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Intraperitoneal Vancomycin Plus Either Oral Moxifloxacin or Intraperitoneal Ceftazidime for the Treatment of Peritoneal Dialysis−Related Peritonitis: A Randomized Controlled Pilot Study
Original Investigation Intraperitoneal Vancomycin Plus Either Oral Moxifloxacin or Intraperitoneal Ceftazidime for the Treatment of Peritoneal Dialysis2Related Peritonitis: A Randomized Controlled Pilot Study Rong Xu, MD,1 Zhikai Yang, MD,1 Zhen Qu, MD,1 Huan Wang, BS,1 Xue Tian, MS,1 David W. Johnson, MD,2 and Jie Dong, MD 1 Background: Intraperitoneal administration of antibiotics is recommended as a first treatment for managing peritoneal dialysis (PD)-related peritonitis. However, the efficacy of oral administration of quinolones has not been well studied. Study Design: Randomized controlled pilot study. Setting & Participants: 80 eligible patients with PD-related peritonitis from Peking University First Hospital (40 in each arm). Intervention: Intraperitoneal vancomycin, 1 g, every 5 days plus oral moxifloxacin, 400 mg, every day (treatment group) versus intraperitoneal vancomycin, 1 g, every 5 days plus intraperitoneal ceftazidime, 1 g, every day (control group). Outcomes: The primary end point was complete resolution of peritonitis, and secondary end points were primary or secondary treatment failure. Measurements: PD effluent white blood cell count. Results: Baseline demographic and clinical characteristics of the 2 groups were comparable. There were 24 and 22 Gram-positive organisms, 6 and 7 Gram-negative organisms, 9 and 10 culture-negative samples, and 1 and 1 fungal sample in the treatment and control groups, respectively. Complete resolution of peritonitis was achieved in 78% and 80% of cases in the treatment and control groups, respectively (OR, 0.86; 95% CI, 0.302.52; P 5 0.8). There were 3 and 1 cases of relapse in the treatment and control groups, respectively. Primary and secondary treatment failure rates were not significantly different (33% vs 20% and 10% vs 13%, respectively). In each group, there was 1 peritonitis-related death and 6 transfers to hemodialysis therapy. During the 3-month follow-up period, 7 and 3 successive episodes of peritonitis occurred in the treatment and control groups, respectively. Only 2 adverse drug reactions (mild nausea and mild rash, respectively) were observed in the 2 groups. Limitations: Sample size was relatively small and the eligibility ratio was low. Also, the number of peritonitis episodes was low, limiting the power to detect a difference between groups. Conclusions: This pilot study suggests that intraperitoneal vancomycin with oral moxifloxacin is a safe, well-tolerated, practical, and effective first-line treatment for PD-related peritonitis. Larger adequately powered clinical trials are warranted. Am J Kidney Dis. -(-):---. ª 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. INDEX WORDS: Intraperitoneal vancomycin; oral moxifloxacin; intraperitoneal ceftazidime; peritoneal dialysis (PD); PD-related peritonitis; empirical antibiotic regimen; oral quinolones; complete cure; continuous ambulatory peritoneal dialysis (CAPD); renal failure; randomized clinical trial.
T
he global use of peritoneal dialysis (PD) is rapidly growing, particularly in developing countries, where the number of PD patients has increased 2.5-fold during the past 12 years.1 However, one of the major barriers to PD is PD-related
peritonitis, which adversely affects both technique and patient survival and also increases the financial burden on patients and health care systems. According to the 2010 and 2016 International Society for Peritoneal Dialysis (ISPD) guidelines for the
From the 1Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health; Key Laboratory of Renal Disease, Ministry of Education; Beijing, China; and 2Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia. Received July 13, 2016. Accepted in revised form November 7, 2016. Trial registration: www.ClinicalTrials.gov; study number: NCT02787057.
Address correspondence to Jie Dong, MD, Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health; Key Laboratory of Renal Disease, Ministry of Education; Beijing, China. E-mail: dongjie@medmail. com.cn 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.11.008
Am J Kidney Dis. 2016;-(-):---
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management of peritonitis, empirical antibiotics should cover both Gram-positive and Gram-negative organisms and preferably should be administered intraperitoneally.2,3 However, intraperitoneal administration outside the hospital is difficult, particularly for elderly and diabetic PD patients, who often have impaired visual acuity, dexterity, and cognitive function. Moreover, intraperitoneal administration increases daily treatment time and could lead to an increase in the number of patients discontinuing treatment. These concerns are more prominent for patients with lower socioeconomic status; this includes a large proportion of PD populations in both developed4,5 and developing countries.6,7 Oral administration of antibiotics is a more convenient and economical regimen and could be a substitute or complementary therapy for the treatment of peritonitis. Fluoroquinolones are the most-cited oral agents because of their rapid and substantial absorption in the gut and the achievement of therapeutic concentrations in plasma and dialysate, among others.8 Although oral monotherapy with quinolones is reported to cure only 40% to 78% of peritonitis episodes,9-14 this rate could reach 73% to 94% when combined with cefazolin15,16 or vancomycin.17-21 However, limited studies comparing the efficacy of oral quinolone administration combined with intraperitoneal cefazolin or vancomycin have yielded inconclusive results. Only 2 of these studies were randomized controlled trials and were limited by small sample sizes, short treatment durations, and short follow-up periods.17,21 Thus, in the absence of adequate evidence for clinical efficacy, oral fluoroquinolones are recommended by the 2010 ISPD peritonitis guidelines only for the treatment of mild peritonitis episodes.2 Therefore, we conducted a pilot study to compare the complete cure rate and primary or secondary treatment failure rate of oral quinolones plus intraperitoneal vancomycin (ie, treatment group) and conventional intraperitoneal vancomycin plus ceftazidime (ie, control group). Moxifloxacin is part of a newer generation of fluoroquinolones and was selected for its lower antimicrobial resistance and wider antibacterial spectrum compared with other fluoroquinolones.22-24 Moxifloxacin also has a longer half-life than other quinolones and requires administration only once daily.25 In addition, moxifloxacin is unique among fluoroquinolones in that it is primarily excreted via nonrenal mechanisms, so dosage adjustment is unnecessary in patients with decreased kidney function.25 Vancomycin was chosen for both arms of the trial based on its excellent treatment of Gram-positive organisms, convenient administration, and widespread global use in peritonitis management. We hypothesized that combination therapy of 2
intraperitoneal vancomycin and oral moxifloxacin would result in a complete cure rate and primary or secondary treatment failure rates comparable to those of conventional intraperitoneal vancomycin plus ceftazidime.
METHODS Patient Eligibility The pilot study was conducted in the PD center of Peking University First Hospital in November 2012 to March 2016. All consecutive peritonitis episodes in our center were screened for eligibility for patient enrollment into this prospective, open-label, parallel-arm, randomized, controlled trial. Inclusion criteria were as follows: incident or prevalent continuous ambulatory PD patients, diagnosis of acute peritonitis according to the ISPD guideline,2 and age older than 18 years. Exclusion criteria were receiving antibiotic treatment for other reasons when peritonitis occurred; contraindication to cephalosporin, vancomycin, or fluoroquinolones; concomitant exit-site or tunnel infection; requirement for immediate transfer to hemodialysis therapy due to sepsis, gastrointestinal perforation or visceral inflammation, severe bowel obstruction, or ultrafiltration failure at the initiation of peritonitis; inability to tolerate oral administration due to severe gastrointestinal complication or other reasons; history of psychological illness or condition that interfered with the ability to understand or adhere to the requirements of the study; and pregnant or breast-feeding. If all selection criteria were fulfilled, the patient was randomly assigned by a computer-generated random number list. Reasons for noninclusions were recorded. To avoid contamination bias, participants were not permitted to re-enroll in the trial for subsequent episodes of peritonitis. Researchers and patients were not blinded to treatment allocation, although statisticians analyzing the data were. Written informed consent was obtained from each patient. The ethics committee of Peking University First Hospital approved the study (approval number: 201D22).
Interventions Eligible patients were randomly assigned to receive either intraperitoneal vancomycin, 1 g, every 5 days combined with oral moxifloxacin, 400 mg, every day (treatment group), or intraperitoneal vancomycin, 1 g, every 5 days combined with intraperitoneal ceftazidime, 1 g, every day (control group). Moxifloxacin had to be taken at an interval of 2 hours before or 4 hours after taking aluminum- or magnesium-containing antacids or iron supplements in order to ensure that the effect of any interaction was not clinically relevant. For both the treatment and control groups, further treatment adjustment for peritonitis (with either resistant pathogens or sensitive pathogens) was based on patients’ clinical responses and results of PD effluent culture according to ISPD guideline recommendations.2 If the peritonitis episode failed to respond to the assigned antibiotics by day 3, the antibiotics were adjusted according to bacterial culture results or changed to second-line antibiotics if the bacterial cultures gave negative results. Duration of treatment was based on ISPD guideline recommendations.2 Routine follow-up visits were scheduled on days 1, 3, 5, 7, 10, 14, and 21 following initiation of treatment. Patients were switched to hemodialysis therapy and their PD catheters were subsequently removed if they had a lack of improvement after 7 to 14 days of appropriate antibiotic therapy, PD dialysate grew yeast species or Mycobacterium tuberculosis at any time, or a concomitant tunnel infection was diagnosed, as suggested by the ISPD guidelines.2 Am J Kidney Dis. 2016;-(-):---
Empirical Antibiotics for PD-Related Peritonitis
Outcomes The primary end point in this study was complete cure, which was defined as complete resolution of peritonitis (normalization of body temperature, resolution of abdominal pain, clearing of dialysate, and PD effluent white blood cell [WBC] count , 100 cells/ mL with ,50% polymorphonuclear cells) by using antibiotics alone without relapse within 4 weeks of completion of therapy.26 Secondary end points were primary or secondary treatment failure. Primary treatment failure was defined as the presence of fever, abdominal pain, or turbid peritoneal dialysate, together with a total peritoneal WBC count . 50% of the pretreatment value after 3 days of treatment with the assigned antibiotics.27 Secondary treatment failure was defined as treatment failure despite adjustment of antibiotics or changing to second-line antibiotics for at least 3 days in patients with primary treatment failure.27 Peritonitis episodes occurring within 3 months after complete resolution of peritonitis were recorded and categorized as relapsing, recurrent, or repeat according to ISPD guidelines.2 For episodes that occurred more than 4 weeks after completion of therapy of a prior episode with a different organism, we defined it as “other type.” Peritonitis-related death was defined as death of a patient with active peritonitis, admitted with peritonitis, or within 2 weeks of a peritonitis episode.
Statistical Analyses Statistical analysis was performed by SPSS for Windows software, version 13.0 (SPSS Inc). All data were expressed as mean 6 standard deviation for normally distributed data and median with interquartile range for skewed data. Categorical variables were expressed as percentage. Patients’ data were compared using c2 test for categorical variables, t test for normally distributed continuous variables, and Mann-Whitney U test for skewed continuous variables. Changes over time of effluent WBC counts were also compared between groups using a mixed-model analysis of variance, with bootstrap covariance accounting for correlation among repeated measures within a patient. The baseline value of the effluent WBC count was adjusted as a model covariate.
RESULTS
(0.23 episode/patient-year). Of the 207 episodes, 127 were excluded (45, not meeting inclusion criteria; 47, declined to participate; and 35, other reasons; Fig 1). This left 80 episodes for analysis. Patients with these episodes were randomly assigned and equally allocated into either the treatment (ie, intraperitoneal vancomycin plus oral moxifloxacin) or control group (ie, intraperitoneal vancomycin plus intraperitoneal ceftazidime). There were no significant differences in demographics, clinical parameters, or outcomes between patients with included and excluded episodes. Clinical Characteristics Baseline demographic, clinical, and laboratory characteristics were similar between the treatment and control groups (Table 1). Microbiological spectra of peritonitis episodes were also similar between the 2 groups; the proportions of Gram-positive and Gramnegative bacteria were 77% and 19% in the treatment group and 73% and 23% in the control group, respectively (Table 2). Culture-negative rates were 23% and 25% for the treatment and control groups, respectively. There was 1 episode of fungal peritonitis in each group (Table 2). The effluent WBC count between days 0 and 10 was not significantly different between groups. In addition, the effluent WBC count in both the treatment and control groups decreased comparably over time (Table 3). Antibiotics were adjusted in 7 (18%) patients in the treatment group and 6 patients (15%) in the control group (P 5 0.8; Table 3). Primary and Secondary Outcomes
Enrollment and Follow-up There were 207 episodes of peritonitis in our center from November 1, 2012, through March 11, 2016
Primary Outcome The complete cure rate was 78% in the treatment group and 80% in the control group (odds ratio [OR],
Assessment for elegibility (n=207) Excluded (n=127) . Not meeting inclusion criteria (n=45) . Declined to participate (n=47) . Other reason (n=35) Randomized (n=80)
Allocated to Vancomycin+Moxifloxacin . Received allocated intervention (n=40) . Did not receive allocated intervention (n=0)
Allocated to Vancomycin+Cefoperazone . Received allocated intervention (n=40) . Did not receive allocated intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Analyzed (n=40) . Excluded from analysis (n=0)
Analyzed (n=40) . Excluded from analysis (n=0)
Figure 1. Study flow chart. Am J Kidney Dis. 2016;-(-):---
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Xu et al Table 1. Baseline Demographic and Clinical Data for the Treatment and Control Groups
Age, y Male sex PD vintage, mo Diabetes mellitus CVD history First peritonitis episode Hemoglobin, g/L Albumin, g/L Total Kt/V RKF, mL/min
Treatment (n 5 40)
Control (n 5 40)
57.2 6 13.0 25 (63) 31.1 [9.5-62.1] 19 (48) 11 (28) 31 (78) 111.7 6 14.4 36.8 6 4.9 1.90 6 0.3 1.0 [0-4.5]
58.0 6 15.7 24 (60) 36.7 [10.2-73] 13 (33) 16 (40) 26 (65) 109.6 6 15.0 36.2 6 4.2 1.83 6 0.4 0.4 [0-2.9]
Note: Treatment, intraperitoneal vancomycin plus oral moxifloxacin; control, intraperitoneal vancomycin plus intraperitoneal ceftazidime. Values for categorical variables are given as count (percentage); values for continuous variables, as mean 6 standard deviation or median [interquartile range]. Abbreviations: CVD, cardiovascular disease; Kt/V, (urinary 1 peritoneal) urea clearance; PD, peritoneal dialysis; RKF, residual kidney function.
Secondary Outcomes Comparing the treatment and control groups, primary (33% vs 20%; OR, 1.93 [95% CI, 0.70-5.34]; P 5 0.2) and secondary (10% vs 13%; OR, 0.78 [95% CI, 0.19-3.14]; P 5 0.7) treatment failure rates were not significantly different. Six patients in each group transferred to hemodialysis therapy (in randomly assigned treatment group: 5 due to peritonitis treatment failure and 1 due to fungal peritonitis; in the control group: 3, 1, 1, and 1 due to peritonitis treatment failure, congestive heart failure, fungal peritonitis, and fungal superinfection, respectively). Two peritonitis-related deaths were recorded; 1 in the treatment group due to gastrointestinal hemorrhage and 1 in the control group due to sepsis. There were no deaths during the 3 months of follow-up (ie, after completion of peritonitis therapy). Details of peritonitis outcomes in the treatment and control groups are shown in Fig 2A and B.
Adverse Events 0.86; 95% confidence interval [CI], 0.30-2.52; P 5 0.8). There were 3 relapse episodes in the treatment group and 1 in the control group (OR, 2.62; 95% CI, 0.63-10.95; P 5 0.2; Table 3). In addition, there were 4 patients in the treatment group (1 recurrent, 1 repeat, 1 other type, and 1 for whom effluent was not sent for bacterial culturing) and 2 patients in the control group (1 repeat and 1 other type) who had successive episodes of peritonitis during the study period. Table 2. Causative Microorganisms in the Treatment and Control Groups Total
Treatment
Control
Gram-positive organism Staphylococcus epidermidis Staphylococcus aureus Streptococcus Enterococcus Other
46 20 7 9 2 8
(75) (33) (12) (15) (3) (13)
24 10 3 4 2 5
(77) (32) (10) (13) (7) (16)
22 10 4 5 0 3
(73) (33) (13) (17) (0) (10)
Gram-negative organism Escherichia coli Klebsiella spp Acinetobacter baumannii Other
13 1 3 2 7
(21) (2) (5) (3) (12)
6 1 0 1 4
(19) (3) (0) (3) (13)
7 0 3 1 3
(23) (0) (10) (3) (10)
Fungi Culture-negative
2 (3) 19 (24)a
1 (3) 9 (23)a
1 (3) 10 (25)a
Note: Treatment, intraperitoneal vancomycin plus oral moxifloxacin; control, intraperitoneal vancomycin plus intraperitoneal ceftazidime. Values are given as count (percentage). Except where indicated, denominators for percentages are culturepositive episodes in the applicable group. P for overall distribution 5 0.7. a Denominators for percentages are all episodes in the applicable group. 4
One patient in the treatment group reported mild nausea after oral moxifloxacin; the nausea disappeared after adjusting the time of administration. One patient in the control group reported a mild rash, which resolved following treatment with oral antiallergy drugs. No other adverse events were reported.
DISCUSSION Peritonitis is still a leading complication of PD and contributes to technique failures, hospitalizations, and occasionally deaths.2 When clinical evidence of infectious peritonitis manifests, empirical antibiotic therapy must be initiated as soon as possible.2 However, as previously discussed, the intraperitoneal administration of antibiotics, which is the standard therapy recommended by the ISPD,2 has many limitations in clinical practice. Thus, treatments that save time and are less manpower dependent without reducing efficacy would be highly valuable. Few studies have addressed this issue; therefore, we conducted a pilot study to explore the effectiveness of a convenient and less expensive regimen (ie, intraperitoneal vancomycin plus oral moxifloxacin) with the traditional empirical regimen (ie, intraperitoneal vancomycin plus intraperitoneal ceftazidime). Our results demonstrate that there are no substantial differences in therapeutic response between the 2 regimens; thus, the combination of intraperitoneal vancomycin and oral moxifloxacin could be a suitable initial empirical regimen for the treatment of PD-related peritonitis. In this study, intraperitoneal vancomycin plus oral moxifloxacin resulted in a complete cure rate of 78%, which is higher than the rate reported in most previous fluoroquinolone-related studies (40%-78%).9-14 One possible reason for this is that moxifloxacin has Am J Kidney Dis. 2016;-(-):---
Empirical Antibiotics for PD-Related Peritonitis Table 3. Comparisons of Primary and Secondary Outcomes Between Treatment and Control Groups Treatment (n 5 40)
Control (n 5 40)
1,460 [737-3,000] 275 [95-1,265] 85 [31-390] 27 [5-80] 43 [6-95] 7 [1-88]
2,050 [1,013-3,154] 375 [130-1,082] 82 [20-229] 10 [2-22] 5 [1-19] 2 [2-12]
Primary end point Complete cure
31 (78)
32 (80)
0.86 (0.30-2.52)
0.8
Secondary end points Primary treatment failure Secondary treatment failure
13 (33) 4 (10)
8 (20) 5 (13)
1.93 (0.70-5.34) 0.78 (0.19-3.14)
0.2 0.7
Adjustment of antibiotics Transfer to HD Congestive heart failure Persistent elevation of effluent WBC count Fungal peritonitis Fungal superinfection
7 (18) 6 (15) 0 (0) 5 (13) 1 (3) 0 (0)
6 (15) 6 (15) 1 (3) 3 (8) 1 (3) 1 (3)
1.20 (0.37-3.96) 1.00 (0.29-1.41)
0.8 0.9
Peritonitis-related death Sepsis Gastrointestinal hemorrhage
1 (3) 0 (0) 1 (3)
1 (3) 1 (3) 0 (0)
1.00 (0.06-16.56)
0.9
Successive episodes of peritonitis during 3-mo follow-up Relapsing peritonitis Recurrent peritonitis Repeat peritonitis Bacteria untested Other
7 (18) 3 (8) 1 (3) 1 (3) 1 (3) 1 (3)
3 1 0 1 0 1
2.62 (0.63-10.95)
0.2
Outcome of successive episodes of peritonitis Transfer to HD Maintenance of PD
1.40 (0.88-2.24)b
0.3
2 (29) 5 (71)
0 (0) 3 (100)
All-cause death during 3-mo follow-up
0 (0)
0 (0)
—
—
Effluent WBC count (cells/mL) Day 0 Day 1 Day 3 Day 5 Day 7 Day 10
(8) (3) (0) (3) (0) (3)
OR (95% CI)a
P
0.3 0.5 0.5 0.5 0.07 0.09 0.3
Note: Treatment, intraperitoneal vancomycin plus oral moxifloxacin; control, intraperitoneal vancomycin plus intraperitoneal ceftazidime. Values for categorical variables are given as count (percentage); values for continuous variables, as median [interquartile range]. Abbreviations: CI, confidence interval; HD, hemodialysis; OR, odds ratio; PD, peritoneal dialysis; WBC, white blood cell. Definitions: All-cause death, all causes of death within 3 months of completion of therapy; catheter removal and HD transfer (temporary or permanent), removal of the PD catheter was considered for patients with primary treatment failure whose peritonitis failed to improve after adjusting antibiotic regimen(s) for 3 to 5 days (ie, secondary treatment failure), patients were then put on temporary HD therapy, and patients were switched to long-term HD therapy according to their desire, when attempts at Tenckhoff catheter reinsertion failed because of peritoneal adhesion or there was ultrafiltration failure from peritoneal sclerosis; complete cure, complete resolution of peritonitis (ie, normalization of body temperature, resolution of abdominal pain, clearing of dialysate, PD effluent neutrophil count , 100 cells/mL, and proportion of polynuclear cells , 50%) by use of antibiotics alone, without relapse, within 4 weeks of therapy completion; other type, an episode that occurs more than 4 weeks after completion of therapy of a prior episode with different organism; peritonitis-related death, death of a patient with active peritonitis, admitted with peritonitis, or within 2 weeks of a peritonitis episode; primary treatment failure, presence of abdominal pain, fever, and turbid peritoneal dialysate, as well as total peritoneal WBC counts . 50% of pretreatment values, after 3 days of treatment by assigned antibiotics; recurrent peritonitis, an episode that occurs within 4 weeks of completion of therapy of a prior episode but with different organism; relapsing peritonitis, an episode that occurs within 4 weeks of completion of therapy of a prior episode with same organism or 1 sterile episode; repeat peritonitis, an episode that occurs more than 4 weeks after completion of therapy of a prior episode with same organism; secondary treatment failure, treatment failure despite antibiotic adjustment or changing to second-line antibiotics for 3 to 5 days in patients with primary treatment failure. a Control group as reference. b Risk for transferring to HD therapy for successive episodes of peritonitis.
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Xu et al
A
Primary treatment success n=27
Relapsed after peritonitis resolved (n=3)
Treatment group n=40
Primary treatment failure n=13
Antibiotics adjustment if needed
Peritonitis resolved without relapsing (n=24)
Peritonitis resolved without relapsing (n=7)
WCC decreased less than 50% within 3 days (i.e. secondary treatment failure) and transferred to HD (n=4) WCC decreased more than 50% within 3 days but transferred to HD due to WCC persistently higher than 100/ul (n=1)
Complete cure (n=31)
B
Primary treatment success n=32
Transferred to HD due to fungal superinfection (n=1)
Transferred to HD after identified as fungal peritonitis (n=1)
Control group n=40
Primary treatment failure n=8
Antibiotics adjustment if needed
Peritonitis resolved without relapsing (n=31) Peritonitis resolved without relapsing (n=1)
WCC decreased less than 50% within 3 days (i.e. secondary treatment failure, n=4) and transferred to HD (n=3) or death (n=1) WCC decreased more than 50% within 3 days but transferred to HD due to heart failure (n=1) Transferred to HD after identified as fungal peritonitis (n=1)
Complete cure (n=32) Peritonitis resolved with relapsing (n=1)
Figure 2. Details of peritonitis outcomes in the (A) treatment group and (B) control group. Abbreviations: HD, hemodialysis; WCC, white blood cell count.
a wider antibiotic spectrum, greater antibiotic activity, and lower antimicrobial resistance than former generations of fluoroquinolones.22-24 Another possible reason is that the combination with vancomycin, rather than a first-generation cephalosporin, increased the rate of successful treatment. Vancomycin will likely be included in more initial regimens for Grampositive coverage in light of the increasing worldwide incidence of methicillin-resistant Staphylococcus in dialysis patients.28,29 In this study, 14 of 20 cases of Staphylococcus epidermidis and 2 of 7 cases of Staphylococcus aureus were methicillin resistant. However, it should be noted that moxifloxacin has better Gram-positive coverage but less broad Gramnegative coverage than other quinolones,25 and this empirical choice may not be optimal in areas with high fluoroquinolone resistance. The number of peritonitis cases that relapsed within 4 weeks was low overall, although higher in the treatment group than in the control group (3 vs 1; 6
P 5 0.3). This finding is not necessarily indicative of ineffective treatment. First, the pathogens causing the relapses in the treatment group were S epidermidis (2 cases) and Proteus mirabilis (1 case). Both S epidermidis strains were methicillin resistant and sensitive to vancomycin, and the P mirabilis strain was sensitive to moxifloxacin. Therefore, the new empirical regimen covered these pathogens adequately. Second, the effluent WBC count in all 3 episodes decreased to ,100 cells/mL within 5 days, which supports the efficacy of the new empirical regimen. Previous studies have shown that relapsing peritonitis is possibly caused by bacteria sequestered in biofilm30; further investigation with a larger sample size is necessary to determine whether the new regimen increases the risk for relapsing peritonitis and thus an infection not susceptible to antibiotics administered intraperitoneally or systemically. To our knowledge, this is the first study investigating the efficacy and safety of intraperitoneal Am J Kidney Dis. 2016;-(-):---
Empirical Antibiotics for PD-Related Peritonitis
vancomycin plus oral moxifloxacin for the treatment of PD-related peritonitis. Our findings provide important information for this potential first-line empirical regimen. Based on this pilot study, a welldesigned multicenter study with a large sample size is needed to further clarify the efficacy and costeffectiveness of this empirical regimen. There were some limitations to our study. First, although this pilot study had a larger sample size than most previous studies,9-21 statistical power for discerning small differences in efficacy and harms between the treatment and control groups was limited. Particularly, with only 13 Gram-negative rods and 19 culture-negative peritonitis episodes, the efficacy of moxifloxacin versus ceftazidime was really based on only 32 episodes of peritonitis. According to our analysis based on a noninferiority trial design (if the noninferiority limit is set at 10%), we estimate that 275 patients in each arm would be needed to provide 90% statistical power (for a 1-tailed test with a error 5 0.05) to discern differences between the groups. An extensive multicenter randomized controlled trial with a large sample size will need to be conducted to improve statistical power. Second, the eligibility ratio was low, and 61% of episodes that occurred at our center during the study were excluded. However, the demographics, clinical parameters, and outcomes were not significantly different between patients with included and excluded episodes. Finally, 71% of episodes in this study were first episodes; however, clinicians often have to manage successive episodes of peritonitis. According to our center’s database, about half the peritonitis episodes were repeat cases. Future studies should be undertaken to confirm whether our results hold for repeat cases. Patient enrollment was relatively slow in this study. Only 39% of peritonitis episodes occurring during the study period qualified for the study; this was lower than our initial estimate (60%). A multicenter trial could speed up the enrollment and meet sample size requirements for further analysis. The proposed studies are not sophisticated or time consuming. All enrolled patients were able to follow our protocol, no patients were lost during follow-up, and no severe adverse events were reported. This pilot study suggests that intraperitoneal vancomycin plus oral moxifloxacin is a safe, welltolerated, and effective treatment that potentially could be used as a first-line empirical treatment regimen for PD-related peritonitis. Patients appeared to adhere well to the treatment regimen, which would reduce medical expenses compared to daily intraperitoneal antibiotic administration. These results support implementation of a randomized, multicenter, controlled study with a larger sample size.
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ACKNOWLEDGEMENTS The authors thank the patients, doctors, and nursing staff of the Peritoneal Dialysis Center of Peking University First Hospital. Support: This work is supported in part by a Renal Research Grant (Baxter, China), an International Society of Nephrology (ISN) Research Award from the ISN Global Outreach Research and Prevention Committee, and a Capital Characteristic Clinic Research Grant from the Beijing Science & Technology Committee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: JD; data collection: ZY, ZQ, HW, XT; data analysis/interpretation: RX, JD; statistical analysis: RX; mentorship: DWJ. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JD takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned and registered have been explained. Peer Review: Evaluated by 2 external peer reviewers, a Statistical Editor, a Co-Editor, and Editor-in-Chief Levey.
REFERENCES 1. Jain AK, Blake P, Cordy P, Garg AX. Global trends in rates of peritoneal dialysis. J Am Soc Nephrol. 2012;23(3):533-544. 2. Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int. 2010;30(4):393-423. 3. Li PK, Szeto CC, Piraino B, et al. ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int. 2016;9-10;36(5):481-508. 4. Chidambaram M, Bargman JM, Quinn RR, et al. Patient and physician predictors of peritoneal dialysis technique failure: a population based, retrospective cohort study. Perit Dial Int. 2011;31(5):565-573. 5. Grace BS, Clayton P, Cass A, McDonald SP. Socio-economic status and incidence of renal replacement therapy: a registry study of Australian patients. Nephrol Dial Transplant. 2012;27(11):4173-4180. 6. Martin LC, Caramori JC, Fernandes N, et al. Geographic and educational factors and risk of the first peritonitis episode in Brazilian Peritoneal Dialysis study (BRAZPD) patients. Clin J Am Soc Nephrol. 2011;6(8):1944-1951. 7. Sanabria M, Munoz J, Trillos C, et al. Dialysis Outcomes in Colombia (DOC) study: a comparison of patient survival on peritoneal dialysis vs hemodialysis in Colombia. Kidney Int Suppl. 2008;108:S165-S172. 8. Nikolaidis P. Newer quinolones in the treatment of continuous ambulatory peritoneal dialysis (CAPD) related infections. Perit Dial Int. 1990;10(2):127-133. 9. 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. 1990;15(2):155-159. 10. 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. 1991;11(1):27-30.
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Xu et al 11. 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. 1990;26(suppl F):73-76. 12. Tapson JS, Orr KE, George JC, et al. A comparison between oral ciprofloxacin and intraperitoneal vancomycin and netilmicin in CAPD peritonitis. J Antimicrob Chemother. 1990;26(suppl F):63-71. 13. 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. 1993;13(suppl 2):S351-S354. 14. Ignatius KP, Cheng SL, Fang GX, et al. A randomized prospective comparison of oral versus intraperitoneal ofloxacin as the primary treatment of CAPD peritonitis. Nephrology (Carlton). 1997;3(6):431-435. 15. Lima RC, Barreira A, Cardoso FL, Lima MH, Leite M Jr. Ciprofloxacin and cefazolin as a combination for empirical initial therapy of peritoneal dialysis-related peritonitis: five-year followup. Perit Dial Int. 2007;27(1):56-60. 16. Troidle L, Gorban-Brennan N, Kliger A, Finkelstein F. Once-daily intraperitoneal cefazolin and oral ciprofloxacin as empiric therapy for the treatment of peritonitis. Adv Perit Dial. 1999;15:213-216. 17. 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. 1993;13(suppl 2):S348-S350. 18. Nye KJ, Gibson SP, Nwosu AC, et al. Single-dose intraperitoneal vancomycin and oral ciprofloxacin for the treatment of peritonitis in CAPD patients: preliminary report. Perit Dial Int. 1993;13(1):59-60. 19. Goffin E, Pouthier D, Vandercam B, Gigi J. IV vancomycin-oral ciprofloxacin: a safe and efficient therapeutic protocol for CAPD peritonitis (preliminary report). Perit Dial Int. 1996;16(2):174-177. 20. Goffin E, Pouthier D, Vandercam B, Gigi J, van Ypersele de Strihou C. Oral ciprofloxacin to treat bacterial peritonitis
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associated with peritoneal dialysis. Clin Nephrol. 1997;48(6):391392. 21. 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. 1998;18(4):371-375. 22. Blot S, De Waele JJ, Vogelaers D. Essentials for selecting antimicrobial therapy for intra-abdominal infections. Drugs. 2012;72(6):e17-e32. 23. Karageorgopoulos DE, Falagas ME. New antibiotics: optimal use in current clinical practice. Int J Antimicrob Agents. 2009;34(suppl 4):S55-S62. 24. Simoens S, Decramer M. A pharmacoeconomic review of the management of respiratory tract infections with moxifloxacin. Expert Opin Pharmacother. 2008;9(10):1735-1744. 25. Zhanel GG, Fontaine S, Adam H, et al. A review of new fluoroquinolones: focus on their use in respiratory tract infections. Treat Respir Med. 2006;5(6):437-465. 26. Szeto CC, Kwan BC, Chow KM, et al. Recurrent and relapsing peritonitis: causative organisms and response to treatment. Am J Kidney Dis. 2009;54(4):702-710. 27. 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. 2005;68(5):23752380. 28. Zacharioudakis IM, Zervou FN, Ziakas PD, Mylonakis E. Meta-analysis of methicillin-resistant Staphylococcus aureus colonization and risk of infection in dialysis patients. J Am Soc Nephrol. 2014;25(9):2131-2141. 29. Kitterer D, Latus J, Pohlmann C, Alscher MD, Kimmel M. Microbiological surveillance of peritoneal dialysis associated peritonitis: antimicrobial susceptibility profiles of a referral center in Germany over 32 years. PLoS One. 2015;10(9):e0135969. 30. Troidle L, Gorban-Brennan N, Kliger A, Finkelstein FO. Continuous peritoneal dialysis-associated peritonitis: a review and current concepts. Semin Dial. 2003;16(6):428-437.
Am J Kidney Dis. 2016;-(-):---
T
he global use of peritoneal dialysis (PD) is rapidly growing, particularly in developing countries, where the number of PD patients has increased 2.5-fold during the past 12 years.1 However, one of the major barriers to PD is PD-related
peritonitis, which adversely affects both technique and patient survival and also increases the financial burden on patients and health care systems. According to the 2010 and 2016 International Society for Peritoneal Dialysis (ISPD) guidelines for the
From the 1Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health; Key Laboratory of Renal Disease, Ministry of Education; Beijing, China; and 2Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia. Received July 13, 2016. Accepted in revised form November 7, 2016. Trial registration: www.ClinicalTrials.gov; study number: NCT02787057.
Address correspondence to Jie Dong, MD, Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health; Key Laboratory of Renal Disease, Ministry of Education; Beijing, China. E-mail: dongjie@medmail. com.cn 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.11.008
Am J Kidney Dis. 2016;-(-):---
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Xu et al
management of peritonitis, empirical antibiotics should cover both Gram-positive and Gram-negative organisms and preferably should be administered intraperitoneally.2,3 However, intraperitoneal administration outside the hospital is difficult, particularly for elderly and diabetic PD patients, who often have impaired visual acuity, dexterity, and cognitive function. Moreover, intraperitoneal administration increases daily treatment time and could lead to an increase in the number of patients discontinuing treatment. These concerns are more prominent for patients with lower socioeconomic status; this includes a large proportion of PD populations in both developed4,5 and developing countries.6,7 Oral administration of antibiotics is a more convenient and economical regimen and could be a substitute or complementary therapy for the treatment of peritonitis. Fluoroquinolones are the most-cited oral agents because of their rapid and substantial absorption in the gut and the achievement of therapeutic concentrations in plasma and dialysate, among others.8 Although oral monotherapy with quinolones is reported to cure only 40% to 78% of peritonitis episodes,9-14 this rate could reach 73% to 94% when combined with cefazolin15,16 or vancomycin.17-21 However, limited studies comparing the efficacy of oral quinolone administration combined with intraperitoneal cefazolin or vancomycin have yielded inconclusive results. Only 2 of these studies were randomized controlled trials and were limited by small sample sizes, short treatment durations, and short follow-up periods.17,21 Thus, in the absence of adequate evidence for clinical efficacy, oral fluoroquinolones are recommended by the 2010 ISPD peritonitis guidelines only for the treatment of mild peritonitis episodes.2 Therefore, we conducted a pilot study to compare the complete cure rate and primary or secondary treatment failure rate of oral quinolones plus intraperitoneal vancomycin (ie, treatment group) and conventional intraperitoneal vancomycin plus ceftazidime (ie, control group). Moxifloxacin is part of a newer generation of fluoroquinolones and was selected for its lower antimicrobial resistance and wider antibacterial spectrum compared with other fluoroquinolones.22-24 Moxifloxacin also has a longer half-life than other quinolones and requires administration only once daily.25 In addition, moxifloxacin is unique among fluoroquinolones in that it is primarily excreted via nonrenal mechanisms, so dosage adjustment is unnecessary in patients with decreased kidney function.25 Vancomycin was chosen for both arms of the trial based on its excellent treatment of Gram-positive organisms, convenient administration, and widespread global use in peritonitis management. We hypothesized that combination therapy of 2
intraperitoneal vancomycin and oral moxifloxacin would result in a complete cure rate and primary or secondary treatment failure rates comparable to those of conventional intraperitoneal vancomycin plus ceftazidime.
METHODS Patient Eligibility The pilot study was conducted in the PD center of Peking University First Hospital in November 2012 to March 2016. All consecutive peritonitis episodes in our center were screened for eligibility for patient enrollment into this prospective, open-label, parallel-arm, randomized, controlled trial. Inclusion criteria were as follows: incident or prevalent continuous ambulatory PD patients, diagnosis of acute peritonitis according to the ISPD guideline,2 and age older than 18 years. Exclusion criteria were receiving antibiotic treatment for other reasons when peritonitis occurred; contraindication to cephalosporin, vancomycin, or fluoroquinolones; concomitant exit-site or tunnel infection; requirement for immediate transfer to hemodialysis therapy due to sepsis, gastrointestinal perforation or visceral inflammation, severe bowel obstruction, or ultrafiltration failure at the initiation of peritonitis; inability to tolerate oral administration due to severe gastrointestinal complication or other reasons; history of psychological illness or condition that interfered with the ability to understand or adhere to the requirements of the study; and pregnant or breast-feeding. If all selection criteria were fulfilled, the patient was randomly assigned by a computer-generated random number list. Reasons for noninclusions were recorded. To avoid contamination bias, participants were not permitted to re-enroll in the trial for subsequent episodes of peritonitis. Researchers and patients were not blinded to treatment allocation, although statisticians analyzing the data were. Written informed consent was obtained from each patient. The ethics committee of Peking University First Hospital approved the study (approval number: 201D22).
Interventions Eligible patients were randomly assigned to receive either intraperitoneal vancomycin, 1 g, every 5 days combined with oral moxifloxacin, 400 mg, every day (treatment group), or intraperitoneal vancomycin, 1 g, every 5 days combined with intraperitoneal ceftazidime, 1 g, every day (control group). Moxifloxacin had to be taken at an interval of 2 hours before or 4 hours after taking aluminum- or magnesium-containing antacids or iron supplements in order to ensure that the effect of any interaction was not clinically relevant. For both the treatment and control groups, further treatment adjustment for peritonitis (with either resistant pathogens or sensitive pathogens) was based on patients’ clinical responses and results of PD effluent culture according to ISPD guideline recommendations.2 If the peritonitis episode failed to respond to the assigned antibiotics by day 3, the antibiotics were adjusted according to bacterial culture results or changed to second-line antibiotics if the bacterial cultures gave negative results. Duration of treatment was based on ISPD guideline recommendations.2 Routine follow-up visits were scheduled on days 1, 3, 5, 7, 10, 14, and 21 following initiation of treatment. Patients were switched to hemodialysis therapy and their PD catheters were subsequently removed if they had a lack of improvement after 7 to 14 days of appropriate antibiotic therapy, PD dialysate grew yeast species or Mycobacterium tuberculosis at any time, or a concomitant tunnel infection was diagnosed, as suggested by the ISPD guidelines.2 Am J Kidney Dis. 2016;-(-):---
Empirical Antibiotics for PD-Related Peritonitis
Outcomes The primary end point in this study was complete cure, which was defined as complete resolution of peritonitis (normalization of body temperature, resolution of abdominal pain, clearing of dialysate, and PD effluent white blood cell [WBC] count , 100 cells/ mL with ,50% polymorphonuclear cells) by using antibiotics alone without relapse within 4 weeks of completion of therapy.26 Secondary end points were primary or secondary treatment failure. Primary treatment failure was defined as the presence of fever, abdominal pain, or turbid peritoneal dialysate, together with a total peritoneal WBC count . 50% of the pretreatment value after 3 days of treatment with the assigned antibiotics.27 Secondary treatment failure was defined as treatment failure despite adjustment of antibiotics or changing to second-line antibiotics for at least 3 days in patients with primary treatment failure.27 Peritonitis episodes occurring within 3 months after complete resolution of peritonitis were recorded and categorized as relapsing, recurrent, or repeat according to ISPD guidelines.2 For episodes that occurred more than 4 weeks after completion of therapy of a prior episode with a different organism, we defined it as “other type.” Peritonitis-related death was defined as death of a patient with active peritonitis, admitted with peritonitis, or within 2 weeks of a peritonitis episode.
Statistical Analyses Statistical analysis was performed by SPSS for Windows software, version 13.0 (SPSS Inc). All data were expressed as mean 6 standard deviation for normally distributed data and median with interquartile range for skewed data. Categorical variables were expressed as percentage. Patients’ data were compared using c2 test for categorical variables, t test for normally distributed continuous variables, and Mann-Whitney U test for skewed continuous variables. Changes over time of effluent WBC counts were also compared between groups using a mixed-model analysis of variance, with bootstrap covariance accounting for correlation among repeated measures within a patient. The baseline value of the effluent WBC count was adjusted as a model covariate.
RESULTS
(0.23 episode/patient-year). Of the 207 episodes, 127 were excluded (45, not meeting inclusion criteria; 47, declined to participate; and 35, other reasons; Fig 1). This left 80 episodes for analysis. Patients with these episodes were randomly assigned and equally allocated into either the treatment (ie, intraperitoneal vancomycin plus oral moxifloxacin) or control group (ie, intraperitoneal vancomycin plus intraperitoneal ceftazidime). There were no significant differences in demographics, clinical parameters, or outcomes between patients with included and excluded episodes. Clinical Characteristics Baseline demographic, clinical, and laboratory characteristics were similar between the treatment and control groups (Table 1). Microbiological spectra of peritonitis episodes were also similar between the 2 groups; the proportions of Gram-positive and Gramnegative bacteria were 77% and 19% in the treatment group and 73% and 23% in the control group, respectively (Table 2). Culture-negative rates were 23% and 25% for the treatment and control groups, respectively. There was 1 episode of fungal peritonitis in each group (Table 2). The effluent WBC count between days 0 and 10 was not significantly different between groups. In addition, the effluent WBC count in both the treatment and control groups decreased comparably over time (Table 3). Antibiotics were adjusted in 7 (18%) patients in the treatment group and 6 patients (15%) in the control group (P 5 0.8; Table 3). Primary and Secondary Outcomes
Enrollment and Follow-up There were 207 episodes of peritonitis in our center from November 1, 2012, through March 11, 2016
Primary Outcome The complete cure rate was 78% in the treatment group and 80% in the control group (odds ratio [OR],
Assessment for elegibility (n=207) Excluded (n=127) . Not meeting inclusion criteria (n=45) . Declined to participate (n=47) . Other reason (n=35) Randomized (n=80)
Allocated to Vancomycin+Moxifloxacin . Received allocated intervention (n=40) . Did not receive allocated intervention (n=0)
Allocated to Vancomycin+Cefoperazone . Received allocated intervention (n=40) . Did not receive allocated intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Analyzed (n=40) . Excluded from analysis (n=0)
Analyzed (n=40) . Excluded from analysis (n=0)
Figure 1. Study flow chart. Am J Kidney Dis. 2016;-(-):---
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Xu et al Table 1. Baseline Demographic and Clinical Data for the Treatment and Control Groups
Age, y Male sex PD vintage, mo Diabetes mellitus CVD history First peritonitis episode Hemoglobin, g/L Albumin, g/L Total Kt/V RKF, mL/min
Treatment (n 5 40)
Control (n 5 40)
57.2 6 13.0 25 (63) 31.1 [9.5-62.1] 19 (48) 11 (28) 31 (78) 111.7 6 14.4 36.8 6 4.9 1.90 6 0.3 1.0 [0-4.5]
58.0 6 15.7 24 (60) 36.7 [10.2-73] 13 (33) 16 (40) 26 (65) 109.6 6 15.0 36.2 6 4.2 1.83 6 0.4 0.4 [0-2.9]
Note: Treatment, intraperitoneal vancomycin plus oral moxifloxacin; control, intraperitoneal vancomycin plus intraperitoneal ceftazidime. Values for categorical variables are given as count (percentage); values for continuous variables, as mean 6 standard deviation or median [interquartile range]. Abbreviations: CVD, cardiovascular disease; Kt/V, (urinary 1 peritoneal) urea clearance; PD, peritoneal dialysis; RKF, residual kidney function.
Secondary Outcomes Comparing the treatment and control groups, primary (33% vs 20%; OR, 1.93 [95% CI, 0.70-5.34]; P 5 0.2) and secondary (10% vs 13%; OR, 0.78 [95% CI, 0.19-3.14]; P 5 0.7) treatment failure rates were not significantly different. Six patients in each group transferred to hemodialysis therapy (in randomly assigned treatment group: 5 due to peritonitis treatment failure and 1 due to fungal peritonitis; in the control group: 3, 1, 1, and 1 due to peritonitis treatment failure, congestive heart failure, fungal peritonitis, and fungal superinfection, respectively). Two peritonitis-related deaths were recorded; 1 in the treatment group due to gastrointestinal hemorrhage and 1 in the control group due to sepsis. There were no deaths during the 3 months of follow-up (ie, after completion of peritonitis therapy). Details of peritonitis outcomes in the treatment and control groups are shown in Fig 2A and B.
Adverse Events 0.86; 95% confidence interval [CI], 0.30-2.52; P 5 0.8). There were 3 relapse episodes in the treatment group and 1 in the control group (OR, 2.62; 95% CI, 0.63-10.95; P 5 0.2; Table 3). In addition, there were 4 patients in the treatment group (1 recurrent, 1 repeat, 1 other type, and 1 for whom effluent was not sent for bacterial culturing) and 2 patients in the control group (1 repeat and 1 other type) who had successive episodes of peritonitis during the study period. Table 2. Causative Microorganisms in the Treatment and Control Groups Total
Treatment
Control
Gram-positive organism Staphylococcus epidermidis Staphylococcus aureus Streptococcus Enterococcus Other
46 20 7 9 2 8
(75) (33) (12) (15) (3) (13)
24 10 3 4 2 5
(77) (32) (10) (13) (7) (16)
22 10 4 5 0 3
(73) (33) (13) (17) (0) (10)
Gram-negative organism Escherichia coli Klebsiella spp Acinetobacter baumannii Other
13 1 3 2 7
(21) (2) (5) (3) (12)
6 1 0 1 4
(19) (3) (0) (3) (13)
7 0 3 1 3
(23) (0) (10) (3) (10)
Fungi Culture-negative
2 (3) 19 (24)a
1 (3) 9 (23)a
1 (3) 10 (25)a
Note: Treatment, intraperitoneal vancomycin plus oral moxifloxacin; control, intraperitoneal vancomycin plus intraperitoneal ceftazidime. Values are given as count (percentage). Except where indicated, denominators for percentages are culturepositive episodes in the applicable group. P for overall distribution 5 0.7. a Denominators for percentages are all episodes in the applicable group. 4
One patient in the treatment group reported mild nausea after oral moxifloxacin; the nausea disappeared after adjusting the time of administration. One patient in the control group reported a mild rash, which resolved following treatment with oral antiallergy drugs. No other adverse events were reported.
DISCUSSION Peritonitis is still a leading complication of PD and contributes to technique failures, hospitalizations, and occasionally deaths.2 When clinical evidence of infectious peritonitis manifests, empirical antibiotic therapy must be initiated as soon as possible.2 However, as previously discussed, the intraperitoneal administration of antibiotics, which is the standard therapy recommended by the ISPD,2 has many limitations in clinical practice. Thus, treatments that save time and are less manpower dependent without reducing efficacy would be highly valuable. Few studies have addressed this issue; therefore, we conducted a pilot study to explore the effectiveness of a convenient and less expensive regimen (ie, intraperitoneal vancomycin plus oral moxifloxacin) with the traditional empirical regimen (ie, intraperitoneal vancomycin plus intraperitoneal ceftazidime). Our results demonstrate that there are no substantial differences in therapeutic response between the 2 regimens; thus, the combination of intraperitoneal vancomycin and oral moxifloxacin could be a suitable initial empirical regimen for the treatment of PD-related peritonitis. In this study, intraperitoneal vancomycin plus oral moxifloxacin resulted in a complete cure rate of 78%, which is higher than the rate reported in most previous fluoroquinolone-related studies (40%-78%).9-14 One possible reason for this is that moxifloxacin has Am J Kidney Dis. 2016;-(-):---
Empirical Antibiotics for PD-Related Peritonitis Table 3. Comparisons of Primary and Secondary Outcomes Between Treatment and Control Groups Treatment (n 5 40)
Control (n 5 40)
1,460 [737-3,000] 275 [95-1,265] 85 [31-390] 27 [5-80] 43 [6-95] 7 [1-88]
2,050 [1,013-3,154] 375 [130-1,082] 82 [20-229] 10 [2-22] 5 [1-19] 2 [2-12]
Primary end point Complete cure
31 (78)
32 (80)
0.86 (0.30-2.52)
0.8
Secondary end points Primary treatment failure Secondary treatment failure
13 (33) 4 (10)
8 (20) 5 (13)
1.93 (0.70-5.34) 0.78 (0.19-3.14)
0.2 0.7
Adjustment of antibiotics Transfer to HD Congestive heart failure Persistent elevation of effluent WBC count Fungal peritonitis Fungal superinfection
7 (18) 6 (15) 0 (0) 5 (13) 1 (3) 0 (0)
6 (15) 6 (15) 1 (3) 3 (8) 1 (3) 1 (3)
1.20 (0.37-3.96) 1.00 (0.29-1.41)
0.8 0.9
Peritonitis-related death Sepsis Gastrointestinal hemorrhage
1 (3) 0 (0) 1 (3)
1 (3) 1 (3) 0 (0)
1.00 (0.06-16.56)
0.9
Successive episodes of peritonitis during 3-mo follow-up Relapsing peritonitis Recurrent peritonitis Repeat peritonitis Bacteria untested Other
7 (18) 3 (8) 1 (3) 1 (3) 1 (3) 1 (3)
3 1 0 1 0 1
2.62 (0.63-10.95)
0.2
Outcome of successive episodes of peritonitis Transfer to HD Maintenance of PD
1.40 (0.88-2.24)b
0.3
2 (29) 5 (71)
0 (0) 3 (100)
All-cause death during 3-mo follow-up
0 (0)
0 (0)
—
—
Effluent WBC count (cells/mL) Day 0 Day 1 Day 3 Day 5 Day 7 Day 10
(8) (3) (0) (3) (0) (3)
OR (95% CI)a
P
0.3 0.5 0.5 0.5 0.07 0.09 0.3
Note: Treatment, intraperitoneal vancomycin plus oral moxifloxacin; control, intraperitoneal vancomycin plus intraperitoneal ceftazidime. Values for categorical variables are given as count (percentage); values for continuous variables, as median [interquartile range]. Abbreviations: CI, confidence interval; HD, hemodialysis; OR, odds ratio; PD, peritoneal dialysis; WBC, white blood cell. Definitions: All-cause death, all causes of death within 3 months of completion of therapy; catheter removal and HD transfer (temporary or permanent), removal of the PD catheter was considered for patients with primary treatment failure whose peritonitis failed to improve after adjusting antibiotic regimen(s) for 3 to 5 days (ie, secondary treatment failure), patients were then put on temporary HD therapy, and patients were switched to long-term HD therapy according to their desire, when attempts at Tenckhoff catheter reinsertion failed because of peritoneal adhesion or there was ultrafiltration failure from peritoneal sclerosis; complete cure, complete resolution of peritonitis (ie, normalization of body temperature, resolution of abdominal pain, clearing of dialysate, PD effluent neutrophil count , 100 cells/mL, and proportion of polynuclear cells , 50%) by use of antibiotics alone, without relapse, within 4 weeks of therapy completion; other type, an episode that occurs more than 4 weeks after completion of therapy of a prior episode with different organism; peritonitis-related death, death of a patient with active peritonitis, admitted with peritonitis, or within 2 weeks of a peritonitis episode; primary treatment failure, presence of abdominal pain, fever, and turbid peritoneal dialysate, as well as total peritoneal WBC counts . 50% of pretreatment values, after 3 days of treatment by assigned antibiotics; recurrent peritonitis, an episode that occurs within 4 weeks of completion of therapy of a prior episode but with different organism; relapsing peritonitis, an episode that occurs within 4 weeks of completion of therapy of a prior episode with same organism or 1 sterile episode; repeat peritonitis, an episode that occurs more than 4 weeks after completion of therapy of a prior episode with same organism; secondary treatment failure, treatment failure despite antibiotic adjustment or changing to second-line antibiotics for 3 to 5 days in patients with primary treatment failure. a Control group as reference. b Risk for transferring to HD therapy for successive episodes of peritonitis.
Am J Kidney Dis. 2016;-(-):---
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Xu et al
A
Primary treatment success n=27
Relapsed after peritonitis resolved (n=3)
Treatment group n=40
Primary treatment failure n=13
Antibiotics adjustment if needed
Peritonitis resolved without relapsing (n=24)
Peritonitis resolved without relapsing (n=7)
WCC decreased less than 50% within 3 days (i.e. secondary treatment failure) and transferred to HD (n=4) WCC decreased more than 50% within 3 days but transferred to HD due to WCC persistently higher than 100/ul (n=1)
Complete cure (n=31)
B
Primary treatment success n=32
Transferred to HD due to fungal superinfection (n=1)
Transferred to HD after identified as fungal peritonitis (n=1)
Control group n=40
Primary treatment failure n=8
Antibiotics adjustment if needed
Peritonitis resolved without relapsing (n=31) Peritonitis resolved without relapsing (n=1)
WCC decreased less than 50% within 3 days (i.e. secondary treatment failure, n=4) and transferred to HD (n=3) or death (n=1) WCC decreased more than 50% within 3 days but transferred to HD due to heart failure (n=1) Transferred to HD after identified as fungal peritonitis (n=1)
Complete cure (n=32) Peritonitis resolved with relapsing (n=1)
Figure 2. Details of peritonitis outcomes in the (A) treatment group and (B) control group. Abbreviations: HD, hemodialysis; WCC, white blood cell count.
a wider antibiotic spectrum, greater antibiotic activity, and lower antimicrobial resistance than former generations of fluoroquinolones.22-24 Another possible reason is that the combination with vancomycin, rather than a first-generation cephalosporin, increased the rate of successful treatment. Vancomycin will likely be included in more initial regimens for Grampositive coverage in light of the increasing worldwide incidence of methicillin-resistant Staphylococcus in dialysis patients.28,29 In this study, 14 of 20 cases of Staphylococcus epidermidis and 2 of 7 cases of Staphylococcus aureus were methicillin resistant. However, it should be noted that moxifloxacin has better Gram-positive coverage but less broad Gramnegative coverage than other quinolones,25 and this empirical choice may not be optimal in areas with high fluoroquinolone resistance. The number of peritonitis cases that relapsed within 4 weeks was low overall, although higher in the treatment group than in the control group (3 vs 1; 6
P 5 0.3). This finding is not necessarily indicative of ineffective treatment. First, the pathogens causing the relapses in the treatment group were S epidermidis (2 cases) and Proteus mirabilis (1 case). Both S epidermidis strains were methicillin resistant and sensitive to vancomycin, and the P mirabilis strain was sensitive to moxifloxacin. Therefore, the new empirical regimen covered these pathogens adequately. Second, the effluent WBC count in all 3 episodes decreased to ,100 cells/mL within 5 days, which supports the efficacy of the new empirical regimen. Previous studies have shown that relapsing peritonitis is possibly caused by bacteria sequestered in biofilm30; further investigation with a larger sample size is necessary to determine whether the new regimen increases the risk for relapsing peritonitis and thus an infection not susceptible to antibiotics administered intraperitoneally or systemically. To our knowledge, this is the first study investigating the efficacy and safety of intraperitoneal Am J Kidney Dis. 2016;-(-):---
Empirical Antibiotics for PD-Related Peritonitis
vancomycin plus oral moxifloxacin for the treatment of PD-related peritonitis. Our findings provide important information for this potential first-line empirical regimen. Based on this pilot study, a welldesigned multicenter study with a large sample size is needed to further clarify the efficacy and costeffectiveness of this empirical regimen. There were some limitations to our study. First, although this pilot study had a larger sample size than most previous studies,9-21 statistical power for discerning small differences in efficacy and harms between the treatment and control groups was limited. Particularly, with only 13 Gram-negative rods and 19 culture-negative peritonitis episodes, the efficacy of moxifloxacin versus ceftazidime was really based on only 32 episodes of peritonitis. According to our analysis based on a noninferiority trial design (if the noninferiority limit is set at 10%), we estimate that 275 patients in each arm would be needed to provide 90% statistical power (for a 1-tailed test with a error 5 0.05) to discern differences between the groups. An extensive multicenter randomized controlled trial with a large sample size will need to be conducted to improve statistical power. Second, the eligibility ratio was low, and 61% of episodes that occurred at our center during the study were excluded. However, the demographics, clinical parameters, and outcomes were not significantly different between patients with included and excluded episodes. Finally, 71% of episodes in this study were first episodes; however, clinicians often have to manage successive episodes of peritonitis. According to our center’s database, about half the peritonitis episodes were repeat cases. Future studies should be undertaken to confirm whether our results hold for repeat cases. Patient enrollment was relatively slow in this study. Only 39% of peritonitis episodes occurring during the study period qualified for the study; this was lower than our initial estimate (60%). A multicenter trial could speed up the enrollment and meet sample size requirements for further analysis. The proposed studies are not sophisticated or time consuming. All enrolled patients were able to follow our protocol, no patients were lost during follow-up, and no severe adverse events were reported. This pilot study suggests that intraperitoneal vancomycin plus oral moxifloxacin is a safe, welltolerated, and effective treatment that potentially could be used as a first-line empirical treatment regimen for PD-related peritonitis. Patients appeared to adhere well to the treatment regimen, which would reduce medical expenses compared to daily intraperitoneal antibiotic administration. These results support implementation of a randomized, multicenter, controlled study with a larger sample size.
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ACKNOWLEDGEMENTS The authors thank the patients, doctors, and nursing staff of the Peritoneal Dialysis Center of Peking University First Hospital. Support: This work is supported in part by a Renal Research Grant (Baxter, China), an International Society of Nephrology (ISN) Research Award from the ISN Global Outreach Research and Prevention Committee, and a Capital Characteristic Clinic Research Grant from the Beijing Science & Technology Committee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: JD; data collection: ZY, ZQ, HW, XT; data analysis/interpretation: RX, JD; statistical analysis: RX; mentorship: DWJ. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JD takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned and registered have been explained. Peer Review: Evaluated by 2 external peer reviewers, a Statistical Editor, a Co-Editor, and Editor-in-Chief Levey.
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