Response-Guided Therapy With Cefotaxime, Ceftriaxone, or Ciprofloxacin for Spontaneous Bacterial Peritonitis: A Randomized Trial: A Validation Study of 2021 AASLD Practice Guidance for SBP

INTRODUCTION

Spontaneous bacterial peritonitis (SBP) is one of the most serious complications of liver cirrhosis (1,2). It can develop without obvious intra-abdominal lesions, such as hollow viscus perforation or abscess (1,2). The mainstay of treatment for SBP is the use of appropriate antibiotics rather than surgical or interventional therapy (2,3). Although several antibiotics, including cefotaxime, ceftriaxone, and ciprofloxacin, are being administered for initial treatment (2,4–6), it is currently unclear whether these drugs are comparable and still appropriate for clinical practice (7). Because there are increasing concerns about antimicrobial resistance (8,9), appropriate treatment strategies need to be ensured to avoid treatment failures and unnecessarily high levels of antibiotic therapy (e.g., meropenem).

The American Association for the Study of Liver Disease (AASLD) 2012 guidelines and recently updated 2021 practice guidance recommend that patients with an ascitic fluid polymorphonucleated (PMN) cell count of ≥250/mm3 in a community-acquired setting, in the absence of recent broad-spectrum antibiotic exposure, should receive empirical antibiotic therapy (10,11). Cefotaxime or a similar third-generation cephalosporin is considered as the treatment of choice for SBP until the results of susceptibility testing are available (10), although broader-spectrum antibiotics are recommended as the first-line therapy for patients with nosocomial infection or sepsis (11). Once the sensitivity results are obtained, the coverage spectrum can be narrowed. However, isolation of the causative organism is not readily available in many cases, and it takes more time to obtain the susceptibility test results even when the pathogen is cultured. Therefore, antibiotic therapy should be guided by ascitic fluid PMN cell counts during the initial stage. With this regard, the recently updated AASLD 2021 practice guidance and the European Association for the Study of the Liver guidelines suggest a routine follow-up of ascitic cell count (11,12). However, there were few data confirming the utility of response-guided therapy for SBP. Considering the increasing trend of quinolone resistance and multidrug-resistant organism (MDRO), outcomes after common empirical antibiotic treatment need to be appropriately re-evaluated and compared (8,13,14).

Our study aimed to evaluate the current efficacy of empirical antibiotics under response-guided therapy, by comparing 3 drugs, namely cefotaxime, ceftriaxone, and ciprofloxacin, commonly used for the treatment of SBP in patients with liver cirrhosis.

METHODS Study design

This study is an investigator-initiated, open-label, randomized, controlled, comparative trial prospectively conducted in 9 tertiary hospitals in South Korea. The primary endpoint was the SBP resolution rate at 120 hours (5 days) of treatment. The secondary endpoints included the following: (i) infection resolution rates at 168 hours (7 days) of treatment, (ii) survival of patients with liver cirrhosis after treatment during 4 weeks of follow-up, and (iii) antibiotic modification and resistance.

Based on previous reports, we hypothesized that the efficacy of cefotaxime, ceftriaxone, and ciprofloxacin would not be significantly different under response-guided therapy. The number of patients needed for this study was calculated with a noninferiority test using the sample size calculation software (PASS 2005; NCSS LLC, Kaysville, UT) assuming 0.83 of SBP resolution rate for cefotaxime group as a control (15). For a maximum allowable difference (δ) of 15%, 87 patients were needed in each group to achieve 80% power at a 5% level of significance, considering a 10% follow-up loss rate. Therefore, a total of 261 patients were required. The randomization table was generated by a statistician (L.J.Y.) using the nQuery Advisor program (version 6.0; Statistical Solutions, Cork, Ireland) in a block size of 6. Serially numbered sealed opaque envelopes were prepared to blind the antibiotic group, the details of which were printed on an individual sheet according to the randomization table.

Study subjects

The inclusion criteria of this study were as follows: (i) patients with liver cirrhosis and ascites, (ii) aged between 16 and 75 years, and (iii) ascitic PMN cell count of ≥250/mm3. Patients were excluded if they met any of the following criteria: (i) allergy to third-generation cephalosporins or quinolones; (ii) a history of antibiotic use within 2 weeks; (iii) an open abdominal surgery within 4 weeks; (iv) evidence of secondary peritonitis; (v) intra-abdominal hemorrhage; (vi) acute pancreatitis; (vii) tuberculous peritonitis; (viii) peritoneal carcinomatosis; (ix) hepatocellular carcinoma with portal vein tumor thrombosis; (x) pregnant or lactating woman; and (xi) human immunodeficiency virus infection. An additional examination was recommended if secondary peritonitis was suspected (see Supplemental Digital Content, https://links.lww.com/AJG/C823).

Informed consent was obtained from all the patients enrolled in the study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The institution's human research committee approved the protocol before study initiation.

Study procedure.

Patients with liver cirrhosis and ascites were screened according to the inclusion and exclusion criteria. Diagnostic paracentesis was recommended in any case of admission due to ascites control, gastrointestinal bleeding, or hepatic encephalopathy. In addition, conditions such as abdominal pain, fever, ileus, or renal dysfunction were indications of paracentesis during hospitalization. After enrollment, the patients were randomized to the cefotaxime (2 g every 8 hours), ceftriaxone (2 g every 24 hours), and ciprofloxacin (200 mg every 12 hours) groups by opening the sealed envelope, and received the assigned antibiotic agent intravenously. Twenty percentage albumin was infused at baseline and 48 hours later to prevent acute kidney injury or mortality at the discretion of the investigator (16,17). A follow-up paracentesis was performed at 48 hours of the initial administration of the antibiotics to determine an initial response to the drug. Continuation of treatment with the same drug was indicated when PMN count decreased by more than 25% compared with that at baseline. Otherwise, the antibiotics were changed to the broader-spectrum antibiotic agents. After 120 hours of treatment, a follow-up paracentesis was again performed to determine the resolution of SBP, which was indicated by a decrease in PMN count less than 250/mm3. Once the resolution was confirmed, intravenous antibiotics were changed to oral norfloxacin (400 mg once a day) and clinically closely monitored for recurrence for 4 weeks. In cases where the ascitic PMN count did not reach <250/mm3, but was considered as a partial response determined by 50% or more reduction, the same drug was continued for 48 hours or more. Otherwise, the antibiotic drug was modified to the broader-spectrum antibiotics such as piperacillin/tazobactam or carbapenems at the discretion of the physician. Treatment response was evaluated again 168 hours after initial antibiotic administration. Laboratory assays performed in this study are described in the Supplemental Digital Content (https://links.lww.com/AJG/C823).

Efficacy and safety measurements

Resolution of SBP at 120 hours of treatment, which is the primary endpoint of the present study, was defined as meeting all the following criteria: (i) decrease in PMN cell count less than 250/mm3, (ii) normalized leukocytosis in the peripheral blood, (iii) no growth of bacteria in the peripheral blood and ascitic fluid culture, and (iv) disappearance of symptoms of intra-abdominal infection such as abdominal pain and fever. Treatment failure was defined as any of the following: (i) no decrease in ascitic PMN count less than 250/mm3 at 120 hours of treatment, (ii) no improvement in symptoms and signs of SBP, such as abdominal pain, fever, and peripheral blood leukocytosis; (iii) death before the resolution of SBP; (iv) isolation of bacteria resistant to the antibiotic agent being administered; or (v) need to stop antibiotics owing to the side effects. Patients were additionally excluded from further participation in the study in case of the criteria described in the Supplemental Digital Content (https://links.lww.com/AJG/C823).

Adverse events and drug side effects were monitored daily during the study period and at every outpatient clinic visit after discharge. SBP recurrence was monitored for 28 days after the SBP resolution.

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences version 18.0 (SPSS, Chicago, IL). To analyze the baseline characteristics of the 3 groups, categorical variables were compared using the χ2 or Fisher exact test, as appropriate. Continuous variables were compared among the 3 groups using ANOVA. Data are presented as mean ± SD or median with interquartile range or number of patients and percentage values, as appropriate. Analysis of the effectiveness of this clinical trial was based on intent-to-treat (ITT) analysis and per-protocol (PP) analysis. Primarily, ITT analysis was performed for patients who received at least 1 dose of the study drug, considering missing patients as treatment failure. PP analysis was performed for patients who underwent a full duration of assigned treatment and modification according to the predefined protocol of the study, which therefore included those with the protocol-based changes of the drug but excluded those with protocol violations. The safety analysis of clinical events was performed on all subjects who received 3 drugs. The primary endpoint was compared using the χ2 test. Secondary endpoints were compared using the χ2 test for SBP resolution rate at 168 hours and by Kaplan-Meier methods and log-rank test for 28-day survival and recurrence rates. Factors associated with 28-day survival were analyzed using multivariate analysis based on the Cox proportional hazard model. Statistical significance was set at P < 0.05.

For noninferiority tests comparing treatment success rates among the cefotaxime, ceftriaxone, and ciprofloxacin groups, 98.3% ([1 − 0.05/3] × 100) 1-sided confidence intervals (CIs) of the proportion difference between pair-wise groups were calculated with Bonferroni-type adjustment for multiple comparisons. Cefotaxime was considered an active control when comparing ceftriaxone and ciprofloxacin. If the absolute value of the lower bound of the interval was lower than the noninferiority margin of 0.15, we concluded that the 2 treatments were noninferior to the control (18).

RESULTS Patients

A total of 261 patients were enrolled between April 2007 and April 2018, randomized to 1 of the 3 drugs, and treated based on the response-guided algorithm (Figure 1). Baseline characteristics of the patients were not significantly different among the cefotaxime, ceftriaxone, and ciprofloxacin groups (Table 1). Only the mean PMN count of the ascitic fluid was different among the groups. The main etiologies of liver cirrhosis were alcohol (43.3%) and hepatitis B (40.2%). Hepatocellular carcinomas were accompanied in 15% of the patients. Two-thirds of the patients had Child-Pugh class C liver function, and the mean model for end-stage liver disease (MELD) score was 20.

F1Figure 1.:

Study diagram. (a) Disposition of the patients, (b) study flow for intention-to-treat analysis, and (c) the study flow for per-protocol analysis. PPA, per protocol analysis; ITT, intention-to-treat. *Excluded from per-protocol analysis.

T1Table 1.:

Baseline characteristics

The most common symptom and the most frequent indication of admission was abdominal pain (see Supplementary Tables 1 and 2, Supplementary Digital Contents 1, https://links.lww.com/AJG/C811 and 2, https://links.lww.com/AJG/C812). At admission, liver failure (14.6%) and kidney failure (10.0%) were the most frequent types of organ failure, and 8 patients (3.1%) presented with septic shock (see Supplementary Table 3, Supplementary Digital Content 3, https://links.lww.com/AJG/C813). To prevent acute kidney injury, 20 g (20–60) of albumin was infused for the initial diagnosis of SBP and 20 g (0–40) after 48 hours. There were no differences in albumin doses between the treatment groups, but the doses were under the recommendation (see Supplementary Table 4, Supplementary Digital Content 4, https://links.lww.com/AJG/C814).

Key clinical outcomes The primary endpoint.

SBP resolution rates at 120 hours of treatment were 67.8% (59/87), 77.0% (67/87), and 73.6% (64/87), respectively (P = 0.388), in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively, as assessed with ITT analysis; PP analysis showed resolution rates of 80.6% (54/67), 85.5% (53/62), and 85.9% (55/64), respectively (P = 0.652) (Figure 2a).

F2Figure 2.:

Treatment response with empirical antibiotics for SBP. (a) SBP resolution rates at 120 hours of treatment. (b) SBP resolution rates at 168 hours of treatment. SBP, spontaneous bacterial peritonitis.

The absolute value of 98.3% CI of differences in the proportion of SBP resolution at 120 hours of treatment between the cefotaxime and other groups satisfied the a priori limit of a noninferiority (d) of 0.15 (Figure 2a), as assessed with ITT and PP analyses.

Secondary endpoints.

The SBP resolution rates at 168 hours of treatment were 78.2% (68/87), 82.8% (72/87), and 81.6% (71/87) in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively, as assessed using ITT analysis (P = 0.725) (Figure 2b); then, PP analysis was performed, and the resolution rates were 95.2% (60/63), 96.7% (58/60), and 98.4% (60/61), respectively (P = 0.619). As such, the primary endpoint, the value of 98.3% CI of differences in SBP resolution rates at 168 hours between the cefotaxime and other groups also satisfied a priori limit of a noninferiority of 0.15% in both analyses (Figure 2b).

During treatment, antibiotics were modified according to the on-treatment responses (Figure 3). A total of 9 (10.3%), 5 (5.7%), and 11 patients (12.6%) changed antibiotics in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively (P = 0.206). Thirteen patients (50.0%) received piperacillin/tazobactam, ertapenem, or meropenem.

F3Figure 3.:

Modification of antibiotics during treatment. ITT, intent-to-treat.

The cultured bacteria were Escherichia coli, Klebsiella sp., Streptococcus sp., Staphylococcus sp., Aeromonas sp., Acinetobacter sp., Bacteroides sp., Bacillus sp., and Enterococcus sp. (Table 2). E. coli was the most frequently isolated bacterium (34.1%) (Table 3), 21.4% of which showed resistance to third-generation cephalosporins or quinolones. Supplementary Table 5 (see Supplementary Digital Content 5, https://links.lww.com/AJG/C815) summarizes resistance profiles of multidrug-resistant organisms.

T2Table 2.:

Cultured bacteria from ascites or blood

T3Table 3.:

Antibiotic susceptibility test of cultured bacteria

Subgroup analysis.

Two hundred thirteen patients were diagnosed with SBP within 48 hours of admission, which was considered as community-acquired infection. Subgroup analysis was performed for those with community-acquired SBP. A total of 66 (75.9%), 77 (88.5%), and 70 (80.4%) patients were treated with cefotaxime, ceftriaxone, and ciprofloxacin, respectively. The SBP resolution rates at 120 hours in the 3 groups were 60.6% (40/66), 75.3% (58/77), and 71.4% (50/70), respectively, using ITT analysis (P = 0.148), and 77.6% (38/49), 83.9% (47/56), and 87.2% (41/47), respectively, using PP analysis (P = 0.438) (see Supplementary Table 6, Supplementary Digital Content 6, https://links.lww.com/AJG/C816).

A total of 21 (24.1%), 10 (11.5%), and 17 patients (19.5%) developed SBP after more than 48 hours of hospitalization in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively, and this was considered nosocomial SBP. The SBP resolution rates at 120 hours in the 3 groups were 90.5% (19/21), 90.0% (9/10), and 82.4% (14/17), respectively, using ITT analysis (P = 0.727), and 88.9% (16/18), 100% (6/6), and 82.4% (14/17), respectively, using PP analysis (P = 0.516) (see Supplementary Table 7, Supplementary Digital Content 7, https://links.lww.com/AJG/C817). The characteristics and clinical outcomes of the patients with community-acquired and nosocomial SBP are summarized in Supplementary Table 8 (see Supplementary Digital Content 8, https://links.lww.com/AJG/C818).

We assessed noninferiority of ceftriaxone and ciprofloxacin to cefotaxime in the subgroups. The 98.3% CI of differences in the proportion of SBP resolution at 120 hours between the cefotaxime and other groups satisfied the limit of a noninferiority of 0.15 in patients with community-acquired SBP only but not in those with nosocomial infection, as assessed with ITT and PP analyses (see Supplementary Tables 6 and 7, Supplementary Digital Contents 6, https://links.lww.com/AJG/C816 and 7, https://links.lww.com/AJG/C817).

We also assessed the SBP resolution rates in patients who continued initially assigned antibiotics to 120 hours regardless of the result of 48 hours paracentesis; the treatment responses were less effective than that in those under response-guided therapy (see Supplementary Table 9, Supplementary Digital Content 9, https://links.lww.com/AJG/C819).

We compared the clinical outcomes according to the enrollment periods, but there were no statistical differences in the SBP resolution rate at 120 hours between the periods (see Supplementary Table 10, Supplementary Digital Content 10, https://links.lww.com/AJG/C820). There were no differences in characteristics and clinical outcomes of the patients with the first episode of SBP compared with those of patients with a previous episode of SBP (see Supplementary Table 11, Supplementary Digital Content 11, https://links.lww.com/AJG/C821).

Survival analysis.

Short-term mortality during 30 days was 18.4% (16/87), 20.7% (18/87), and 16.1% (14/87) in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively (P = 0.770) (Figure 4). There was no significant difference among the groups. Factors associated with 30-day survival were evaluated, and serum leukocyte count, bilirubin, albumin, and MELD were independent factors in the univariate analysis. Multivariable analysis showed that serum bilirubin and albumin were significant factors for survival, considering baseline factors only. Including treatment response, MELD score (hazard ratio = 1.06, CI = 1.01–1.10, P = 0.008) and the resolution of SBP on day 5 (hazard ratio = 0.51, CI = 0.29–0.91, P = 0.023) were significant factors for survival (Table 4). In addition, the increasing number of organ failures was significantly associated with poor prognosis (see Supplementary Table 12, Supplementary Digital Content 12, https://links.lww.com/AJG/C822).

F4Figure 4.:

Cumulative survival rate of the patients during 30 days.

T4Table 4.:

Factors associated with survival

DISCUSSION

Ascites develops in patients with liver cirrhosis as a consequence of portal hypertension leading to sodium and water retention due to activation of the renin-angiotensin-aldosterone and sympathetic nervous system (19). Once ascites appears, the prognosis of the patients worsens, and subsequent complications, such as SBP, may occur (12). Antibiotic prophylaxis is indicated in high-risk patients, but it may predispose to the emergence of quinolone-resistant organisms (20,21). Furthermore, hospitalized patients have an increased risk of infection with MDRO (14). Therefore, coping with SBP management and early assessment of the response to antibiotics during treatment is important. The previous AASLD 2012 guidelines did not recommend follow-up paracentesis after 48 hours of SBP treatment for community-acquired infections, whereas the newly updated 2021 guidance changed the statement to repeat paracentesis 2 days after initiation. In this study, we initially evaluated the early response to antibiotics at 48 hours of therapy and then decided to change or maintain the treatment (11). Using this strategy, the resolution rate of SBP at 120 hours, according to ITT analysis, was 67.8%, 77.0%, and 73.6% in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively (P = 0.388). Antimicrobial resistance was observed frequently; therefore, treatment needed to be modified according to initial treatment responses and bacteriologic culture results. After further modification of the antibiotics at 120 hours, the SBP resolution rates increased at 168 hours. The efficacies of the 3 drugs were comparable, and ceftriaxone and ciprofloxacin were not inferior to cefotaxime, which is the current standard of care for community-acquired SBP, when assessed at 120 and 168 hours. The noninferiority of ceftriaxone and ciprofloxacin to cefotaxime was also confirmed in the subgroup of patients with community-acquired SBP.

Short-term mortality was associated with the degree of systemic inflammation and underlying liver function, represented by bilirubin or albumin levels, considering baseline factors only. Including treatment responses, the MELD score and the resolution of SBP on day 5 were the most important factors for short-term survival. These findings suggest that liver function, systemic inflammation, and treatment response are key parameters for the survival of patients with SBP.

Regarding therapeutic responses, cefotaxime has been widely studied for SBP treatment (22,23). In the early 1990s, the resolution rate of SBP after 5 days of cefotaxime treatment was as high as 93%, similar to that after 10 days of the same treatment (23). Hence, the AASLD recommends intravenous third-generation cephalosporins such as cefotaxime as an initial treatment for SBP (10,11). In this study, the response rate was 67.8% with ITT analysis and 80.6% with PP analysis at 120 hours. Although the response rates were lower than those in previous reports, on-treatment modification and extension of therapy improved the treatment response further.

The response rate to ceftriaxone was previously reported to be up to 95% until the early 2000s. Although only 77.0% and 85.5% of the response rates at 120 hours with ITT and PP analyses, respectively, were observed in this study, the rate of ceftriaxone was the highest among the 3 antibiotics without statistical significance, and noninferiority to cefotaxime was confirmed. However, an increase in the failure rate was observed, which could be attributed to antibiotic resistance to third-generation cephalosporins (13,14).

Ciprofloxacin is an intravenous and orally available antibiotic that can be used for SBP treatment (5). The response rates of ciprofloxacin were 73.6% and 85.9% at 120 hours with ITT and PP analyses, respectively, in this study, which are not inferior to those of cefotaxime despite the concern of quinolone resistance (13).

In this study, our subjects mostly comprised patients with community-acquired SBP, and nosocomial SBP cases were relatively few. In addition, exclusion of the recent antibiotic use is considered to be associated with favorable response rates in this study. However, in clinical cases of nosocomial SBP, because most patients are already exposed to antibiotics, empirical therapeutics should be carefully selected considering MDRO. The European guidelines recommend starting with piperacillin/tazobactam or carbapenem according to the prevalence of extended-spectrum beta-lactamase–producing Enterobacteriaceae. In addition, if there is a high prevalence of Gram-positive bacteria, glycopeptides, daptomycin, or linezolid are suggested to be combined (12,24). AASLD 2021 guidance also recommends as such and mentioned that the type of broad-spectrum antibiotics should be tailored to local prevalence and type of MDRO (11). The role of carbapenem and glycopeptides as initial empirical therapies needs to be further validated in the future (25).

This study has several limitations. First, the study period was relatively long; hence, antibiotic sensitivity may have changed during the course of the study. However, we could not find a difference between the SBP resolution rate in the early and that in the late period of this study. Second, the positive bacterial culture rate was relatively low. Although a standard technique using blood culture bottles for ascitic fluid culture was applied, the causative organism was isolated in a limited number of cases, which made it difficult to analyze the changing patterns of antibiotic resistance. Third, although we did not limit the nosocomial SBP in this study, most of the patients experienced community-acquired SBP because of the exclusion of patients who received antibiotics within 2 weeks of screening. However, our results highlight that unnecessary high-level antibiotics may be reserved for community-acquired SBP without recent antibiotic use once short-term therapeutic response is assessed for appropriate modification. To further explore the healthcare-associated or nosocomial SBP, a separately designed prospective study is warranted.

In summary, this study evaluated the current efficacies of cefotaxime, ceftriaxone, and ciprofloxacin as initial therapies for SBP. The efficacy was not significantly different among the groups, and ceftriaxone or ciprofloxacin was not inferior to cefotaxime, which is the current standard for empirical therapy of community-acquired SBP. With the increasing prevalence of antibiotic-resistant organisms, response-guided therapy, considering the result of 48 hours ascitic PMN cell count on paracentesis, ensures the safety of empirical antibiotic therapy in the era of multidrug resistance.

CONFLICTS OF INTEREST

Guarantor of the article: Soon Ho Um, MD, PhD, and Hyung Joon Yim, MD, PhD.

Specific author contributions: Study conception and design: H.J.Y. and S.H.U.; Obtaining funding: S.H.U.; Acquisition of data: H.J.Y., S.J.S., S.Y.Y., Y.G.Y., Y.S.S., M.Y.K., S.K.B., H.S.K., Y.S.K,, S.Y.P., B.I.K., J.Y.P., J.H., J.H.S., N.Y.H., K.H.H., and S.H.U.; Data analysis and interpretation: H.J.Y., T.H.K., and S.J.S. (H.J.Y., T.H.K., and S.J.S. had access to all the data and can vouch for the integrity of the data analyses); writing of report: H.J.Y. and T.H.K.; review and final approval of the submission of the manuscript: all authors.

Financial support: This study was partly funded by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020), and partly by Korea University Research Grant.

Potential competing interests: None to report.

ClinicalTrials.gov identifier: NCT01265173.

Study Highlights

WHAT IS KNOWN ✓ Spontaneous bacterial peritonitis (SBP) is one of the most serious complications of liver cirrhosis. ✓ Cefotaxime, ceftriaxone, and ciprofloxacin are being administered for the initial treatment of SBP, but there are increasing concerns about antimicrobial resistance.

WHAT IS NEW HERE ✓ The efficacy of empirical antibiotics, such as cefotaxime, ceftriaxone, and ciprofloxacin, against SBP was not significantly different. ✓ With the increasing prevalence of antibiotic-resistant organisms, response-guided therapy, considering the result of 48 hours ascitic polymorphonuclear cell count on paracentesis, ensures the safety of empirical antibiotic therapy in the era of multidrug resistance. ✓ Unnecessary high-level antibiotics may be reserved for community-acquired SBP without recent antibiotic use once short-term therapeutic response is assessed for appropriate modification. ACKNOWLEDGMENT

We are grateful to Prof. Juneyoung Lee and Prof. Jaehyung Cha at the Department of Biostatics, Korea University, for providing statistical support.

REFERENCES 1. Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 2008;28(1):26–42. 2. Sheer TA, Runyon BA. Spontaneous bacterial peritonitis. Dig Dis 2005;23(1):39–46. 3. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis 1998;27(4):669–74; quiz 75–6. 4. Rimola A, Salmerón JM, Clemente G, et al. Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis in cirrhosis: Results of a prospective, randomized, multicenter study. Hepatology 1995;21(3):674–9. 5. Terg R, Cobas S, Fassio E, et al. Oral ciprofloxacin after a short course of intravenous ciprofloxacin in the treatment of spontaneous bacterial peritonitis: Results of a multicenter, randomized study. J Hepatol 2000;33(4):564–9. 6. Tuncer I, Topcu N, Durmus A, et al. Oral ciprofloxacin versus intravenous cefotaxime and ceftriaxone in the treatment of spontaneous bacterial peritonitis. Hepatogastroenterology 2003;50(53):1426–30. 7. Fiore M, Gentile I, Maraolo AE, et al. Are third-generation cephalosporins still the empirical antibiotic treatment of community-acquired spontaneous bacterial peritonitis? A systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2018;30(3):329–36. 8. Rostkowska KA, Szymanek-Pasternak A, Simon KA. Spontaneous bacterial peritonitis - therapeutic challenges in the era of increasing drug resistance of bacteria. Clin Exp Hepatol 2018;4:224–31. 9. Sunjaya DB, Lennon RJ, Shah VH, et al. Prevalence and predictors of third-generation cephalosporin resistance in the empirical treatment of spontaneous bacterial peritonitis. Mayo Clinic Proc 2019;94(8):1499–508. 10. Runyon BA. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013;57(4):1651–3. 11. Biggins SW, Angeli P, Garcia-Tsao G, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2021;74(2):1014–48. 12. European Association for the Study of the Liver Electronic address [email protected], European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69(2):406–60. 13. Ardolino E, Wang SS, Patwardhan VR. Evidence of significant ceftriaxone and quinolone resistance in cirrhotics with spontaneous bacterial peritonitis. Dig Dis Sci 2019;64(8):2359–67. 14. Fernández J, Acevedo J, Castro M, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: A prospective study. Hepatology 2012;55(5):1551–61. 15. Ricart E, Soriano G, Novella MT, et al. Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients. J Hepatol 2000;32(4):596–602. 16. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341(6):403–9. 17. Elsabaawy MM, Abdelhamid SR, Alsebaey A, et al. The impact of paracentesis flow rate in patients with liver cirrhosis on the development of paracentesis induced circulatory dysfunction. Clin Mol Hepatol 2015;21(4):365–71. 18. Hahn S. Understanding noninferiority trials. Korean J Pediatr 2012;55(11):403–7. 19. Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8(5):1151–7. 20. Yim HJ, Suh SJ, Jung YK, et al. Daily norfloxacin vs. weekly ciprofloxacin to prevent spontaneous bacterial peritonitis: A randomized controlled trial. Am J Gastroenterol 2018;113(8):1167–76. 21. Dupeyron C, Mangeney N, Sedrati L, et al. Rapid emergence of quinolone resistance in cirrhotic patients treated with norfloxacin to prevent spontaneous bacterial peritonitis. Antimicrob Agents Chemother 1994;38(2):340–4. 22. Felisart J, Rimola A, Arroyo V, et al. Cefotaxime is more effective than is ampicillin-tobramycin in cirrhotics with severe infections. Hepatology 1985;5(3):457–62. 23. Runyon BA, McHutchison JG, Antillon MR, et al. Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. Gastroenterology 1991;100(6):1737–42. 24. Piano S, Fasolato S, Salinas F, et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a randomized, controlled clinical trial. Hepatology 2016;63(4):1299–309. 25. Fernández J, Piano S, Bartoletti M, et al. Management of bacterial and fungal infections in cirrhosis: The MDRO challenge. J Hepatol 2021;75(Suppl 1):S101–17.

留言 (0)

沒有登入
gif