatment failure Relapse Microbiological eradication Adverse effects
Treatment failure
Treatment failure Relapse Catheter removal Hospitalization rate and duration Microbiological eradication Treatment failure Relapse
Note: Age expressed as mean ⫾ SD or mean (range) unless specified otherwise. Abbreviations: IP, intraperitoneal; IV, intravenous; LD, loading dose; MD, maintenance dose; PO, oral; NS, not specified; SEM, standard error of the mean; bd, twice daily; od, once daily; qid, 4 times daily; BSA, body surface area; WCC, white cell count; tds, three times daily.
972
Wiggins et al
Table 2. Characteristics of Trials Comparing Different Regimens of IP Antimicrobial Agents in the Treatment of Peritoneal Dialysis–Associated Peritonitis Study Population Demographics
Reference
Year
Age (y)
Sex (men:women)
Control group, 47.1 ⫾ 2.6 (SEM) Treatment group, 42.8 ⫾ 2.1 (SEM) 48 (26-74)
Control group, 51% men Treatment group, 46% men 17:13
Control group, 66.7 ⫾ 12 Treatment group, 66.9 ⫾ 13
Control group, 23:16 Treatment group, 13:16
United Kingdom
NS
NS
Vancomycin
Germany multicenter
11.4 (0.7-21.8)
NS
Vancomycin
Location
Glycopeptide v first-generation cephalosporin 1991 United States Flanigan and Lim51
Khairullah et al55
2002
United States
Lupo et al59
1997
Italy multicenter
Vancomycin v teicoplanin Bowley et al45 1998 Schaefer et al53
1999
Control Intervention
Antibiotic
Vancomycin
25 mg/L dialysate
Vancomycin
1 g/L dialysate d 1 & 5 or 8 40 mg od LD, 400 mg IV; MD, 40 mg qid LD, 120 mg IM; MD, 10 mg qid
Gentamicin Teicoplanin Tobramycin
Ceftazidime
Other antibiotic combinations tested head to head Anwar et al54* 1995 United Kingdom
Anwar et al54*
1995
United Kingdom
Intervention
Control group, 55.0 ⫾ 2.5 Treatment group, 49.4 ⫾ 3.0
Control group, 16:14 Treatment group, 17:13
Vancomcyin
Control group, 55.0 ⫾ 2.5 Treatment group, 49.4 ⫾ 3.0
Control group, 16:14 Treatment group, 17:13
Imipenem Vancomcyin
Netilmycin
Netilmycin
LD, 50 mg qid (48 h); MD, 25 mg qid LD, 15 mg/kg; MD, 30 mg/L dialysate qid or 30 mg/kg d 1 & 7 LD, 250 mg/L dialysate; MD, 125 mg/L dialysate qid or LD, 500 mg/L dialysate; MD, 250 mg/L dialysate od LD, 250 mg; MD, 25 mg bd LD, 30-50 mg; MD, 20-25 mg bd 1 g bd LD, 250 mg; MD, 25 mg bd LD, 30-50 mg;MD, 20-25 mg bd 250 mg/L dialysate qid
De Fijter et al56
2001
The Netherlands
Control group, 56.9 (22-76) Treatment group, 61.2 (28-76)
Control group, 24:30 Treatment group, 26:18
Cephradine
Friedland et al46
1990
United Kingdom
Control group, (2277) Treatment group, (47-79)
Control group, 13:7 Treatment group, 11:9
Vancomycin
12.5 mg/L dialysate qid
Gentamicin
4 mg/L dialysate bd
Gucek et al47
1997
Slovenia
57.2 ⫾ 13.6
NS
Vancomycin Ceftazidime
2 g every 5-7 d LD, 1 g; MD, 250 mg qid
Jimenez et al48
1996
Spain
NS
NS
Vancomycin Tobramycin
NS NS
Leung et al57
2004
Hong Kong
Control group, 57.1 ⫾ 12.2 Treatment group, 61.0 ⫾ 12.2
Control group, 25:26 Treatment group, 26:25
Cefazolin
LD, 1 g; MD, 250 mg/ 2 L dialysate LD, 1 g; MD, 250 mg/ 2 L dialysate
(Continued)
Ceftazidime
Treatments for Peritoneal Dialysis–Associated Peritonitis
973
Table 2 (Cont’d). Characteristics of Trials Comparing Different Regimens of IP Antimicrobial Agents in the Treatment of Peritoneal Dialysis–Associated Peritonitis Experimental Intervention
Antibiotic
Intervention
Cephazolin
50 mg/L dialysate
Cephazolin
LD, 1 g; MD, 125 mg/L dialysate qid 40 mg od LD, 2 g IV; MD, 500 mg bd
Gentamicin Cephalothin Tobramycin
LD, 120 mg IM; MD, 10 mg qid
Teicoplanin
LD, 50 mg qid (48 h); MD, 25 mg qid LD, 7.5 mg/kg; MD, 20 mg/L dialysate qid or 15 mg/kg d 1 & 7
Teicoplanin
No. of Patients/ No. of Peritonitis Episodes
Duration of Treatment (d)
Follow-Up (d)
131/263
14
14
Treatment failure Relapse Catheter removal
30/51
14-21
NS
68/68
21
28
Treatment failure Relapse Catheter removal Treatment failure Relapse Microbiological eradication Adverse effects
11/12
7
NS
90/195
10
60/60
Until 5 d after dialysate cleared and WCC ⬍ 100/L
14
Treatment failure Relapse Catheter removal Seizures
98/98
14
28
Treatment failure Relapse Catheter removal Microbiological eradication Adverse effects Treatment failure Relapse Catheter removal Adverse effects Technique failure Treatment failure
Median, 19 mo
Ceftazidime
LD, 250 mg/L dialysate; MD, 125 mg/L dialysate qid or LD, 500 mg/L dialysate; MD, 250 mg/L dialysate od
Imipenem
1 g bd; changed to 0.5 g bd midstudy
Imipenem Vancomcyin
Ciprofloxacin
0.5 mg bd LD, 250 mg; MD, 25 mg bd LD, 30-50 mg; MD, 2025 mg bd 50 mg/L dialysate qid
Rifampicin
50 mg/L dialysate qid
Ciprofloxacin
20 mg/L dialysate qid
40/40
10
28
Cephazolin
34/52
14-28
NS
Vancomycin
LD, 500 mg; MD, 250 mg qid LD, 80-120 mg; MD, 40 mg od NS
47/47
NS
NS
Cefotaxime
NS
Imipenem
LD, 500 mg; MD, 100 mg/2 L dialysate qid
102/102
Up to 21 d
120
Netilmycin
Netilmycin
(Continued)
Outcomes Reported
Treatment failure Relapse Treatment failure Relapse Decrease in residual renal function Adverse effects
Treatment failure Relapse Catheter removal Treatment failure Catheter removal
974
Wiggins et al Table 2 (Cont’d). Characteristics of Trials Comparing Different Regimens of IP Antimicrobial Agents in the Treatment of Peritoneal Dialysis–Associated Peritonitis Study Population Demographics
Reference Lui et al58
Wale et al49
Year 2005
1992
Age (y)
Sex (men:women)
Control group, 63.7 ⫾ 14.6 Treatment group, 66.7 ⫾ 12.2
Control group, 29:23 Treatment group, 26:26
Cefazolin
1 g/2 L dialysate daily
Netilmycin
0.6 mg/kg/d
Control group, 54.7 Treatment group, 51.3
Control group, 15:15 Treatment group, 19:11
Teicoplanin
20 mg/L dialysate qid 250 mg/L dialysate qid
Location Hong Kong
United Kingdom
Control Intervention
Antibiotic
Aztreonam
Intervention
Were et al50
1992
United Kingdom
NS
NS
Vancomycin Netilmycin
50 mg bd LD, 50 mg; MD, 25 mg bd
Wong et al52
2001
Hong Kong
Control group, 59 ⫾ 10 Treatment group, 58 ⫾ 14
Control group, 18:16 Treatment group, 23:16
Vancomycin Netilmycin
1gd1&7 LD, 80 mg; MD, 40 mg od
(Continued)
tobramycin (1 trial, 80 patients; RR, 3.52; 95% CI, 1.26 to 9.81).33
Oral Versus IP Administration (different antibiotics)
Oral Versus IP Administration (same antibiotic) Oral administration of quinolone antibiotics (ciprofloxacin and ofloxacin) was not associated with a statistically significant difference in treatment failures compared with IP administration (2 trials, 80 patients; RR, 1.66; 95% CI, 0.98 to 2.83).36,37 Treatment failure rates were high in both arms of these studies (52.4% and 31.7% in the oral and IP groups, respectively). There was no statistically significant difference in relapse (2 trials, 80 patients; RR, 3.38; 95% CI, 0.74 to 15.35)36,37 or catheter removal rates (1 trial, 48 patients; RR, 2.00; 95% CI, 0.19 to 20.61).37 However, low precision and point estimates favored IP therapy.
Oral compared with IP antibiotic regimens were not associated with a statistically significant difference in treatment failure rates (7 trials, 451 patients; RR, 1.17; 95% CI, 0.86 to 1.59).35,38-43 Subgroup analysis showed this to be applicable to IP aminoglycoside/glycopeptide combinations (5 trials, 303 patients; RR, 1.22; 95% CI, 0.85 to 1.75)35,39-41,43 and IP cephalosporins (2 trials, 148 patients; RR, 1.05; 95% CI, 0.58 to 1.90).38,42 There was no significant statistical heterogeneity for this outcome (-square ⫽ 2.12; P ⫽ 0.9; I2 ⫽ 0%). Microbiological eradication and relapse rates were similar in both groups (1 trial, 39 patients; RR, 1.26; 95% CI, 0.46 to 3.4640; 5 trials, 303 episodes; RR, 1.17; 95% CI, 0.63 to 2.14,35,39-41,43 respectively; Fig 2).
Treatments for Peritoneal Dialysis–Associated Peritonitis
975
Table 2 (Cont’d). Characteristics of Trials Comparing Different Regimens of IP Antimicrobial Agents in the Treatment of Peritoneal Dialysis–Associated Peritonitis Experimental Intervention Antibiotic
Intervention
No. of Patients/ No. of Peritonitis Episodes
Duration of Treatment (d)
Follow-Up (d) 42
Cefazolin Ceftazidime
1 g/2 L dialysate daily 1 g/2 L dialysate daily
104/104
14
Cefuroxime
125 mg/L dialysate qid
60/60
Cefuroxime
40 mg/L dialysate qid
20/20
Minimum 10; 5 from clearing of dialysate 5 from clearing of dialysate
Cefepime
LD, 2 g; MD, 1 g od
73/73
10
6 mo
14
28
Outcomes Reported Treatment failure Relapse Catheter removal Decrease in residual renal function Treatment failure Relapse All-cause mortality Treatment failure Catheter removal All-cause mortality Treatment failure Relapse Hospitalization Adverse events All-cause mortality
Note: Antibiotics were administered by the IP route unless specified otherwise. Age expressed as mean ⫾ SD or mean (range) unless specified otherwise. Abbreviations: SEM, standard error of the mean; LD, loading dose; MD, maintenance dose; bd, twice daily; od, once daily; qid, 4 times daily; NS, not specified; IP, intraperitoneal; IV, intravenous; IM, intramuscular; WCC, white cell count. *Imipenem dose changed midstudy because of a high number of seizures in the imipenem group.
Comparison of Different Regimens of Oral Antibiotics There were no statistically significant differences between oral rifampicin and ofloxacin compared with oral ofloxacin alone for treatment failure (1 trial, 74 episodes; RR, 0.88; 95% CI, 0.35 to 2.17), microbiological eradication (1 trial, 74 episodes; RR, 0.33; 95% CI, 0.04 to 3.06), and catheter removal (1 trial, 74 episodes; RR, 2.00; 95% CI, 0.19 to 21.11).42 Tests for statistical heterogeneity were not applicable considering that these aspects were explored by only individual trials. IP Glycopeptide (Vancomycin or Teicoplanin) Versus First-Generation Cephalosporin-Based Regimens The risk of treatment failure was greater for cephazolin than vancomycin (2 trials, 305 patients; RR, 1.67; 95%, CI 1.10 to 2.55)51,55 and cephalothin than teicoplanin (1 trial, 55 patients; RR, 4.63; 95% CI, 1.04 to 20.58).59 However, on combined analysis, cephalosporins were not significantly inferior to glycopeptides (3 trials, 370
patients; RR, 1.84; 95% CI, 0.95 to 3.58). There was no significant statistical heterogeneity among these trials (Fig 3). IP Vancomycin Versus Teicoplanin-Based Regimen Vancomycin was not significantly superior to teicoplanin at decreasing treatment failure (2 trials, 178 patients; RR, 1.08; 95% CI, 0.37 to 3.12)45,53 or relapse rates (2 trials, 178 episodes; RR, 0.93; 95%, CI 0.53 to 1.64).45,53 There was no significant statistical heterogeneity associated with either of these outcomes. Other IP Antibiotics Compared Head to Head Of the other 10 trials in which different combinations of IP antibiotics were compared head to head, the only statistically significant outcome was that rifampicin/ciprofloxacin was superior to cephradine at decreasing treatment failure (1 trial, 98 patients; RR, 0.50; 95% CI, 0.28 to 0.89).56 Results of individual trials are listed in Table 6.
976
Wiggins et al
Table 3. Characteristics of Trials Comparing Intermittent and Continuous Administration of Intraperitoneal Antimicrobial Agents in the Treatment of Peritoneal Dialysis–Associated Peritonitis Study Population Demographics Reference
Year
Location
Age (y)
Sex (men:women)
Continuous Dosing Antibiotic
Dose
Boyce et al62
1988 Australia
NS
NS
Vancomycin
Lye et al60
1995 Singapore
Control group, 56.6 ⫾ 11.7 Treatment group, 59.6 ⫾ 13.1 11.4 (0.7-21.8)
Control group, 14:22 Treatment group, 16:21 NS
Gentamicin
LD, 1 g; MD, 30 mg/L dialysate qid 10 mg/2 L dialysate qid
Vancomycin
1g
Ceftazidime
LD, 250 mg/L dialysate; MD, 125 mg/L dialysate qid LD, 15 mg/kg; MD, 30 mg/L dialysate qid LD, 7.5 mg/kg; MD, 20 mg/L dialysate qid LD, 500 mg/L dialysate for 6 h; MD, 15 mg/L dialysate qid
Schaefer et al53
1999 Germany multicenter
Vancomycin or Teicoplanin Velasquez-Jones et al61
1995 Mexico
(8-17)
11:10
Vancomycin
(Continued)
High-Dose Versus Low-Dose Antibiotic Low-dose imipenem (total, 1 g/d IP) was associated with a significant increase in treatment failure and relapse rates compared with highdose imipenem (2 g/d IP; 1 trial, 28 patients; RR, 4.00; 95% CI, 1.17 to 13.66; RR, 12.00; 95% CI, 1.60 to 90.23, respectively).54 Intermittent Versus Continuous IP Antibiotics The treatment failure rate was no worse with intermittent than continuous dosing (4 trials, 338 patients; RR, 0.69; 95% CI, 0.37 to 1.30).53,60-62 Relapse rates (19.9% versus 20.9%) also were similar between groups (4 trials, 324 patients; RR, 0.93; 95% CI, 0.63 to 1.39)53,60-62 (Fig 4). Fibrinolytic Agents There was increased treatment failure with urokinase compared with catheter removal/ replacement (1 trial, 37 patients; RR, 2.35; 95% CI, 1.13 to 4.91)65 and relapse (1 trial, 37 patients; RR, 2.35; 95% CI, 1.13 to 4.91).65 Urokinase was no more effective than placebo at decreasing treatment failure and relapse rates.26,63,64 Catheter removal was not decreased by urokinase treatment compared with placebo (2 trials, 168 patients; RR, 0.70; 95% CI, 0.37 to 1.30)63,64 (Fig 5).
Peritoneal Lavage There was no statistically significant decrease in treatment failures with a 24-hour period of peritoneal lavage compared with no lavage (1 trial, 36 patients; RR, 2.50; 95% CI, 0.56 to 11.25).27 Lavage had no significant effect on technique failure (1 trial, 36 patients; RR, 3.00; 95% CI, 0.13 to 69.09).27 Again, tests for heterogeneity were not applicable because these aspects were explored by only individual trials. IP Immunoglobulin Use of IP immunoglobulin was associated with a statistically significant decrease in time for the dialysate white blood cell count to decrease to less than 100 cells/mL (1 trial, 24 episodes; weighted mean difference, ⫺7.30; 95% CI, ⫺8.12 to ⫺6.48).66 There were no treatment failures or relapses in any patient in this trial. Other Outcomes
Other outcomes were assessed in a small number of trials. These results are listed in Table 7. The only statistically significant finding was an increased rate of nausea and vomiting with oral compared with IP antibiotics (3 trials; RR, 9.14; 95% CI, 1.73 to 48.32).35,39,40 Of note, highdose imipenem was not associated with a statistically significant increase in number of seizures
Treatments for Peritoneal Dialysis–Associated Peritonitis
977
Table 3 (Cont’d). Characteristics of Trials Comparing Intermittent and Continuous Administration of Intraperitoneal Antimicrobial Agents in the Treatment of Peritoneal Dialysis–Associated Peritonitis Intermittent Dosing Antibiotic
Dose
No. of Patients/ No. of Peritonitis Episodes
Duration of Treatment (d)
Vancomycin
30 mg/kg d 1 & 8
90/90
Gentamicin Vancomycin
40 mg od 1g
73/100
5 from clearing of dialysate 14
Ceftazidime
LD, 500 mg/L dialysate; MD, 250mg/L dialysate od 30 mg/kg d 1 & 7
90/195
10
21/21
10
Vancomycin or Teicoplanin Vancomycin
15 mg/kg d 1& 7 30 mg/kg d 1 & 7
Follow-Up (d)
28 14
Median, 19 mo
Outcomes Reported
Treatment failure Relapse Treatment failure Relapse
Treatment failure Relapse Adverse effects Decrease in residual renal function Treatment failure Relapse
Note: Antibiotics administered by the intraperitoneal route unless specified otherwise. Age expressed as mean ⫾ SD or mean (range) unless specified otherwise. Abbreviations: LD, loading dose; MD, maintenance dose; od, once daily; qid, 4 times daily; NS, not specified.
(1 trial; RR, 0.60; 95% CI, 0.03 to 11.23).54 However, in the trial considering this outcome, the study protocol was modified midstudy from high-dose to low-dose imipenem because of several seizures in the high-dose group. DISCUSSION
We found that intermittent and continuous dosing of vancomycin, gentamicin, ceftazidime, and teicoplanin were equivalent in the treatment of patients with peritonitis, simultaneous catheter removal/replacement was superior to urokinase in relapsing and remitting PD-associated peritonitis, and IP antibiotics were more effective than IV therapy. Other clinically relevant findings of this systematic review were that most antibiotic classes tested in RCTs had similar efficacy rates, available trial evidence did not clearly show superiority of glycopeptide-based antibiotic regimens to first-generation cephalosporins, and peritoneal lavage did not improve response rates to concomitant antibiotic therapy. We also found that IP immunoglobulin decreased the time for the dialysate white blood cell count to decrease, but did not show a difference in treatment failure or relapse rates. Finally, our review showed a paucity of evidence underlying
many widely used and accepted practices in the treatment of patients with peritonitis, a condition associated with significant patient morbidity and, on occasion, mortality. Consequently, we are uncertain about some aspects of treatment, such as duration of antibiotic therapy and optimal timing of catheter removal. To our knowledge, this is the first systematic review of RCTs of all treatments for patients with PD-associated peritonitis. A review of antimicrobial treatment of patients with PD-associated peritonitis published in 1991 concluded that the optimal empirical treatment was weekly vancomycin and ceftazidime.67 However, this review predated many trials included in our review and was not confined to RCTs. The mainstay of peritonitis treatment is timely administration of empirical antimicrobial agents that are likely to eradicate common causative agents. This is endorsed by guidelines of the International Society of Peritoneal Dialysis and the Australian and New Zealand Society of Nephrology, which both stated that treatment with broad-spectrum antibiotics designed to cover both gram-negative and gram-positive organisms should be initiated when peritonitis is suspected.28,29 Because of insufficient evidence, nei-
978
Wiggins et al Table 4. Characteristics of Trials Comparing Nonantimicrobial Interventions With Placebo or Standard Treatment Study Population Demographics Reference
Year
Location
Fibrinolytic agents Innes et al26
1994
United Kingdom
Median, 57 (32-76)
14:10
Placebo (5 mL normal saline)
Gadallah et al63
2000
United States
Control group, 48.2 ⫾ 3.3 (SEM) Treatment group, 45.1 ⫾ 12.8 (SEM)
Control group, 18:22 Treatment group, 19:21
No urokinase
Tong et al64
2005
China
Control group, 58.5 ⫾ 12.8 Treatment group, 57.3 ⫾ 13.1
Control group, 18:26 Treatment group, 23:21
Placebo (20 mL normal saline)
Williams et al65
1989
United Kingdom multicenter
Control group, 54.1 ⫾ 4.0 Treatment group, 52.1 ⫾ 4.2
Control group, 11:9 Treatment group, 10:7
Simultaneous catheter removal and replacement
Peritoneal lavage Ejlersen et al27
1991
Denmark
NS
NS
2 rapid flush exchanges
Control group, 53.2 ⫾ 7.6 Treatment group, 52.6 ⫾ 5.9
Control group, 7:5 Treatment group, 6:6
Intraperitoneal immunoglobulin Coban et al66 2004 Turkey
Age (y)
Sex (men:women)
Control Intervention
(Continued)
ther group was able to suggest more specific agents. This is supported by the finding in our review that in 21 trials comparing different antibiotic classes, treatment failure rates were generally in the range of 10% to 30%, and only 2 studies showed a substantial difference between treatment arms.51,56 In both cases, applicability to current practice was low. De Fijter et al56 found IP ciprofloxacin/rifampicin to be superior to IP cephradine. However, monotherapy with a first-generation cephalosporin is uncommon in
clinical practice and was associated in this case with a low response rate of 50%. Furthermore, the broad-spectrum action of both ciprofloxacin and rifampicin predisposes to emergence of multiresistant organisms, thereby reducing their desirability as empirical agents. A meta-analysis of 2 trials comparing IP cephazolin and vancomycin found vancomycin to be superior. However, this result was influenced strongly by a larger number of patients in the trial by Flanigan and Lim,51 in which the cephazolin dose (50 mg/L)
Treatments for Peritoneal Dialysis–Associated Peritonitis
979
Table 4 (Cont’d). Characteristics of Trials Comparing Nonantimicrobial Interventions With Placebo or Standard Treatment
Experimental Intervention
IP Antibiotic Therapy
Urokinase, 5,000 Ploug units* diluted in 5 mL of normal saline Urokinase, 5,000 IU diluted in 2.5 mL of normal saline; 4-h dwell time
Determined by culture and sensitivity results Empirical IP vancomycin and gentamicin; later adjusted according to culture and sensitivity results Empirical IP cephazolin and netilmycin; later adjusted according to culture and sensitivity results Determined by culture and sensitivity results
Urokinase, 60,000 IU IP diluted in 20 mL of normal saline
Urokinase, 5,000 IU in 2 mL saline into the Tenckhoff catheter; 2-h dwell. Repeated d 2 and 4
No. of Patients
Duration of Treatment (d)
24
14
28 d
Treatment failure
80
Unclear
6 mo
Relapse Catheter removal Duration of peritonitis Severity of symptoms
88
Unclear
28 d
37
10
3-12 mo
Treatment failure Relapse Catheter removal Death from peritonitis Hospitalization duration Treatment failure Relapse Catheter removal Adverse effects
Follow-Up (d)
Outcomes Reported
Rapid peritoneal lavage for 24 h (2-L exchanges, no dwell time, with 60 L dialysate containing 20 mg/L vancomycin and 10 mg/L netilmycin)
IP vancomycin: LD, 40 mg/L dialysate (first 2 exchanges); MD, 20 mg/L dialysate IP netilmycin, 10 mg/L dialysate
36
10
1 mo after cessation of antibiotic treatment
Treatment failure Relapse Time to resolution of peritonitis Adverse effects
2 mL (320 mg) IP immunoglobulin G with each exchange
IP
24
14
3 mo
Treatment failure Relapse Time to decrease in dialysate WCC Time until pain-free exchange
ampicillin/sulbactam, 1 g tds IP netilmycin: LD, 150 mg; MD, 50 mg od (added to night exchange)
Note: Age expressed as mean ⫾ SD or mean (range) unless specified otherwise. Abbreviations: SEM, standard error of the mean; IP, intraperitoneal; LD, loading dose; MD, maintenance dose; NS, not specified; WCC, white cell count; od, once daily; tds, three times daily. *1 Ploug unit is equivalent to 1.5 IU.
was 2.5 times less than that recommended in the International Society of Peritoneal Dialysis guidelines.28 Similar efficacy rates among several antibiotic regimens facilitates consideration of logistical factors and adverse-effect profiles when selecting antibiotics.68 The International Society of Peritoneal Dialysis guidelines stated there should be center-specific selection of agent(s) according to local causative microorganism and resistance
patterns.28 The impact of local microbial resistance on outcomes was apparent in 2 trials comparing oral and IP quinolone use.36,37 In these studies, response rates were low for both treatment arms (41.7% and 55.6% in the oral and 66.7% and 70.6% in the IP groups, respectively). Microorganism resistance to quinolones was the major cause of treatment failure, and previous quinolone exposure was a risk factor for infection with resistant microorganisms.
980
Wiggins et al Table 5. Quality Metrics of Included Studies Blinding
Reference
Year
Allocation Concealment
Participants
Trials of antibiotic therapy Comparison of different routes of antibiotic therapy Intravenous v intraperitoneal (same antibiotic) Bailie et al34 1987 Unclear No Bennet-Jones et al33 1987 Unclear No Oral v intraperitoneal (same antibiotic) Boeschoten et al44 1985 Inadequate No Cheng et al37 1993 Unclear No Cheng et al36 1997 Unclear No Oral v intraperitoneal (different antibiotic(s)) Bennet-Jones et al35 1990 Unclear No Chan et al42 1990 Unclear No Cheng et al41 1991 Adequate No Cheng et al43 1998 Adequate No Gucek et al38 1994 Unclear No Lye et al39 1993 Unclear No Tapson et al40 1990 Adequate No Comparisons of different regimens of antibiotic therapy Glycopeptide v first-generation cephalosporin Flanigan and Lim51 1991 Inadequate NS Khairullah et al55 2002 Inadequate No Lupo et al59 1997 Unclear NS Vancomycin v teicoplanin Bowley et al45 1998 Unclear NS Schaefer et al53 1999 Adequate No Other antibiotic combinations tested head to head Anwar et al54 1995 Unclear No De Fijter et al56 2001 Unclear No Friedland46 1990 Adequate No Gucek et al47 1997 Unclear NS Jimenez et al48 1996 Unclear Unclear Leung et al57 2004 Inadequate No Lui et al58 2005 Adequate No Wale et al49 1992 Unclear No Were et al50 1992 Unclear No Wong et al52 2001 Adequate No Comparisons of intermittent and continuous antibiotic dosing Boyce et al62 1988 Unclear No Lye et al60 1995 Inadequate No Velasquez-Jones et al61 1995 Inadequate No Trials of nonantimicrobial interventions Fibrinolytic agents Innes et al26 1994 Unclear Yes Gadallah et al63 2000 Inadequate No Tong et al64 2005 Unclear Yes Williams et al65 1989 Unclear No Peritoneal lavage Ejlersen et al27 1991 Unclear No Intraperitoneal immunoglobulin Coban et al66 2004 Inadequate No Note: Data for loss to follow-up expressed as number (percent). Abbreviation: NS, not stated.
Investigators
Outcome Assessors
Intentionto-Treat Analysis
Loss to FollowUp
No No
NS NS
Yes No
0/20 (0) 5/80 (6.3)
No No No
NS NS NS
No No No
45/106 (42.5) 6/54 (11.1) 8/36 (22.2)
No No No No No No No
NS NS NS NS NS NS NS
No No Yes Yes Yes Yes Yes
3/51 (5.8) 6/117 (5.1) 3/46 (6.5) 1/101 (1) 0/23 (0) 0/63 (0) 0/50 (0)
NS No NS
NS NS NS
No No No
0/263 (0) 9/51 (17.6) 8/73 (11.0)
NS No
NS NS
Yes Yes
0/11 (0) 98/152 (64.5)
No No No NS Unclear No No No No No
NS NS NS NS Unclear No No NS NS NS
Yes Yes Yes Yes Unclear Yes Yes Yes Yes No
4/60 (6.7) 5/98 (5.1) 0/40 (0) 0/34 (0) 0/24 (0) 1/102 (1) 2/102 (2) 7/60 (11.7) 0/20 (0) 8/81 (9.9)
No No No
NS NS NS
No Yes No
39/90 (43.3) 0/73 (0) 0/21 (0)
NS No Yes No
NS NS NS NS
Yes No Yes Yes
0/24 (0) 0/80 (0) 0/88 (0) 0/37 (0)
No
NS
No
0/36 (0)
No
NS
Yes
0/24 (0)
Treatments for Peritoneal Dialysis–Associated Peritonitis Figure 2. Forest plots for the outcomes of treatment failure, relapse, and catheter removal in trials in which intraperitoneal (IP) and oral (PO) regimens of different antibiotic agents were compared. For individual trials: filled-in square, relative risk (RR); lines, 95% confidence interval (CI); diamond plot, overall results of grouped analyses. Figures that cross the vertical line are not statistically significant. Abbreviations: n, number of patients reaching the outcome; N, total number of patients in the study arm.
981
982 Wiggins et al
Figure 3. Forest plots for the outcomes of treatment failure and relapse in trials in which intraperitoneal (IP) glycopeptide and first-generation cephalosporin antibiotic regimens were compared. For individual trials: filled-in square, relative risk (RR); lines, 95% confidence interval (CI); diamond plot, overall results of grouped analyses. Abbreviations: n, number of patients reaching the outcome; N, total number of patients in the study arm.
Treatments for Peritoneal Dialysis–Associated Peritonitis
983
Table 6. Results for the Outcomes of Treatment Failure, Relapse, and Catheter Removal of Trials in Which IP Antibiotic Regimens Were Tested Head to Head Treatment Failure 95% CI
Relapse RR
95% CI
Catheter Removal
Reference
Year
Intervention
RR
RR
95% CI
Anwar et al54 De Fijter et al56 Friedland et al46 Gucek et al47
1995 2001 1990 1997
1.40 0.50* 0.50 0.80
0.50-3.89 0.28-0.89 0.10-2.43 0.24-2.65
1.67 0.44-6.31 0.40 0.08-1.89 0.49 0.10-2.41 0.41 0.04-3.80 3.00 0.13-69.52 0.25 0.03-2.05 — — — —
Jimenez et al48
1996
0.94
0.49-1.83
0.62 0.25-1.51
0.72 0.31-1.67
Leung et al57 Lui et al58
2004 2005
0.96 1.06
0.65-1.42 0.62-1.81
— — 1.00 0.15-6.83
1.00 0.35-2.89 1.00 0.38-2.65
Wale et al49 Were et al50 Wong et al52
1992 1992 2001
Vancomycin/netilmycin v imipenem Cephradine v ciprofloxacin/rifampicin Vancomycin/gentamicin v ciprofloxacin Vancomycin/ceftazidime v cephazolin/ netilmycin Vancomycin/tobramycin v vancomycin/ cefotaxime Cephazolin/ceftazidime v imipenem Cephazolin/netilmycin v cephazolin/ ceftazidime Teicoplanin/aztreonam v cefuroxime Vancomycin/netilmycin v cefuroxime IP vancomycin/netilmycin v cefepime
1.40 5.00 1.20
0.50-3.92 1.02 0.68-1.54 0.70-35.50 — — 0.55-2.63 1.16 0.28-4.83
— — 0.33 0.02-7.32 — —
Abbreviations: RR, relative risk; CI, confidence interval; IP, intraperitoneal. *Statistically significant.
Initial antibiotic therapy often is administered IP because this theoretically achieves the greatest dialysate drug levels. However, in this review, we did not show a benefit of IP compared with oral therapy. This result may reflect small patient numbers and insufficient power to detect a difference. However, evidence from other studies about the relative importance of dialysate
antibiotic levels is unclear. A study of oral versus IP ciprofloxacin found that dialysate levels were lower in the IP group, but this did not affect patient outcomes.37 Baroonalertpaisarn et al69 reported that daily dosing of ceftazidime in patients with peritonitis led to serum levels greater than the minimum inhibitory concentration throughout 24 hours, whereas dialysate levels
Figure 4. Forest plots for the outcomes of treatment failure and relapse in trials in which intermittent and continuous intraperitoneal (IP) antibiotic administration were compared. For individual trials: filled-in square, relative risk (RR); lines, 95% confidence interval (CI); diamond plot, overall results of grouped analyses. Figures that cross the vertical line are not statistically significant. Abbreviations: n, number of patients reaching the outcome; N, total number of patients in the study arm.
984
Wiggins et al Table 7. Other Outcomes Evaluated in Trials of Treatment for Peritoneal Dialysis–Associated Peritonitis
Outcome Analyzed
No. of Studies Reporting Outcome
Trials of antimicrobial therapies Intravenous v IP antibiotics Rash Other adverse effects Oral v IP (same antibiotic) Hospitalization rate Nausea and vomiting Oral v IP (different antibiotic) Microbiological eradication Hospitalization rate All-cause mortality Nausea and vomiting Other adverse effects Comparison of oral antibiotic regimens Nausea Rash Glycopeptide v first-generation cephalosporin Microbiological eradication IP vancomycin/netilmycin v imipenem Convulsions IP cephradine v IP ciprofloxacin/rifampicin Rash Gastrointestinal activity IP teicoplanin/aztreonam v IP cefuroxime All-cause mortality IP vancomycin/netilmycin v IP cefuroxime Treatment failure Catheter removal IP vancomycin/netilmycin v IP cefepime Death due to peritonitis Hospitalization rate Infusion pain High- v low-dose antibiotic Seizures Intermittent v continuous antibiotics Rash Trials of fibrinolytic agents Hospitalization Death Trials of peritoneal lavage Technique failure Other adverse events Trials of IP immunoglobulin Time to decrease in dialysate WCC*
No. of Patients
RR
95% CI
1 1
20 92
5.00 3.90
0.27-92.62 0.45-33.60
1 1
48 48
1.00 0.50
0.51-1.95 0.05-5.15
1 1 1 3 2
39 45 46 158 98
1.26 0.70 0.36 9.14 2.03
0.45-3.46 0.30-1.63 0.02-8.46 1.73-48.32 0.13-31.17
1 1
74 74
3.00 3.00
0.13-71.34 0.13-71.34
1
45
0.83
0.62-1.13
1
60
5.00
0.25-99.95
1 1
98 98
0.41 0.61
0.02-9.76 0.06-6.55
1
47
0.19
0.01-3.80
1 1
20 20
5.00 0.33
0.70-35.50 0.02-7.32
1 1 1
73 73 73
0.75 2.63
not estimable 0.28-2.01 0.11-62.39
1
30
0.60
0.03-11.23
1
51
0.70
0.05-10.57
1 1
21 88
0.26 1.00
0.02-2.83 0.21-4.69
1 1
36 36
3.00 3.00
0.13-69.09 0.13-69.09
1
24
⫺7.30
⫺8.12 to ⫺6.48
Abbreviations: RR, relative risk; CI, confidence interval; IP, intraperitoneal; WCC, white cell count. *Weighted mean difference calculated instead of RR.
were less than the minimum inhibitory concentration for several hours on days 1 and 4. Despite this, the response rate was 90%. Benefits of intermittent (daily) dosing of antibiotics include facilitation of outpatient management and continuation of APD. In the general population, daily dosing of aminoglycosides decreased
ototoxicity.70 In this review, intermittent and continuous antibiotic dosing had similar outcomes. Adequate duration of antibiotic activity with daily dosing is facilitated by long drug half-lives. Studies of CAPD patients without peritonitis showed that serum and dialysate levels of several antibiotics remained at greater than the minimum inhibitory
Treatments for Peritoneal Dialysis–Associated Peritonitis
985
Figure 5. Forest plot for the outcome of treatment failure in trials in which urokinase was compared with simultaneous catheter removal/replacement or placebo. For individual trials: filled-in square, relative risk (RR); lines, 95% confidence interval (CI); diamond plot, overall results of grouped analyses. Figures that cross the vertical line are not statistically significant. Abbreviations: IP, intraperitoneal; PO, oral; n, number of patients reaching the outcome; N, total number of patients in the study arm.
concentration for up to 48 hours.71,72 Many drugs have peak serum levels 6 hours after administration, suggesting this should be the minimum dwell time. Postantibiotic effects of drugs also may contribute to the efficacy of intermittent dosing. The applicability of results from trials of intermittent drug therapy in CAPD to APD is unclear because drug half-lives are greater and clearances are more rapid in cycler compared with noncycler dwells.73 The high rate of complications arising from peritonitis despite rapid institution of antibiotic therapy suggests a need for adjuvant treatments. One such treatment is administration of IP urokinase; the rationale is to dissolve fibrin and allow access of antibiotics to entrapped bacteria.25 This treatment was considered in several trials that consistently showed no benefit compared with placebo or clear inferiority compared with catheter removal. Lack of effect may be caused by bacterial colonization of the catheter unrelated to fibrin entrapment. Peritoneal lavage potentially removes inflammatory cells and microorganisms from the peritoneal cavity while providing symptomatic relief and was used successfully in hemodynamically compromised patients in the setting of abdominal surgery.74 There is only 1 RCT of this treatment in patients with PD-associated peritonitis,27 in which patients with hypotension and shock were excluded. In that study, lavage did not improve response rates. This may be a true effect caused by inadvertent removal of macro-
phages and other components of the immune system and thereby a decrease in local host defenses. Additional trials to evaluate this therapy further may be useful. A novel strategy is administration of IP immunoglobulin in conjunction with antibiotics to improve local host defenses.75 The study of Coban et al66 of 24 patients found that biochemical and clinical parameters of improvement were achieved sooner and duration of antibiotic therapy was shorter with immunoglobulin treatment. However, the response rate of 100% was unusually high and there were no relapses during 3 months of follow-up. In a larger population, a difference in response rates may have become apparent. Although valuable information was gained from this review, there are limitations. There is insufficient evidence regarding several aspects of management that are clinically important because of deficits in study design or absence of studies. Trials tended to focus on choice and route of antibiotic without consideration of such variables as total duration of therapy, drug dose, and the role of patient factors, including comorbidities and residual renal function. No RCT was conducted to determine whether early catheter removal is beneficial in patients not responding to therapy. The follow-up period of most trials was 28 days or fewer; hence, long-term outcomes, such as technique failure and mortality, were not evaluated. Loss of residual renal function during peritonitis may be accelerated by
986
Wiggins et al
aminoglycoside therapy.76 However, this was considered in very few trials, although of note, Lui et al58 described no increased loss of residual renal function with a netilmycin-based regimen. The method quality of included trials was suboptimal. In particular, inadequate randomization and concealment methods were common. Definitions of peritonitis, successful treatment, and relapse varied among trials, thereby reducing their comparability. Many trials had small patient numbers with significant potential for type II statistical errors in some of our analyses. As a result, the finding of nonsignificant differences does not necessarily mean no association exists. Trials often predated the current era of lower peritonitis rates, newer antibiotic therapies, and increased awareness of multiresistant organisms, thereby potentially reducing the applicability of our meta-analyses or the individual trial results. In conclusion, currently available evidence from RCTs did not identify a single antibiotic regimen to be superior for the treatment of patients with PDassociated peritonitis. Intermittent antibiotic dosing appears to be as effective as continuous dosing; however, the applicability of this practice to APD is unclear. There is no clear role for such adjunctive therapies as urokinase and peritoneal lavage. At the present time, broad-spectrum antibiotics should be initiated when a diagnosis of peritonitis is made. When choosing antibiotics, side-effect profile, local drug resistance patterns, and previous antibiotic use and infection history in the individual concerned should be considered. Additional trials are required to establish the most effective treatment for patients with PD-associated peritonitis. Future research should be adequately powered to assess such outcomes as catheter removal and mortality and should include long-term follow-up of such parameters as ultrafiltration failure, loss of residual renal function, and technique failure. ACKNOWLEDGEMENTS We thank Ruth Mitchell and Gail Higgins (Trial Search Coordinators of the Cochrane Renal Group) for providing search strategies for our analyses. Support: This study was funded by the Cochrane Renal Group and the National Health and Medical Research Council (NHMRC) Centre for Clinical Research Excellence in Renal Medicine. Financial Disclosure: Dr Johnson is a consultant for Baxter Healthcare Pty Ltd and previously received research funds from this company. He also received speakers’ honoraria and research grants from Fresenius Medical Care.
REFERENCES 1. Voinescu CG, Khanna R: Peritonitis in peritoneal dialysis. Int J Artif Organs 25:249-260, 2002 2. Bazzato G, Landini S, Coli U, Lucatello S, Fracasso A, Moracchiello M: A new technique of continuous ambulatory peritoneal dialysis (CAPD): Double-bag system for freedom to the patient and significant reduction of peritonitis. Clin Nephrol 13:251-254, 1980 3. Monteon F, Correa-Rotter R, Paniagua R, et al: Prevention of peritonitis with disconnect systems in CAPD: A randomized controlled trial. The Mexican Nephrology Collaborative Study Group. Kidney Int 54:2123-2128, 1998 4. Strippoli GF, Tong A, Johnson D, Schena FP, Craig JC: Catheter-related interventions to prevent peritonitis in peritoneal dialysis: A systematic review of randomized, controlled trials. J Am Soc Nephrol 15:2735-2746, 2004 5. Kawaguchi Y: National comparisons: Optimal peritoneal dialysis outcomes among Japanese patients. Perit Dial Int 19:(suppl 3)S9-S16, 1999 6. Grunberg J, Verocay MC, Rebori A, et al: Twenty years’ pediatric chronic peritoneal dialysis in Uruguay: Patient and technique survival. Pediatr Nephrol 20:13151319, 2005 7. Oxton LL, Zimmerman SW, Roecker EB, Wakeen M: Risk factors for peritoneal dialysis-related infections. Perit Dial Int 14:137-144, 1994 8. Juergensen PH, Gorban-Brennan N, Troidle L, Finkelstein FO: Racial differences and peritonitis in an urban peritoneal dialysis center. Adv Perit Dial 18:117-118, 2002 9. Lim WH, Johnson DW, McDonald SP: Higher rate and earlier peritonitis in Aboriginal patients compared to nonAboriginal patients with end-stage renal failure maintained on peritoneal dialysis in Australia: Analysis of ANZDATA. Nephrology (Carlton) 10:192-197, 2005 10. McDonald SP, Collins JF, Rumpsfeld M, Johnson DW: Obesity is a risk factor for peritonitis in the Australian and New Zealand peritoneal dialysis patient populations. Perit Dial Int 24:340-346, 2004 11. Alves FR, Dantas RC, Lugon JR: Higher incidence of catheter-related infections in a tropical climate. Adv Perit Dial 9:244-247, 1993 12. Szeto CC, Chow KM, Wong TY, Leung CB, Li PK: Influence of climate on the incidence of peritoneal dialysisrelated peritonitis. Perit Dial Int 23:580-586, 2003 13. Troidle L, Watnick S, Wuerth DB, Gorban-Brennan N, Kliger AS, Finkelstein FO: Depression and its association with peritonitis in long-term peritoneal dialysis patients. Am J Kidney Dis 42:350-354, 2003 14. Oo TN, Roberts TL, Collins AJ: A comparison of peritonitis rates from the United States Renal Data System database: CAPD versus continuous cycling peritoneal dialysis patients. Am J Kidney Dis 45:372-380, 2005 15. Huang JW, Hung KY, Yen CJ, Wu KD, Tsai TJ: Comparison of infectious complications in peritoneal dialysis patients using either a twin-bag system or automated peritoneal dialysis. Nephrol Dial Transplant 16:604-607, 2001 16. Smit W, van den Berg N, Schouten N, Aikens E, Struijk DG, Krediet RT: Free-water transport in fast trans-
Treatments for Peritoneal Dialysis–Associated Peritonitis port status: A comparison between CAPD peritonitis and long-term PD. Kidney Int 65:298-303, 2004 17. Ates K, Koc R, Nergizoglu G, et al: The longitudinal effect of a single peritonitis episode on peritoneal membrane transport in CAPD patients. Perit Dial Int 20:220-226, 2000 18. Davies SJ, Bryan J, Phillips L, Russell GI: Longitudinal changes in peritoneal kinetics: The effects of peritoneal dialysis and peritonitis. Nephrol Dial Transplant 11:498506, 1996 19. Coles GA, Topley N: Long-term peritoneal membrane changes. Adv Ren Replace Ther 7:289-301, 2000 20. Kawanishi H, Watanabe H, Moriishi M, Tsuchiya S: Successful surgical management of encapsulating peritoneal sclerosis. Perit Dial Int 25:S39-S47, 2005 (suppl 4) 21. Rigby RJ, Hawley CM: Sclerosing peritonitis: The experience in Australia. Nephrol Dial Transplant 13:154159, 1998 22. Fried LF, Bernardini J, Johnston JR, Piraino B: Peritonitis influences mortality in peritoneal dialysis patients. J Am Soc Nephrol 7:2176-2182, 1996 23. Choi P, Nemati E, Banerjee A, Preston E, Levy J, Brown E: Peritoneal dialysis catheter removal for acute peritonitis: A retrospective analysis of factors associated with catheter removal and prolonged postoperative hospitalization. Am J Kidney Dis 43:103-111, 2004 24. Heaf J: Underutilization of peritoneal dialysis. JAMA 291:740-742, 2004 25. Pickering SJ, Fleming SJ, Bowley JA, et al: Urokinase: A treatment for relapsing peritonitis due to coagulase-negative staphylococci. Nephrol Dial Transplant 4:62-65, 1989 26. Innes A, Burden RP, Finch RG, Morgan AG: Treatment of resistant peritonitis in continuous ambulatory peritoneal dialysis with intraperitoneal urokinase: A double-blind clinical trial. Nephrol Dial Transplant 9:797-799, 1994 27. Ejlersen E, Brandi L, Lokkegaard H, Ladefoged J, Kopp R, Haarh P: Is initial (24 hours) lavage necessary in treatment of CAPD peritonitis? Perit Dial Int 11:38-42, 1991 28. Piraino B, Bailie GR, Bernardini J, et al: Peritoneal dialysis-related infections recommendations: 2005 Update. Perit Dial Int 25:107-131, 2005 29. CARI: The CARI Guidelines (Caring for Australians with Renal Impairment). Nephrology (Carlton) 9:S41-S106, 2004 (suppl 3) 30. Passadakis P, Oreopoulos D: The case for oral treatment of peritonitis in continuous ambulatory peritoneal dialysis. Adv Perit Dial 17:180-190, 2001 31. Fielding RE, Clemenger M, Goldberg L, Brown EA: Treatment and outcome of peritonitis in automated peritoneal dialysis, using a once-daily cefazolin-based regimen. Perit Dial Int 22:345-349, 2002 32. Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 327:557560, 2003 33. Bennett-Jones D, Wass V, Mawson P: A comparison of intraperitoneal and intravenous/oral antibiotics in CAPD peritonitis. Perit Dial Bull 7:31-33, 1987 34. Bailie GR, Morton R, Ganguli L, Keaney M, Waldek S: Intravenous or intraperitoneal vancomycin for the treatment of continuous ambulatory peritoneal dialysis associated gram-positive peritonitis? Nephron 46:316-318, 1987
987 35. Bennett-Jones DN, Russell GI, Barrett A: A comparison between oral ciprofloxacin and intra-peritoneal vancomycin and gentamicin in the treatment of CAPD peritonitis. J Antimicrob Chemother 26:S73-S76, 1990 (suppl F) 36. Cheng I, Lui S, Fang G, et al: A randomised prospective comparison of oral versus intraperitoneal ofloxacin as the primary treatment of CAPD peritonitis. Nephrology 3:431-435, 1997 37. Cheng IK, Chan CY, Wong WT, et al: A randomized prospective comparison of oral versus intraperitoneal ciprofloxacin as the primary treatment of peritonitis complicating continuous ambulatory peritoneal dialysis. Perit Dial Int 13:S351-S354, 1993 (suppl 2) 38. Gucek A, Bren AF, Lindic J, Hergouth V, Mlinsek D: Is monotherapy with cefazolin or ofloxacin an adequate treatment for peritonitis in CAPD patients? Adv Perit Dial 10:144-146, 1994 39. Lye WC, Lee EJ, van der Straaten J: Intraperitoneal vancomycin/oral pefloxacin versus intraperitoneal vancomycin/gentamicin in the treatment of continuous ambulatory peritoneal dialysis peritonitis. Perit Dial Int 13:S348-S350, 1993 (suppl 2) 40. Tapson JS, Orr KE, George JC, Stansfield E, Bint AJ, Ward MK: A comparison between oral ciprofloxacin and intraperitoneal vancomycin and netilmicin in CAPD peritonitis. J Antimicrob Chemother 26:S63-S71, 1990 (suppl F) 41. Cheng IK, Chan CY, Wong WT: A randomised prospective comparison of oral ofloxacin and intraperitoneal vancomycin plus aztreonam in the treatment of bacterial peritonitis complicating continuous ambulatory peritoneal dialysis (CAPD). Perit Dial Int 11:27-30, 1991 42. Chan MK, Cheng IK, Ng WS: A randomized prospective trial of three different regimens of treatment of peritonitis in patients on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 15:155-159, 1990 43. Cheng IK, Fang GX, Chau PY, et al: A randomized prospective comparison of oral levofloxacin plus intraperitoneal (IP) vancomycin and IP netromycin plus IP vancomycin as primary treatment of peritonitis complicating CAPD. Perit Dial Int 18:371-375, 1998 44. Boeschoten EW, Rietra PJ, Krediet RT, Visser MJ, Arisz L: CAPD peritonitis: A prospective randomized trial of oral versus intraperitoneal treatment with cephradine. J Antimicrob Chemother 16:789-797, 1985 45. Bowley JA, Pickering SJ, Scantlebury AJ, Ackrill P, Jones DM: Intraperitoneal teicoplanin in the treatment of peritonitis associated with continuous ambulatory peritoneal dialysis. J Antimicrob Chemother 21:S133-S139, 1988 (suppl A) 46. Friedland JS, Iveson TJ, Fraise AP, Winearls CG, Selkon JB, Oliver DO: A comparison between intraperitoneal ciprofloxacin and intraperitoneal vancomycin and gentamicin in the treatment of peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). J Antimicrob Chemother 26:S77-S81, 1990 (suppl F) 47. Gucek A, Bren AF, Hergouth V, Lindic J: Cefazolin and netilmicin versus vancomycin and ceftazidime in the treatment of CAPD peritonitis. Adv Perit Dial 13:218-220, 1997 48. Jimenez C, Selgas R, Sanchez S, et al: Initial empiric treatment of peritonitis in CAPD with vancomycin ⫹ tobra-
988 mycin vs. vancomycin ⫹ cefotaxime in a CAPD unit. Nefrologia 16:569A, 1996 (abstr) 49. Wale M, Finch R, Morgan A, Burden R, Holliday A: A prospective randomised trial of teicoplanin plus aztreonam versus cefuroxime in CAPD peritonitis. Int J Antimicrob Agents 1:S7-S14, 1992 (suppl 1) 50. Were A, Marsden A, Tooth A, Ramsden R, Mistry C, Gokal R: Netilmycin and vancomycin in the treatment of peritonitis in CAPD patients. Clin Nephrol 37:2009-2213, 1992 51. Flanigan MJ, Lim VS: Initial treatment of dialysis associated peritonitis: A controlled trial of vancomycin versus cefazolin. Perit Dial Int 11:31-37, 1991 52. Wong KM, Chan YH, Cheung CY, et al: Cefepime versus vancomycin plus netilmicin therapy for continuous ambulatory peritoneal dialysis-associated peritonitis. Am J Kidney Dis 38:127-131, 2001 53. Schaefer F, Klaus G, Muller-Wiefel DE, Mehls O: Intermittent versus continuous intraperitoneal glycopeptide/ ceftazidime treatment in children with peritoneal dialysisassociated peritonitis. The Mid-European Pediatric Peritoneal Dialysis Study Group (MEPPS). J Am Soc Nephrol 10:136-145, 1999 54. Anwar N, Merchant M, Were T, Tooth A, Uttley L, Gokal R: A prospective, randomized study of the comparative safety and efficacy of intraperitoneal imipenem versus vancomycin and netilmicin in the treatment of peritonitis on CAPD. Perit Dial Int 15:167-171, 1995 55. Khairullah Q, Provenzano R, Tayeb J, Ahmad A, Balakrishnan R, Morrison L: Comparison of vancomycin versus cefazolin as initial therapy for peritonitis in peritoneal dialysis patients. Perit Dial Int 22:339-344, 2002 56. de Fijter CW, ter Wee PM, Oe LP, Verbrugh HA: Intraperitoneal ciprofloxacin and rifampicin versus cephradine as initial treatment of (C)APD-related peritonitis: A prospective randomized multicenter comparison (CIPPER trial). Perit Dial Int 21:480-486, 2001 57. Leung CB, Szeto CC, Chow KM, et al: Cefazolin plus ceftazidime versus imipenem/cilastatin monotherapy for treatment of CAPD peritonitis—A randomized controlled trial. Perit Dial Int 24:440-446, 2004 58. Lui SL, Cheng SW, Ng F, et al: Cefazolin plus netilmicin versus cefazolin plus ceftazidime for treating CAPD peritonitis: Effect on residual renal function. Kidney Int 68:2375-2380, 2005 59. Lupo A, Rugiu C, Bernich P, et al: A prospective, randomized trial of two antibiotic regimens in the treatment of peritonitis in CAPD patients: Teicoplanin plus tobramycin versus cephalothin plus tobramycin. J Antimicrob Chemother 40:729-732, 1997 60. Lye WC, Wong PL, van der Straaten JC, Leong SO, Lee EJ: A prospective randomized comparison of single versus multidose gentamicin in the treatment of CAPD peritonitis. Adv Perit Dial 11:179-181, 1995 61. Velasquez-Jones L, Sanchez-Aguilar J, Castelares G, et al: Efficacy of intraperitoneal vancomycin in children on continuous ambulatory peritoneal dialysis: Comparison of intermittent and continuous therapy. Bol Med Hospital Infantil Mexico 52:154-159, 1995
Wiggins et al 62. Boyce NW, Wood C, Thomson NM, Kerr P, Atkins RC: Intraperitoneal (IP) vancomycin therapy for CAPD peritonitis—A prospective, randomized comparison of intermittent v continuous therapy. Am J Kidney Dis 12:304-306, 1988 63. Gadallah MF, Tamayo A, Sandborn M, Ramdeen G, Moles K: Role of intraperitoneal urokinase in acute peritonitis and prevention of catheter loss in peritoneal dialysis patients. Adv Perit Dial 16:233-236, 2000 64. Tong MK, Leung KT, Siu YP, et al: Use of intraperitoneal urokinase for resistant bacterial peritonitis in continuous ambulatory peritoneal dialysis. J Nephrol 18:204-208, 2005 65. Williams AJ, Boletis I, Johnson BF, et al: Tenckhoff catheter replacement or intraperitoneal urokinase: A randomised trial in the management of recurrent continuous ambulatory peritoneal dialysis (CAPD) peritonitis. Perit Dial Int 9:65-67, 1989 66. Coban E, Ozdogan M, Tuncer M, Bozcuk H, Ersoy F: The value of low-dose intraperitoneal immunoglobulin administration in the treatment of peritoneal dialysis-related peritonitis. J Nephrol 17:427-430, 2004 67. Milikin SMG, Keane WF: Antimicrobial treatment of peritonitis associated with continuous ambulatory peritoneal dialysis. Perit Dial Int 11:252-260, 1991 68. Kan GW, Thomas MA, Heath CH: A 12-month review of peritoneal dialysis-related peritonitis in Western Australia: Is empiric vancomycin still indicated for some patients? Perit Dial Int 23:465-468, 2003 69. Booranalertpaisarn V, Eiam-Ong S, Wittayalertpanya S, Kanjanabutr T, Na Ayudhya DP: Pharmacokinetics of ceftazidime in CAPD-related peritonitis. Perit Dial Int 23: 574-579, 2003 70. Deamer RL, Dial LK: The evolution of aminoglycoside therapy: A single daily dose. Am Fam Physician 53:17821786, 1996 71. Grabe DW, Bailie GR, Eisele G, Frye RF: Pharmacokinetics of intermittent intraperitoneal ceftazidime. Am J Kidney Dis 33:111-117, 1999 72. Manley HJ, Bailie GR, Asher RD, Eisele G, Frye RF: Pharmacokinetics of intermittent intraperitoneal cefazolin in continuous ambulatory peritoneal dialysis patients. Perit Dial Int 19:65-70, 1999 73. Manley HJ, Bailie GR: Treatment of peritonitis in APD: Pharmacokinetic principles. Semin Dial 15:418-421, 2002 74. O’Brien PE, Tait N, Bushell M: Management of diffuse peritonitis by prolonged postoperative peritoneal lavage. Aust N Z J Surg 57:181-184, 1987 75. Carozzi S, Nasini MG, Kunkl A, Cantarella S, Lamperi S: Response of CAPD patients with a high incidence of peritonitis to intraperitoneal immunoglobulin therapy. ASAIO Trans 34:635-639, 1988 76. Termorshuizen F, Korevaar JC, Dekker FW, van Manen JG, Boeschoten EW, Krediet RT: The relative importance of residual renal function compared with peritoneal clearance for patient survival and quality of life: An analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2. Am J Kidney Dis 41:1293-1302, 2003
