Meropenem versus Cefotaxime as Empirical Treatment of Spontaneous Bacterial Peritonitis: Prospective, Randomized Clinical Trial

INTRODUCTION

Spontaneous bacterial peritonitis (SBP) is the most common bacterial illness among cirrhotic patients. It is one of the most significant consequences of cirrhotic ascites, accounting for over 25% of all bacterial infections [1]. Nevertheless, over the last decade, there has been a reported shift in SBP microbial patterns, with an increase in the prevalence of gram-positive bacteria. Gram-positive bacteria have been found to account for almost half of culture-positive SBP. Another issue in SBP therapy is the rise of multidrug-resistant (MDR) bacteria, particularly in nosocomial infections [2] The current approach recommends third-generation cephalosporin (cefotaxime or ceftriaxone) or piperacillin-tazobactam as the first-line strategy for community-acquired spontaneous bacterial peritonitis; the latter is also to be considered for healthcare-associated and nosocomial spontaneous bacterial peritonitis in areas with low prevalence of infections by multidrug-resistant organisms [3].

Meropenem combined with glycopeptides or daptomycin has been suggested as the primary approach for healthcare-associated spontaneous bacterial peritonitis or in severe infections in areas with a high prevalence of multidrug-resistant organisms, and for nosocomial spontaneous bacterial peritonitis in general [3, 4]. Given the high rates of resistance, empirical cephalosporin treatment for noncommunity-acquired SBP is not indicated.

Furthermore, it is known that one of the most common precipitants of hepatic encephalopathy is an acute infection with SBP [6]. Mortality from the first episode of SBP is 36% and 46% in culture-negative neutrocytic ascites (CNNA). After the sentinel episode of SBP, one-third of the patients can experience recurrent episodes of SBP within a year, and one-year mortality is approximately 32% [7].

This work was conducted to evaluate the efficacy of meropenem versus cefotaxime as an empirical treatment of spontaneous bacterial peritonitis.

METHODS

Study setting& design:

A single-center, prospective, randomized, clinical trial was conducted at Al-Rajhi University Hospital, Assiut University between January 2023 and January 2024.

The study was conducted according to the principles of the Declaration of Helsinki and was authorized by the Ethical Committee of the faculty of medicine, Assiut University, Assiut, Egypt (IRB no: 17101825/ 2022). The study was explained to all patients and only patients who were signing an informed consent participated in the study. This study was registered on clinicaltrials.gov with the identifier: NCT05427747.

Selection criteria:

All cirrhotic patients with ascites were diagnosed by ascitic fluid analysis as SBP (ascitic fluid polymorphonuclear cell (PMNC) count equal to or more than 250/mm³ [8]. Patients with ascites due to causes other than liver cirrhosis, HCC, and/or died within 48 hours after enrollment were excluded.

Sample size calculation and randomization:

Based on the previously reported in-hospital mortality rate that was 25.8% in the carbapenem group [9], the estimated minimum required total sample size is 112 participants with the following assumption; 5% alpha error, 80% power of the study, 95% confidence interval.

We enrolled a total of 162 patients with SBP during the period of the study. Out of them 8 patients died within 48 hours and were excluded. So, a total of 154 patients were recruited in the study and subdivided into two groups (figure 1).

Simple randomization was done with a ratio of 1:1. Each patient was randomly assigned to his group using the quick Calcs method for randomization either the meropenem group or the cefotaxime group.

 Methodology

All patients were evaluated with history taking and clinical evaluation. Pelvic-abdominal ultrasonography examination was performed. Total leucocytic count, serum albumin, total bilirubin, serum urea, serum creatinine, and international normalized ratio were done. In addition to, the assessment of Child-Pugh and MELD scores.

The ascitic fluid analysis included measurement of protein and albumin, WBCs, and PMNL cell counts by automated counter.The ascitic fluid culture was done on blood broth (modified culture method and antibiotic sensitivity tests were done for all cases)

Treatment options that were given:

-          Group A patients were treated with intravenous meropenem one gram / eight-hour

• Group B patients were treated with intravenous cefotaxime two gram/eight hour.

After 48 hours of starting the antibiotics:

 Ascitic fluid analysis was done, and the following interpretations were considered [10]:

-          If PMNL in ascitic fluid decreased by 25% or more of the initial result. This indicates a good response to treatment, and we continued on the same antibiotic to complete 5 days of treatment.

-          If PMNL in ascitic fluid decreased by less than 25% or increased more than the initial result, that indicates poor response, and we shifted to another antibiotic according to culture and sensitivity test in case of positive ascitic fluid culture for 5 days. Piperacillin-tazobactam ln case of negative ascitic fluid culture

The study outcome

The primary outcome was to determine the success rate of each antibiotic that was assessed by the percentage of reduction of ascitic fluid PMNL > 25% from the baseline count within 48 hours. The secondary outcome was determining theestimated number of patients who needed to be treated (number to treat; NTT) with meropenem for one additional patient would respond to empirical therapy.

Statistics

Recorded data were analyzed using the statistical package for social sciences, version 20.0 (SPSS Inc., Chicago, Illinois, USA). The Shapiro test was done at first to assess normality of the data. Quantitative data were expressed as mean ± Standard Deviation (SD) and compared with Student t test. Qualitative data were expressed as frequency and percentage and compared with Chi² test.

To calculate NTT, we determine at first; relative risk (RR) as follows; RR= (frequency of failure in meropenem group)/ (frequency of failure in cefotaxime group). Then the absolute risk reduction (ARR) was the difference between the frequency of failure in both groups. Then, NNT is the inverse of ARR. P value was significant if < 0.05.

RESULTS

Baseline characteristics data of studied groups (table 1):

The majority of patients were males and had normal BMI. The most frequent etiology of liver cirrhosis was HCV (83.1% vs. 76.6%) followed by HBV (11.7% vs. 14.3%). Both groups had comparable baseline data.

Clinical presentation and baseline laboratory data among the groups studied (table 2):

Both groups had insignificant differences as regards clinical presentation and baseline laboratory data. A total of 7 (9.09%) and 6 (7.79%) patients in the Meropenem and Cefotaxime groups were asymptomatic.

Results of ascitic fluid culture among the studied groups at the start of the study (table 3):

The most frequently isolated organisms were E. coli (44.2% v. 50.6%) and Acinetobacter species (9.1% vs. 2.6%) followed by Klebsiella species (5.2% vs. 2.6%) and Pseudomonas species (2.6% vs. 2.6%). Enterobacter aerogenes was isolated in only one patient. A total of 30 (39%) and 31 (40.3%) patients of meropenem and cefotaxime groups had no growth in the culture.

Ascitic fluid analysis after 48 hours of starting treatment to assess response (table 4):

The Meropenem group showed a significantly higher frequency of response to empirical therapy (71.4% vs. 55.8%; p= 0.03) in comparison to the cefotaxime group.

Number to treat in the current study:

Calculation of relative risk (RR)

RR to avoid failure of empirical treatment of SBP by usage of meropenem was calculated as follows, RR= (frequency of failure in meropenem group)/ (frequency of failure in cefotaxime group) = 28.6%/ 44.2%= 0.65 with 95% confidence interval (CI) was between 0.25 to 0.98. This means that patients who used meropenem for empirical treatment of SBP had a risk of failure of 0.65 lower than those who received cefotaxime.

Calculation of the number needed to treat (NNT)

Firstly, we calculated the absolute risk reduction (ARR) which is the difference between the frequency of failure in both groups 44.2%- 26.6% = 17.6%.

Secondly, NNT is the inverse of ARR= 1/0.176= 6 cases. So, this means that the estimated number of patients who needed to be treated with meropenem for one additional patient would respond to empirical therapy was 6 cases to avoid failure of empirical therapy in patients with SBP.

 Table (1). Baseline characteristics of studied groups

Data expressed as frequency (percentage), and mean (SD). P value was significant if < 0.05. BMI: body mass index; IHD: ischemic heart disease; LC: liver cirrhosis; HCV: hepatitis C virus; HBV: hepatitis B virus.

Table (2). Clinical presentation and baseline laboratory data among the studied groups

              Data expressed as mean (SD), and frequency (percentage). P value was significant if < 0.05. INR: international randomized ratio; MELD: model for end-stage liver disease; PMNL: polymorphonuclear leucocytes.

Table (3). Results of ascitic fluid culture among the studied groups

                      Data expressed as frequency (percentage). P value was significant if < 0.05.

 Table (4): Ascitic fluid analysis after 48 hours of starting treatment

Data expressed as mean (SD), and frequency (percentage). P value was significant if < 0.05. PMNL: polymorphonuclear leucocytes

*This was defined with > 25% reduction in PMNL in ascitic fluid after 48 hours

 DISCUSSION