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Clinical |
Division of Nephrology,1 University Hospital Juan Canalejo; Department of Medicine,2 Health Science Institute, University of A Coruña, A Coruña, Spain
Correspondence to: M. Pérez Fontán, Division of Nephrology, University Hospital Juan Canalejo, Xubias 84, 15006 A Coruña, Spain. mfontan{at}canalejo.org
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ABSTRACT |
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 TOP ABSTRACT POPULATION AND METHODRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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Background: There is controversy about the preferred
initial antibiotic therapy for peritoneal dialysis (PD)-related peritonitis.
Quinolones have been used extensively in this setting, yet their long-term
effectiveness is unknown. Aim: To analyze the results of a protocol of treatment
of PD-related peritonitis with ciprofloxacin, maintained over two
decades. Method: We analyzed the clinical outcome of 682
episodes of bacterial peritonitis treated with intraperitoneal ciprofloxacin
monotherapy, and the time course of bacterial susceptibility to this
antimicrobial, in a historical cohort of 641 PD patients (1988–2007).
Main outcome variables included changes to initial therapy and rates of
hospital admission, catheter removal, relapse, reinfection, PD dropout, and
mortality. For comparisons we divided the study period into phases A
(1988–1994), B (1995–2000), and C (2001–2007). Results: The incidence of Staphylococcus
aureus peritonitis decreased, while the incidences of polymicrobial and
negative-culture peritonitis increased after phase A. In vitro
susceptibility to ciprofloxacin decreased significantly only among
coagulase-negative staphylococci (87.0% susceptible strains in phase A vs
70.0% in B and 70.1% in C, p = 0.006). Overall success rates
(catheter not removed and ongoing PD after the episode) remained stable, at
over 85%. However, the proportion of patients treated solely with
ciprofloxacin declined from 75.7% (A) to 47.3% (B) to 32.4% (C) (p
< 0.0005) and admission rates increased from 12.7% to 16.8% to 24.9%
respectively (p = 0.001). These changes affected all the etiologic
groups except culture-negative peritonitis. In vitro resistance to
ciprofloxacin was a marker of multiresistance and correlated strongly with
clinical outcome of peritonitis. Among isolates susceptible to ciprofloxacin,
changing initial therapy for any reason also predicted a poor outcome. Conclusions: Following satisfactory early results, the
effectiveness of ciprofloxacin as monotherapy for PD-related peritonitis has
declined markedly in the long term. This decline cannot be explained solely by
a decrease of in vitro susceptibility to this antimicrobial, which
was significant only among coagulase-negative staphylococci. Resistance to
ciprofloxacin is a strong marker of in vitro multiresistance and poor
clinical outcome of peritonitis.
KEY WORDS: Ciprofloxacin; peritonitis; susceptibility; resistance.
Peritonitis represents a permanent threat for the patient undergoing peritoneal dialysis (PD). Despite continuous work during past decades to improve preventive measures and therapy, these infections are still responsible for 20% – 30% of cases of PD technique failure (1,2) and portend a significant risk of direct mortality (3).
Timely, appropriately designed, and properly implemented antibiotic therapy significantly increases the chances for an uncomplicated clinical course of PD-related bacterial peritonitis (4). It is obvious that the antibiotic susceptibility patterns of the etiologic agent(s) must guide the final therapy of any episode of peritonitis. On the other hand, the choice of the antibiotic schedule at diagnosis but before any microbiologic information is available is more controversial. There are some accepted general premises, including the convenience of empiric coverage of both gram-positive and gram-negative bacteria until an isolation is obtained (4) but, beyond these, there is a remarkable lack of unanimity concerning decisions such as the preferable antibiotic administration route, the use of continuous versus intermittent treatment schedules, and the duration of therapy. The spectrum of antibiotic regimes applied for the primary treatment of PD-related peritonitis is endless (5). Local differences in the epidemiology of these infections and a relative paucity of quality evidence to clarify the question (6) are two of the main factors favoring such heterogeneity of approaches.
Quinolones are a family of antibiotics that target bacterial topoisomerases II and IV and have been successful as antimicrobial agents during the past two decades (7). Their success is based on their favorable pharmacologic properties and wide spectrum of antibacterial activity. Older quinolones [including ciprofloxacin (Cpx)] have demonstrated an equilibrated activity against gram-positive and gram-negative bacteria (including Pseudomonas aeruginosa), while newer quinolones show improved activity against gram-positives, Chlamydia spp, Mycoplasma spp, mycobacteria, and selected anaerobes (8). Oral and intraperitoneal (IP) quinolones have been extensively used for the management of PD-related peritonitis, with overall satisfactory results (9–18). However, and similarly to other antibiotics, development of bacterial resistance may compromise the long-term results of this family of antimicrobials. In our center, we have used IP Cpx for initial treatment of PD-related peritonitis for the past two decades. This circumstance affords an excellent opportunity to assess the long-term effectiveness of this antimicrobial for the treatment of these infections, both on clinical grounds and in terms of in vitro susceptibility.
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POPULATION AND METHOD |
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TOPABSTRACTPOPULATION AND METHODRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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INCLUSION AND EXCLUSION CRITERIA
We considered for preliminary analysis all episodes of PD-related
peritonitis recorded during the study period and then applied the following
exclusion criteria:
Specifically, seemingly infectious but negative-culture peritonitis were considered for the clinical analysis. For the cases of mixed infections and for bacterial infections treated with antibiotics other than Cpx, we reviewed the in vitro susceptibility of the isolated bacteria to Cpx but did not consider these episodes for clinical analysis.
STUDY POPULATION
During the study period, 641 patients were treated with PD in our center
for at least 2 months, including 359 males (56.0%) and 282 females (44.0%).
Mean age was 58 ± 16 (range 7 – 87) years and mean follow-up on
PD was 25 ± 22 (range 2 – 122) months. The etiologic spectrum of
renal diseases was standard; 217 patients (33.9%) were diabetic. The baseline
Charlson comorbidity score was 5.1 ± 1.8 (range 2 – 11).
Continuous ambulatory peritoneal dialysis (CAPD) was the main mode of PD
therapy in 402 patients (62.8%), while 238 patients (38.2%) underwent
automated forms of PD. All CAPD patients used Y-type systems (Baxter
Healthcare, Deerfield, IL, USA; and Fresenius Medical Care, Heidelberg,
Germany) and volumetric cyclers (HomeChoice, Baxter) predominated, except for
a few patients using gravity cyclers (PacXtra, Baxter) during phase A.
DEFINITIONS
All the terms used for definitions in this study, including infectious and
noninfectious peritonitis, exit-site infection, refractory peritonitis,
relapse, and reinfection, are in agreement with current recommendations
(4).
TREATMENT OF PERITONITIS AND EXIT-SITE INFECTIONS
The protocol for empiric therapy of peritonitis included IP Cpx with a
loading dose of 100 mg/L dialysate, followed by 50 mg/L as maintenance dose.
During the first 2 years of follow-up, oral Cpx (500 mg three times per day)
was substituted for IP Cpx after the fifth day of therapy (provided full
remission was obtained), but we used the IP route exclusively thereafter due
to poor tolerance to oral Cpx in a significant proportion of patients and
distrust of the consistency of this route to generate adequate IP levels of
the drug (13). Therapy was
maintained for a minimum of 2 weeks and extended to 3 or 4 weeks, as
indicated, according to standard criteria for management of these infections
(slowly responsive, clinically aggressive, or relapsing infections).
The criteria for catheter removal and for changes to the initial antibiotic therapy were individualized, also following usual recommendations in the field. Refractoriness to therapy and in vitro resistance to Cpx were the main criteria for substitution of Cpx, while an expected aggressive or relapsing behavior (e.g., P. aeruginosa) or, again, partial refractoriness to Cpx alone were common reasons for adding a second antibiotic to Cpx.
Treatment of exit-site infections varied widely during the study period. In general, oral antibiotics (according to bacterial susceptibility) or intravenous vancomycin for gram-positive infections were extensively used until the mid-1990s. During the past 10 years, we have increasingly used topical mupirocin, Cpx, and gentamicin for local treatment of superficial infections, reserving oral or parenteral therapy for refractory or aggressive infections.
Systematic screening and treatment (mupirocin) of Staphylococcus aureus nasal carriage started in 1989; screening and treatment of catheter exit-site colonization started in 1996. Asymptomatic colonization of the exit site by gram-negative bacteria is not routinely treated with antibiotics.
SUSCEPTIBILITY TESTING
Susceptibilities to Cpx, amoxicillin–clavulanic acid, cefazolin,
cefotaxime, ceftazidime (only gram negatives), imipenem/cilastatin, vancomycin
(only gram positives), and gentamicin were tested using a standard minimal
inhibitory concentration (MIC) method
(19) in the majority of cases.
In 91 strains isolated during the first 3 years of the study, a standard disc
diffusion method was used. An MIC of >2 µg/mL, or any category beyond
full susceptibility by disc diffusion, was used for categorization of
bacterial resistance to Cpx. We applied the following cutoff points for
susceptibility according to MIC for other antibiotics: 
8 µg/mL for
amoxicillin–clavulanic acid, cefazolin, cefotaxime, and ceftazidime, and
4 µg/mL for imipenem/cilastatin, vancomycin, and gentamicin.
STRATEGY OF ANALYSIS
As designed, the study had two well-defined subjects of analysis: First,
for each episode of peritonitis included in the study, we analyzed the
following outcome variables: Cpx as final treatment (versus change/addition
to/of other antibiotics), main reason for change of antibiotic (when
indicated), hospital admission, catheter removal, relapse, reinfection,
immediate dropout to hemodialysis after the episode, and death (under any
circumstances) during the episode or immediately thereafter. Catheter removal,
dropout to hemodialysis, and death formed a composite variable of overall
adverse outcome. Second, we analyzed susceptibility to Cpx for each individual
species of bacteria isolated from dialysate during the study period. Thus, we
included separately for this analysis the different bacteria isolated in each
polymicrobial infection, and also (as indicated above) bacteria isolated in
mixed infections and bacterial infections treated with antibiotics other than
Cpx, which were not considered for clinical analysis.
To analyze the time course of clinical results and bacterial susceptibility to Cpx, we arbitrarily divided the study period into three phases, namely A (1988 – 1994), B (1995 – 2000), and C (2001 – 2007).
STATISTICS
Numeric variables are presented as mean ± standard deviation (SD)
and range when appropriate. Comparison between categorical variables was
performed according to chi-square distribution and Fisher's exact test.
Comparison between numeric variables was carried out using Student's t-test
and analysis of variance. The SPSS 15.0 software (SPSS Inc., Chicago, IL, USA)
was used to produce these analyses.
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RESULTS |
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TOPABSTRACTPOPULATION AND METHODRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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During the study period, we recorded 832 episodes of peritonitis. The incidence of peritonitis decreased from 0.68 episodes/patient/year during phase A to 0.47 during phase B to 0.38 during phase C (p < 0.0005). Seventy episodes were fully excluded from analysis due to their noninfectious origin or common bacteria-free etiology, and two others due to incomplete clinical information. Seventy-eight episodes were considered only for Cpx susceptibility analysis (initial therapy including antibiotics other than Cpx and/or mixed flora with anaerobic bacteria or yeasts), leaving 682 episodes that met the inclusion criteria for clinical analysis. The etiologic spectrum in this final group for each study phase is presented in Table 1. The incidence of S. aureus peritonitis fell, while incidences of polymicrobial and negative-culture peritonitis increased after phase A; phases B and C showed similar distributions of etiologic agents of infection. The overall incidences of infections by methicillin-resistant Staphylococcus aureus (MRSA) and non-fermenting gram-negatives (including P. aeruginosa) were low. We recorded a single case of peritonitis by an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli during the whole study period.
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IN VITRO BACTERIAL SUSCEPTIBILITY TO Cpx
The main results are presented in Table
2. Overall, bacterial susceptibility to Cpx was reasonably well
preserved during the study period. Coagulase-negative staphylococcus was the
only etiologic group displaying a significant decline in susceptibility to
Cpx, with E. coli displaying a similar nonsignificant trend.
Susceptibility of enterococci to Cpx was stable at nonoptimal levels during
follow-up. The small number of non-fermenting gram-negative bacteria did not
permit a valid conclusion on the behavior of this subgroup after long-term use
of Cpx.
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In vitro susceptibility to Cpx was strongly associated with susceptibility to the other antibiotics tested. Strains resistant to Cpx were also more frequently resistant to amoxicillin–clavulanic acid (22.5%, compared with 68.5% if susceptible to Cpx, p < 0.0005), cefazolin (35.5% vs 78.2%, p < 0.0005), cefotaxime (20.7% vs 90.2%, p < 0.0005), ceftazidime (13.3% vs 27.8%, p = 0.09), imipenem/cilastatin (10.5% vs 64.0%, p < 0.0005), and gentamicin (13.0% vs 52.3%, p < 0.0005). The proportion of gram-positive bacteria resistant to cefazolin increased from 23.5% during phase A to 43.0% and 48.9% during phases B and C respectively (p < 0.001). We observed no single instance of vancomycin resistance among gram-positives during follow-up.
CLINICAL RESULTS
The main results of therapy are presented in
Table 3. As shown, there was a
marked progressive decrease in the fraction of patients whose final therapy
was Cpx alone. Incidence of hospital admission increased during phase C; other
outcome variables did not change significantly. The reasons for change of
initial therapy included clinical refractoriness to Cpx alone (61.2%), in
vitro resistance to Cpx despite adequate clinical response (9.7%), and
medical decision despite ongoing clinical response and in vitro
susceptibility to Cpx (28.9%). The main reasons for the latter were presumed
or confirmed aggressiveness of the infection (as estimated by the clinician in
charge), demanding antibiotic associations (Enterococcus spp,
Enterobacteriaceae, P. aeruginosa, polymicrobial), clinically benign
but slowly resolving infections (as commonly observed in peritonitis by
Streptococcus spp), and, less frequently, simultaneous
extraperitoneal infection by other bacteria (e.g., in urinary tract).
The relative distributions of the three main causes for switching initial Cpx
therapy were similar for the three study phases.
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In the 44.9% of cases in which Cpx was not the final therapy, that therapy was based most frequently on vancomycin alone (13.3%), beta-lactams alone (9.8%), or antibiotic associations (20.7%). The latter most frequently included vancomycin (76.0%), aminoglycosides (49.6%), Cpx itself (27.0%), beta-lactams (26.4%), and rifampicin (16.1%).
The decline in the fraction of patients treated solely with Cpx was significant in all the etiologic groups except negative-culture peritonitis, but was particularly patent among gram-positive bacteria and polymicrobial infections (Table 4). Hospital admission rates tended to increase in all the etiologic groups, but the difference was significant only in the case of gram-positive (10.6% in phase A, 13.7% in phase B, 20.8% in phase C; p = 0.01) and polymicrobial infections (9.1%, 18.2%, and 32.1%, respectively; p = 0.04). No etiologic group showed a decline in the composite variable of overall adverse outcome of peritonitis (Table 5).
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CLINICAL RESULTS ACCORDING TO BACTERIAL SUSCEPTIBILITY TO Cpx
Resistance to Cpx was a strong marker of poor outcome of peritonitis
(Table 6). This circumstance
stood to a similar degree when gram-positive and gram-negative bacteria were
considered separately.
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In the particular case of coagulase-negative staphylococci, Cpx alone was the final therapy in 68.6% and 7.1% of susceptible and resistant strains respectively (p < 0.0005). Relapse rates were 12.7% and 28.6% (p = 0.02), hospital admission rates were 8.5% and 19.6% (p = 0.01), and catheter removal was necessary in 4.8% and 7.1% (NS), respectively (PD dropout and mortality rates were too low to permit statistical analysis).
Changes to initial Cpx therapy were also predictive of outcome of infections by bacteria susceptible to Cpx (Table 7). Clinical refractoriness confirmed its wellknown prognostic significance, but medical decision also predicted a poor outcome, probably due to the type of infections leading to such a decision (see above).
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DISCUSSION |
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TOPABSTRACTPOPULATION AND METHODRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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The results of our study could, at first sight, endorse the efficiency of a protocol based on IP Cpx for primary therapy of PD-related peritonitis, with overall success rates consistently over 85% during a period approaching two decades (Table 5). However, a more meticulous analysis of the data downplays this impression. Hospital admission rates increased significantly during follow-up and the fraction of patients treated solely with Cpx decreased progressively during the study period (Table 3), indicating declining effectiveness of this antimicrobial in controlling the full course of these infections. Bacterial resistance might explain this decline only in the case of coagulase-negative staphylococcal species (Table 2). Quinolones are not drugs of choice for the treatment of infections by this family of bacteria, and their relative ineffectiveness in the setting of PD-related infections has been reported previously (9,14,30). Concerning other gram-positives, as also with gram-negative bacteria (with the possible exception of E. coli), in vitro susceptibility to Cpx remained remarkably stable across the study periods in our study. Resistance to Cpx and other quinolones is being increasingly reported in infections affecting the population at large, especially among aggressive bacteria such as MRSA, Enterococcus spp, and Acinetobacter spp, as also with ESBL-producing and non-fermenting gram-negative bacteria (31). Infections by these microbes demand individualized antimicrobial approaches and are not adequately covered by most regimes commonly used for initial treatment of PD-related peritonitis (4,5). Resistance to quinolones is known to occur by at least three mechanisms (31). The first involves single (as in S. aureus or P. aeruginosa) or multiple (as in E. coli) gene mutations for topoisomerases II (gram-positives) and IV (gram-negatives). The second implicates reduced drug permeation and altered regulation of active efflux mechanisms; this mechanism is frequently associated with multiresistance to different antimicrobials. Finally, low-level resistance can be mediated by plasmids producing the Qnr protein.
Analysis of our data provides some clues to the reasons why admission rates increased and initial Cpx monotherapy was substituted in a majority of cases during phases B and C (Table 3). First, some etiologic groups with a higher risk of treatment failure, including polymicrobial infections (Table 1), were clearly more incident in these phases. Second, the prevalence of elderly patients increased during phases B and C, with higher expected morbidity and hospital admission rates in this subgroup. Third, even though in vitro susceptibility to Cpx decreased significantly only among coagulase-negative staphylococci, these bacteria caused 32.2% of the infections, bringing overall susceptibility rates below 80% during phases B and C (Table 2). Finally, our group has progressively adopted clinical recommendations emphasizing the convenience of obtaining rapid and consistent remission of peritonitis (4) to maximize the chances for patient and technique survival. According to this notion, ongoing refractoriness and even slow remission lead to more precocious revisions of therapy, while complicated etiologic subsets have become systematically treated with antibiotic associations. Agile and good-quality bacteriologic information is essential to implement these clinical decisions.
Our results show that in vitro resistance to Cpx is a strong prognostic marker of the outcome of PD-related peritonitis (Table 6). The explanation for this circumstance seemingly goes beyond simple delay to an effective antibiotic therapy. Naturally, aggressive bacteria were overrepresented among Cpx-resistant strains (Table 2), and Cpx resistance is known to be commonly associated with multiresistance patterns (7,30), as observed in our study. On the other hand, even among Cpx-susceptible bacteria, changes to initial Cpx therapy portended a poorer prognosis (Table 7), which is not difficult to explain, both in the case of clinically refractory infections and when changes responded to a medical decision, the latter frequently taken in the presence of infections by aggressive or multiple bacteria.
Limitations of our study include its retrospective nature and lack of a control group. The low incidence of infections by non-fermenting gram-negatives, MRSA, and ESBL-producing bacteria does not permit analyses of these specific etiologic subsets. On the other hand, the results of our study may not be applicable to protocols combining Cpx with other antibiotics for initial therapy for PD-related peritonitis (9,18,23–25). Also, newer quinolones that display higher activity against gram-positive bacteria (8) could represent a significant improvement in the management of these infections, although evidence for this is still needed. Finally, our study does not permit adequate analysis of the results of oral Cpx for PD-related peritonitis. We renounced this route of administration due to poor tolerance to the prescribed dose (500 mg three times per day) in a significant proportion of patients and to distrust of the consistency of this route to generate adequate IP levels of the drug, based on our own results (13). Other groups have reported better outcomes using lower doses of Cpx (250 – 500 mg two times per day) (9,11, 14,21,23). In these studies, plasma and dialysate levels of the drug were usually adequate although, as previously mentioned, with significant interindividual variability.
In summary, after two decades, IP Cpx alone does not stand as a desirable option for initial therapy of PD-related peritonitis, as its efficiency for full treatment of these infections has declined markedly in the long-term. This decline cannot be explained solely by a decrease in in vitro susceptibility to this antimicrobial, which was significant only among coagulase-negative staphylococci. Bacterial resistance to Cpx is a strong marker of antibiotic multiresistance and of poor clinical outcome of peritonitis. The progressive complexity of the resistance patterns of bacteria to antimicrobials, the growing prevalence of high-risk patients in PD programs, and the convenience of obtaining rapid and consistent remission of peritonitis to improve patient and technique survival may favor the choice of expanded rather than restricted antibiotic regimes for the primary treatment of PD-related peritonitis.
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DISCLOSURE |
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TOPABSTRACTPOPULATION AND METHODRESULTSDISCUSSIONDISCLOSUREREFERENCES |
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Received 13 April 2008; accepted 6 August 2008.
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