Linking clinical manifestations and causative organisms may provide clues for the treatment of peritoneal dialysis-associated peritonitis

Abstract

Introduction

Different initial manifestations of peritoneal dialysis-associated peritonitis (PDAP) may depend on the type of pathogenic organism. We investigated the association between the clinical characteristics of PDAP and susceptibility to vancomycin and investigated the possibility of using vancomycin monotherapy alone as an initial treatment regimen for some PDAP patients to avoid unnecessary antibiotic exposure and secondary infection.

Methods

Patients with culture-positive PDAP were retrospectively analyzed and divided into two groups: peritonitis with only cloudy effluent (PDAP-cloudy) or with cloudy effluent, abdominal pain and/or fever (PDAP-multi). The bacterial culture of PD effluent and antibiotic sensitivity test results were compared between groups. Logistic regression was used to investigate factors predicting susceptibility to vancomycin.

Results

Of 162 episodes of peritonitis which had a positive bacterial culture of PD fluid, 30 peritonitis were in the PDAP-cloudy group, and 132 peritonitis were in the PDAP-multi group. Thirty (100%) peritonitis in the PDAP-cloudy group had gram-positive bacterial infections, which was significantly greater than that in the PDAP-multi group (51.5%) (P < 0.001). Twenty-nine (96.7%) peritonitis in the PDAP-cloudy group were susceptible to vancomycin, compared to 67 (50.8%) in the PDAP-multi group (P < 0.001). The specificity of PDAP-cloudy for vancomycin-sensitive peritonitis was 98.48%. Only one patient (3.3%) in the PDAP-cloudy group experienced vancomycin-resistant peritonitis caused by Enterococcus gallinarum, which could neither be covered by vancomycin nor by the initial antibiotic regimen recommended by the current ISPD guidelines. The presence of only cloudy effluent was an independent predictor of susceptibility to vancomycin according to multivariate analysis (OR = 27.678, 95% CI 3.191-240.103, p = 0.003), in addition to PD effluent WBC counts (OR = 0.988, 95% CI 0.980–0.996, p = 0.004), diabetes mellitus (OR = 3.646, 95% CI 1.580–8.416, p = 0.002), first episode peritonitis (OR = 0.447, 95% CI 0.207–0.962, p = 0.039) and residual renal creatinine clearance (OR = 0.956, 95% CI 0.918–0.995, p = 0.027). Addition of these characteristics increased the AUC to 0.813 (95% CI 0.0.749–0.878, P < 0.001). The specificity of presenting with only cloudy effluent for vancomycin-sensitive peritonitis was 98.48%.

Conclusions

Cloudy dialysate, as the only symptom at PDAP onset, was an independent predictor of vancomycin-sensitive PDAP, which is an important new insight that may guide the choice of initial antibiotic treatment.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-024-03756-y.

Introduction

Peritoneal dialysis (PD) is an effective renal replacement therapy for the treatment of end-stage renal disease [1]. However, PD-associated peritonitis (PDAP) is a serious complication that is the greatest contributor to infection-related morbidity, including the risk of hospitalization, temporary or permanent transfer to hemodialysis and mortality [2–5]. Timely and effective treatment of PDAP is essential [6].

A precise etiological diagnosis and early targeted antibiotic therapy are highly desirable [4]. However, the causative organisms are difficult to determine at the time of initial diagnosis of peritonitis [3, 7, 8]. Consequently, ISPD recommends that gram-positive organisms be covered by a first-generation cephalosporin or vancomycin and that gram-negative organisms be covered by a third-generation cephalosporin or an aminoglycoside. However, broad-spectrum antibiotic coverage increases the possibility of secondary infections such as fungal peritonitis episodes and potential problems (including drug interactions and the emergence of resistant strains) with fungal prophylaxis treatment.

According to a previous study, the most common germs causing PDAP were gram-positive, including coagulase-negative staphylococci, which are the most frequent cause of PDAP in many centers, with an oxacillin resistance rate of 69.6% [9, 10]. Theoretically, vancomycin is a tricyclic glycopeptide antibiotic with broad-spectrum activity against gram-positive bacteria. It is effective for the treatment of gram-positive peritonitis, including that caused by coagulase-negative Staphylococcus. In addition to cephazolin, which can only cover some coagulase-negative Staphylococcus strains, vancomycin can also cover methicillin-resistant Staphylococcus aureus (MRSA) [11, 12]. The use of vancomycin as the first treatment for gram-positive peritonitis was found to be an independent predictor of resolution [10]. However, identifying how to treat PDAP with vancomycin alone is a challenge.

In practice, a substantial percentage of peritonitis patients present with only cloudy effluent, without abdominal pain or fever [3]. This manifestation is always linked to gram-positive organisms, including coagulase-negative Staphylococcus [10]. We hypothesized that certain clinical manifestations could be indicators for initial vancomycin monotherapy.

Therefore, In the present study, we analyzed the initial clinical manifestations of culture-positive PDAP, including patients who presented with only cloudy effluent and patients who presented with cloudy effluent, abdominal pain and/or fever. We linked the clinical characteristics of peritonitis to the susceptibility of the causative organism to vancomycin and investigated the possibility of using vancomycin monotherapy as an initial treatment regimen for some patients with PDAP to avoid unnecessary antibiotic exposure and secondary infection.

Materials and methods

Study population

This study retrospectively recruited patients who experienced PDAP in the Department of Nephrology, Peking University Third Hospital, from February 1, 2015, to July 31, 2022. In our center, after PD initiation, all patients were closely followed by dedicated nurse. Most of our patients performed continuous ambulatory peritoneal dialysis and dialysate containing 132 mmol/l of sodium and 1.5 or 2.5% glucose concentration (Dianeal, Baxter Healthcare, Tianjing, China) was used in all the patients.

Patient included in the present study were > 18 years of age and met the diagnostic criteria for PDAP by per International Society for Peritoneal Dialysis (ISPD). Patients were excluded if (1) the initial diagnosis of peritonitis was from another hospital, (2) a culture was not collected or was negative, (3) data for initial clinical manifestations were missing, or (4) relapsing peritonitis. In our center, followed ISPD guideline, our center’s empirical initial antibiotic treatment regimen including gram-positive coverage using vancomycin and gram-negative coverage using ceftazidime.

This study was approved by the Peking University Third Hospital Ethical Committee (M2024088).

Patients’ peritonitis were divided into two groups based on the clinical manifestations at the initial diagnosis of peritonitis: patients who presented with only cloudy effluent and a dialysis effluent with a white cell (WBC) count > 100/mL and > 50% polymorphonuclear leukocytes (PMNs) after a dwell time of at least 2 h were grouped into one group (PDAP-cloudy), whereas patients’ peritonitis who presented with cloudy effluent, abdominal pain and/or fever were grouped into another group (PDAP-multi). In addition, culture-positive patients’ peritonitis was divided based on whether the causative organism was sensitive or resistant to vancomycin.

Data collection

The general characteristics of the patients included sex, age, dialysis vintage, primary disease, and comorbidities (e.g., diabetes, hypertension, cardiovascular disease, cerebrovascular disease). Clinical data related to PDAP collected for patients included date of diagnosis of peritonitis; date of visit; initial clinical manifestations of peritonitis (e.g., cloudy dialysate fluid, abdominal pain, fever, and others); dialysis fluid analysis results (e.g., dialysis effluent WBC count and PMN count); bacterial culture testing results; antimicrobial susceptibility testing results; and clinical biochemical indicators (e.g., hemoglobin, serum albumin, and serum potassium) at the time of visit.

Statistical methods

All the data were analyzed using SPSS 26.0 statistical software (IBM Corp., Armonk, NY, USA). Count data are presented as numbers and percentages. Continuous data are expressed as the mean and standard deviation (SD) when normally distributed or as the median with first and third quartiles when nonnormally distributed. The chi-square test or Fisher’s precision probability test was used to compare count data as appropriate. Student’s t test or the Mann–Whitney U test was used to compare continuous data as appropriate. A conventional receiver-operating characteristic (ROC) curve analysis was employed to calculate the area under the curve for studied factors to find the ability of clinical manifestations to predict susceptibility to vancomycin. The sensitivity, specificity, negative predictive value and positive predictive value were calculated. Factors predicting susceptibility to vancomycin were analyzed using logistic regression. P < 0.05 was considered to indicate statistical significance.

Results

Baseline characteristics

A total of 109 patients with 162 episodes of peritonitis who had a positive bacterial culture of PD effluent were included (see Fig. 1). As shown in Table 1, the dialysis effluent WBC cell count in vancomycin-sensitive peritonitis was significantly lower than that in vancomycin-resistant peritonitis (P < 0.05). The proportion of patients with diabetes was significantly greater among vancomycin-sensitive peritonitis than vancomycin-resistant peritonitis (P < 0.05). Interestingly, vancomycin-sensitive peritonitis was more likely to have only cloudy effluent than vancomycin-resistant peritonitis (PDAP-cloudy group, 96.7% vs. PDAP-multi group, 3.3%, P < 0.001). In general, vancomycin-sensitive peritonitis had better PDAP outcomes with higher medical cure rate (80.2% vs. 50%, p < 0.001), lower peritonitis associated hemodialysis transfer (0% vs. 16.7%, p < 0.001) and lower peritonitis associated death (2.1% vs. 18.2%, p < 0.001) as compared with vancomycin-resistant peritonitis.

Fig. 1.

Flow chart for the study participants enrollment

Table 1.

Characteristics of patients and PDAP outcomes according to susceptibility to Vancomycin

Variable	Vancomycin sensitive (n = 96)	Vancomycin resistant (n = 66)	t/χ2/Z	P
Age	61.9 ± 13.5	62.8 ± 14.3	0.408	0.684
Sex (Male)	44 (45.8)	33 (50.0)	0.272	0.602
Primary disease			-0.023	0.982
Chronic glomerulonephritis	27 (28.1)	22 (33.3)
Chronic interstitial nephritis	5 (5.2)	5 (7.6)
Diabetic nephropathy	41 (42.7)	19 (28.8)
Hypertensive nephropathy	15 (15.6)	7 (10.6)
Polycystic kidney disease	2 (2.1)	7 (10.6)
Immunity, tumor	0	3 (4.5)
Other	6 (6.3)	3 (4.5)
Dialysis vintage (months)	56.5 (25.3, 93.2)	40.5 (21, 73.8)	-1.960	0.050
Comorbidities
Diabetes	53 (55.2)	22 (33.8)	7.108	0.008
Hypertension	74 (77.1)	48 (72.7)	0.399	0.528
Cardiovascular disease	26 (27.1)	15 (22.7)	0.393	0.531
Cerebrovascular disease	16 (16.7)	12 (18.2)	0.063	0.802
Dialysis effluent cell counts
WBC (unit/µl)	1454.5 (656.5, 3460.0)	4543 (1500.0, 9286.5)	-4.393	< 0.001
PMNs (%)	91.0 (86.0, 95.0)	93.0 (87.7, 96.0)	-1.436	0.152
Clinical manifestations			18.670	< 0.001
PDAP-cloudy	29 (96.7)	1 (3.3)
PDAP-multi	67 (50.8)	65 (49.2)
Clinical biochemical indicators
Hemoglobin (g/l)	114.5 ± 14.4	111.4 ± 18.9	-1.101	0.273
Serum albumin (g/l)	33.2 ± 5.2	33.0 ± 6.7	-0.197	0.844
Serum potassium (mmol/l)	4.1 ± 0.7	3.9 ± 0.7	-1.010	0.310
CAPD treatment	93(96.7%)	62 (93.9%)	0.815	0.444
Kt/V total	1.83 ± 0.30	1.90 ± 0.37		0.212
Kt/V residual	0.11 ± 0.22	0.19 ± 0.29		0.070
Ccr total	56.4 ± 8.54	59.2 ± 15.2		0.179
Residual Renal Ccr	4.33 ± 8.54	8.96 ± 15.65		0.031
First episode peritonitis	53(55.2%)	21(31.8%)	8.623	0.003
Medical cure	77(80.2%)	33(50.0%)	16.375	< 0.001
Recurrent peritonitis	1(1.0%)	1(1.5%)	0.072	0.789
Relapsing peritonitis	10 (10.4%)	5(7.6%)	0.376	0.540
Repeat peritonitis	6 (6.3%)	4(6.1%)	0.002	0.961
Peritonitis-associated hemodialysis transfer	0 (0%)	11(16.7%)	17.166	< 0.001
Peritonitis-associated death	2 (2.1%)	12 (18.2%)	12.838	< 0.001

Abbreviation: PDAP, peritoneal dialysis-associated peritonitis; PMNs, polymorphonuclear neutrophils; WBC, white blood cell; Ccr, creatinine clearance

Distribution and vancomycin susceptibility of pathogenic bacteria

Of the 162 peritonitis who had a positive bacterial culture of PD effluent, 30 episodes of peritonitis were in the PDAP-cloudy group, and 132 episodes of peritonitis were in the PDAP-multi group. The comparison of the two groups is presented in Supplement Table 1.

The results of peritoneal effluent culture and vancomycin susceptibility testing are presented in Table 2. Thirty (100%) peritonitis in the PDAP-cloudy group were positive for gram-positive bacteria, which was significantly greater than that in the PDAP-multi group (51.5%) (P < 0.001).

Table 2.

Distribution and Vancomycin susceptibility of pathogenic bacteria in patients with PDAP according to heterogeneity of clinical manifestations

PDAP-cloudy (n = 30)				PDAP-multi (n = 132)
Variable	Pathogen	N (%)	Vancomycin	Variable	Pathogen	N (%)	Vancomycin
G positive cocci		28(93.33)	–	G positive cocci		66(50)	–
	Staphylococcus epidermidis	7(23.33)	S		Staphylococcus epidermidis	20(15.15)	S
	Staphylococcus squirrel	5(16.67)	S		Staphylococcus aureus	11(8.33)	S
	Staphylococcus aureus	3(10.00)	S		Streptococcus salivarius	5(3.79)	S
	Staphylococcus hominis	3(10.00)	S		Enterococcus faecalis	4(3.03)	S
	Streptococcus hemolyticus	3(10.00)	S		Hemolytic Streptococcus	3(2.27)	S
	Streptococcus sanguinis	1(333)	S		Mycobacterium	3(2.27)	S
	Staphylococcus wausii	1(3.33)	S		Angina coccus	2(1.52)	S
	Hemolytic Staphylococcus	1(3.33)	S		Streptococcus sanguinis	2(1.52)	S
	Streptococcus delayed	1(3.33)	S		Other	15(11.36)	S
	Streptococcus agalactiae	1(3.33)	S		Enterococcus gallinarum	1(0.76)	R
	Staphylococcus goatis	1(3.33)	S
	Enterococcus gallinarum	1(3,33)	R
G positive bacillus		2 (6.67)	–	G positive bacillus		2(1.52)	–
	Lactobacillus	1 (3.33)	S		Bacillus cereus	2(1.52)	S
	Corynebacterium tiny	1 (3.33)	S
G negative bacteria		0	–	G negative bacteria		55(41.67)	–
					Escherichia coli	23(17.42)	R
					Pneumonia Kleb	9(6.82)	R
					Pseudomonas aeruginosa	5(3.79)	R
					Serratia marcescens	5(3.79)	R
					Acinetobacter baumannii	2(1.52)	R
					Enterobacter cloacae	2(1.52)	R
					Mirabilis	2(1.52)	R
					Other	7(5.30)	R
G negative coccus		0	–	G negative coccus		1(0.76)	–
					Neisseria mucus	1 (0.76)	R
Fungi		0	–	Fungi		4 (3.03)	–
					Candida parapsilosis	1 (0.76)	R
					Aspergillus nidulans	1 (0.76)	R
					Oriental yeast	1 (0.76)	R
					Candida albicans	1 (0.76)	R
Mixed		0	–	Mixed		4 (3.03)	–
					Escherichia coli, Enterococcus faecalis	1 (0.76)	R
					Klebsiella pneumoniae, Acinetobacter baumannii, fungi	1 (0.76)	R
					Klebsiella pneumoniae, Bacteroides fagillis (anaerobic bacteria)	1 (0.76)	R
					Pseudomonas aeruginosa, Enterobacter cloacae	1 (0.76)	R

Twenty-nine (96.7%) peritonitis in the PDAP-cloudy group were susceptible to vancomycin, compared to 67 (50.8%) in the PDAP-multi group (P < 0.001) (Fig. 2). Only one patient (3.3%) in the PDAP-cloudy group experienced vancomycin-resistant peritonitis caused by Enterococcus gallinarum, which could neither be covered by vancomycin nor by the initial antibiotic regimen recommended by the current ISPD guidelines.

Fig. 2.

Distribution of vancomycin susceptibility between different clinical manifestations group

Factors predicting susceptibility to Vancomycin

Univariate analysis revealed that clinical manifestations (presence of only cloudy effluent) at the initial diagnosis of peritonitis were an independent factor for predicting the sensitivity to vancomycin (OR 28.134, 95% CI 3.723-216.609; P < 0.001). The area under the ROC curve (AUC) was 0.643 (95% CI 0.559–0.727, P = 0.002). According to the multivariate logistic regression model, the presence of only cloudy effluent remained an independent predictor of susceptibility to vancomycin in the multivariate analysis (Table 2). In addition, PD effluent WBC count and, diabetes and first episode peritonitis, residual renal creatinine clearance were factors predicting susceptibility to vancomycin. The addition of these characteristics increased the AUC to 0.813 (95% CI 0.0.749–0.878, P < 0.001) (Fig. 3.). The specificity of PDAP-cloudy for vancomycin-sensitive peritonitis was 98.48%, with a sensitivity of 30.2%. This demonstrated that PDAP-cloudy had positive and negative predictive values of 96.67% and 49.24%, respectively (see Table 3).

Fig. 3.

Receiver operating characteristic curve for predict vancomycin sensitivity

Table 3.

Factors predicting sensitivity to Vancomycin according to logistic regression analysis

	B	SE	Wald	P	OR	95% CI
PDAP-cloudy group (with PDAP-multi group as reference)	3.321	1.102	9.075	0.003	27.678	3.191-240.103
Residual renal Ccr	-0.045	0.020	4.885	0.027	0.956	0.918–0.995
Every increase of 100/µL WBC in peritoneal fluid	-0.012	0.004	8.274	0.004	0.988	0.980–0.996
First episode peritonitis (Yes)	-0.806	0.392	4.240	0.039	0.447	0.207–0.962
Diabetes (Yes)	1.294	0.427	9.192	0.002	3.646	1.580–8.416
Constant	0.811	0.377	4.637	0.031	2.251

Clinical indicator that significantly different (p < 0.1) in comparison between patients with vancomycin sensitive or resistance PDAP group were selected in logistic regression model including PDAP cloudy group, WBC count in the peritoneal effluent, diabetes and first episode peritonitis, residual renal creatinine clearance and dialysis vintage The conditional forward method was used for final model factor selection

Abbreviation: PDAP, peritoneal dialysis-associated peritonitis; WBC, white blood cell; Ccr, creatinine clearance

Discussion

PDAP is a common complication of peritoneal dialysis, and it is the main cause of PD-related technical failure, even leading to death [3]. Few studies have explored the relationship between the clinical manifestations of PDAP and related vancomycin sensitivity.

The ISPD guidelines recommend that gram-positive organisms be covered by a first-generation cephalosporin or vancomycin and that gram-negative organisms be covered by a third-generation cephalosporin or aminoglycoside [3]. We found that cloudy dialysis effluent, as the only clinical manifestation at the onset of PDAP, is an independent indicator of vancomycin-sensitive peritonitis with high specificity, which indicates that vancomycin may be chosen as monotherapy for initial management of PDAP patients with only cloudy dialysis effluent as the initial manifestation.

As documented by this and previous studies, approximately 20-30% of patients are without abdominal pain [3, 13, 14] when peritonitis occurs; if vancomycin could be chosen as the initial treatment for these patients, a substantial percentage of patients could avoid gram-negative antibiotics. Therefore, this strength could theoretically decrease the occurrence of fungal peritonitis and reduce treatment costs.

The ISPD guidelines suggest empiric use of first-generation cephalosporin or vancomycin to treat gram-positive bacteria at the onset of PDAP [3, 15]. However, a number of studies have shown that cefazolin is not suitable as an initial therapy for gram-positive bacteria. Vancomycin is a tricyclic glycopeptide antibiotic with broad-spectrum activity against gram-positive bacteria. It is effective for the treatment of gram-positive infections, including peritonitis, and is the choice for methicillin-resistant Staphylococcus aureus (MRSA) [11, 12]. The ISPD guidelines recommend that vancomycin should be considered in centers with a high prevalence of methicillin-resistant organisms [3]. As reported in a previous study, the number of methicillin-resistant Staphylococcus species has substantially increased [16–18]. A study also showed that, based on in vitro susceptibility data, 25.5% (128/501) of the isolates were resistant to empirical therapy consisting of cefazolin plus tobramycin. Further analysis from this study revealed that 87.6% (439/501) of patients with new episodes of PDAP were susceptible to therapy with vancomycin plus tobramycin [11]. In our study, except for a single case of Enterococcus gallinarum that was naturally resistant to vancomycin in the PDAP-cloudy group [19], all of the gram-positive bacteria were sensitive to vancomycin, including gram-positive bacilli species (Lactobacillus, Corynebacterium, and Bacillus cereus). Enterococcus gallinarum is rare, and it should be noted that this species is resistant to vancomycin, whereas all the cephalosporin and empiric initial antibiotic regimens suggested by the ISPD guidelines cannot cover[19].

Most importantly, by such grouping, our study revealed that the PDAP cloudy group is an independent factor for predicting vancomycin sensitivity with 98.48% specificity and potentially the possibility of vancomycin monotherapy at the initiation of PDAP for patients who present with only cloudy effluent.

It should be noted that for PD center using cefazolin as the initial peritonitis treatment regimen, the approach raising by this study may increase the exposure to vancomycin and perhaps increase the likelihood of vancomycin-resistant organisms. On the other hand, some patients have poorly characterized initial presentation, therefore, in these patients, it is recommended to follow the ISPD guidelines for the treatment of patients who have difficulty in determining the initial manifestations of the disease.

The strengths of this study include the first link between clinical manifestations and the causative organism and vancomycin sensitivity; therefore, vancomycin monotherapy is a potential treatment for some PDAP patients. Despite these strengths, the study had several limitations, including its retrospective design, possible classification bias and small sample size. Moreover, it should be noted that the sensitivity the PDAP cloudy group is an independent factor for predicting vancomycin sensitivity is low as only 30.2%, suggesting many vancomycin-sensitive cases would be missed if this criterion was used alone to guide treatment.

In summary, our study established a relationship between the clinical manifestations of PDAP at onset and the effectiveness of vancomycin antibiotic therapy. Cloudy dialysate, the only symptom at PDAP onset, is an independent predictor of vancomycin-sensitive PDAP, with a specificity of 98.48%, which may be an important new insight that can guide the choice of vancomycin as an initial monotherapy antibiotic for this subgroup of patients with peritonitis. However, prospective randomized controlled studies are required to confirm these findings.

Conclusion

We found that cloudy dialysis effluent, as the only clinical manifestation at the onset of PDAP, is an independent factor associated with vancomycin sensitivity with high specificity, and PDAP patients with cloudy dialysis effluent as the only manifestation may respond to vancomycin monotherapy as initial management.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

Wen Tang and Wang Xiaoxiao conceived of the study, initiated the study design and drafting part of the manuscript. Dongdong Ren and Yue-Juan Pan were responsible for the analysis, drafting and editing of the manuscript and its final contents. Jiandong Nie helped with implementation. All authors discussed the results and contributed to the final manuscript.

Funding

This work was supported by National Natural Science Foundation of China (grant number 82470774) and the Clinical Cohort Construction Program of Peking University Third Hospital (grant number BYSYDL2023004).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participant

This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2024088) and use of data and waiver of individual informed consent by this study were permitted by Peking University Third Hospital Medical Science Research Ethics given the study was a retrospective, non-interventional design and using a de-identified dataset.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.