Summary

Background

The study was conducted to reveal the most appropriate empiric antibiotics for the treatment of community-acquired biliary tract infections (CA-BTI) at a regional hospital in Taiwan.

Methods

The study was performed between October 1, 2010 and October 31, 2012. All positive bile culture results of presumptive community-acquired origins were collected. The associated etiologic microorganisms and their antimicrobial susceptibilities were analyzed. The appropriateness of empiric therapy (defined as the effectiveness of the antibiotics against the etiologic agents) and the subsequent treatment response were examined through the review of medical records.

Results

A total of 115 patients (cholecystitis, 83 cases, 72.2%; cholangitis, 32 cases, 27.8%) and 189 isolates (136 Gram-negative bacilli, 37 Gram-positive cocci, and 16 anaerobes) were analyzed. The most frequent pathogens were Escherichia coli (n  = 69, 36.5%), Klebsiella spp. (n  = 37, 19.6%), enterococci (n  = 29, 15.3%), and Bacteroides spp. (n  = 11, 5.8%). Penicillin resistance (5.4%) was low in Gram-positive cocci, whereas higher resistance (>20%) to cefazolin, cefuroxime, and ampicillin–sulbactam was found in Gram-negative bacilli. Anaerobes also demonstrated high resistance to clindamycin (37.5%) but less to metronidazole (12.5%). Appropriate empiric therapy was found in 92 (80%) cases, and among them, 83 (90.2%) were treated successfully. The treatment success rate (69.6%) was significantly lower among the remaining 23 cases with inappropriate empiric therapy (16 of 23 vs. 83 of 92, p  < 0.05). A high treatment success rate (97.2%) was observed among cases empirically treated with ceftriaxone plus metronidazole.

Conclusion

The combination of ceftriaxone plus metronidazole appears to be the most appropriate empiric antibiotics for the treatment of CA-BTI at this hospital. Because different hospitals may encounter microorganisms of different antimicrobial susceptibilities, similar approaches may be followed by other hospitals where appropriate empiric therapy has not yet been established for the treatment of CA-BTI.

Keywords

Antibiotics ; Biliary tract ; Infections

Introduction

Biliary tract infections (BTI), including cholangitis and cholecystitis, usually result from biliary tract obstruction. From the standpoint of medical treatment, the most important approaches may include supportive treatment, administration of antibiotics, and exploring primary sources, such as biliary drainage, operation for removal of biliary tract stones, and cholecystectomy. Among these approaches, primary source control may be the most important. Early and instantaneous primary source control has been shown to be vital for the treatment of severe infections and may help to decrease mortality [1]  ;  [2] . Furthermore, if biliary obstruction is present, primary source control may facilitate the penetration of antibiotics through the biliary tract, leading to a better bactericidal effect [3]  ;  [4] .

In addition to primary source control, administration of antibiotics is also crucial for the treatment of BTI. The etiologic agents of BTI usually originate from endogenous flora of the gastrointestinal tract, with Escherichia coli , Klebsiella spp., enterococci, and Bacteroides spp. being the most frequent. Hence, antibiotics that are effective against these organisms are usually used empirically to treat BTI [5] ; [6] ; [7] ; [8] ; [9]  ;  [10] . However, inappropriate empiric antibiotics may also incur fatal outcomes [11]  ;  [12] .

Because the causative agents of BTI and the associated antimicrobial susceptibility patterns may vary in different hospitals [7] ; [8] ; [9]  ;  [10] , the establishment of appropriate therapeutic regimens for the individual hospitals appears necessary. The present study was therefore conducted to reveal the most appropriate empiric antibiotics for the treatment of community-acquired BTI (CA-BTI) at a 600-bed regional hospital in southern Taiwan. The bacteriology and the associated antimicrobial susceptibility patterns related to the CA-BTI were analyzed. To achieve the best therapeutic effects, the penetration ability of the antibiotics through the biliary tract was also considered [13]  ;  [14] .

Methods

Between October 1, 2010 and October 31, 2012, all positive results of bile cultures of presumptive community-acquired origins at a regional hospital in southern Taiwan were collected. Both aerobic and anaerobic cultures were routinely performed for bile specimens at this hospital and were included in the analysis. To prevent from the inclusion of some hospital-acquired pathogens, bile specimens that were submitted more than 3 days after hospitalization as well as those from patients readmitted within 6 months were excluded. In addition, medical records of the patients were reviewed, and information regarding age, sex, diagnosis, invasive procedures to collect the bile specimens, empiric antibiotics, and treatment response were collected for further analysis.

The appropriateness of empiric antibiotics was evaluated according to the antimicrobial susceptibility testing results. The empiric antibiotics were categorized as appropriate if the etiologic microorganisms demonstrated susceptibility to the antibiotics used. By contrast, if any of the antibiotics used was categorized as resistant in the associated antimicrobial susceptibility testing, the empiric antibiotics would be deemed as inappropriate. Successful treatment was defined as the improvement of the following three clinical conditions: fever subsided gradually, the patients general condition improved, and laboratory data became normal. If any of the conditions was not achieved, the case would be defined as treatment failure.

Standard laboratory methods were used to perform the bile culture and isolation and identification of microorganisms. Disk diffusion and limited agar dilution methods were used to determine the antimicrobial susceptibility for aerobic and anaerobic bacteria, respectively. The antibiotics tested for Gram-negative bacilli (GNBs) were as follows: cefazolin (30 μg), cefuroxime (30 μg), ceftriaxone (30 μg), ceftazidime (30 μg), gentamicin (10 μg), amikacin (30 μg), levofloxacin (5 μg), and ampicillin–sulbactam (10/10 μg). For Gram-positive cocci (GPCs), penicillin (10 units) and vancomycin (30 μg) were tested. All these antimicrobial disks were purchased from Becton, Dickinson and Company (Franklin Lakes, NJ, USA). Clindamycin (2 μg/4 μg) and metronidazole (8 μg/16 μg) were tested for anaerobes. Both disks were purchased from Creative Media Products, Ltd. (New Taipei City, Taiwan).

Results of the antimicrobial susceptibility testing were interpreted according to the current standards recommended by the Clinical and Laboratory Standards Institute. All intermediate results were regarded as resistant in this study.

The Chi-square test was used for the statistical analysis. A difference was considered statistically significant when the p value was <0.05.

Results

A total of 115 patients and 189 isolates were collected in the present study. Among the 115 patients, 66 (57.4%) were male and 29 (25.2%) were aged <60 years. The majority (83, 72.2%) of the patients had cholecystitis, and the remaining (32, 27.8%) were cholangitis. In the 83 patients with cholecystitis, bile specimens were obtained either from percutaneous gallbladder drainage (54, 65.1%) or through operation (29, 34.9%). In the 32 patients with cholangitis, bile specimens were withdrawn by one of the following procedures: percutaneous transhepatic drainage (14, 43.8%); percutaneous gallbladder drainage (9, 28.1%); operation (7, 21.8%); and endoscopic nasobiliary drainage (2, 6.3%).

The 189 isolates comprised 136 (72.0%) GNBs, 37 (19.5%) GPCs, and 16 (8.5%) anaerobes. Polymicrobial infection, i.e., two or more bacterial species were simultaneously isolated from the same specimens, was found in 45 (39.1%) patients, including 15 (13%) mixed infection with anaerobes. Distribution of the 189 isolates among various bacterial genuses/species and the associated rates of resistance to various antimicrobial agents are listed in Table 1 . The most frequent organisms were E. coli (69, 36.5%) and Klebsiella spp. (37, 19.6%). Some minor GNBs were also found, including three each of Pseudomonas aeruginosa and Proteus mirabilis , one each of Acinetobacter baumannii , Morganella morgannii , Serratia marcescens , Hafnia spp., and one unidentified glucose-nonfermenting GNB. None of the 136 GNBs was resistant to amikacin. Resistance to ceftazidime and gentamicin was also low (4.4%, respectively). Although the overall resistance to ceftriaxone (8.0%) and levofloxacin (13.2%) was not high, a wide range of resistance rates from 0% (for both antibiotics) in Klebsiella spp. to 50.0% (for levofloxacin) in Enterobacter spp. was also noted. High resistance rates (>20%) were observed for the remaining three antibiotics (cefazolin, cefuroxime, and ampicillin–sulbactam), with full resistance (100%) demonstrated by Enterobacter spp. (to all 3 agents) and Aeromonas spp. (to cefazolin and ampicillin–sulbactam).

Table 1. Distribution of the 189 isolates among various bacterial genuses/species and the associated rates of resistance to various antimicrobial agents.
Bacteria No. of isolates Antimicrobial resistance (%)
CZ CXM CRO CAZ GM LVX SAM PCN VAN CLIN MET
Escherichia coli 69 34.8 8.7 4.3 4.3 5.8 15.9 23.2
Klebsiella spp. 37 37.8 2.7 0.0 0.0 0.0 0.0 10.8
Enterobacter spp. 8 100.0 100.0 12.5 12.5 0.0 50.0 100.0
Citrobacter spp. 6 100.0 83.3 16.7 0.0 0.0 16.7 66.7
Aeromonas spp. 5 100.0 20.0 20.0 0.0 0.0 20.0 100.0
Other GNBs 11 90.9 63.6 45.5 18.2 18.2 18.2 63.6
Total GNBs 136 49.3 20.6 8.0 4.4 4.4 13.2 33.8
Enterococci 29 6.9 0.0
Streptococci 8 0.0 0.0
Anaerobes 16 37.5 12.5

All Gram-negative bacilli were susceptible to amikacin.

CAZ = ceftazidime; CLIN = clindamycin; CRO = ceftriaxone; CXM = cefuroxime; CZ = cefazolin; GM = gentamicin; GNBs = Gram-negative bacilli; LVX = levofloxacin; MET = metronidazole; PCN = penicillin; SAM = ampicillin–sulbactam; VAN = vancomycin; — = not tested.

Most of the GPCs were enterococci (29, 15.3%), and the remaining were streptococci (8, 4.2%). All the GPCs were susceptible to both penicillin and vancomycin, except that two penicillin-resistant enterococci were also noted. The anaerobes identified were Bacteroides spp. (n  = 11), Clostridium spp. (n  = 4), and Prevotella spp. (n  = 1). They showed high resistance to clindamycin (37.5%) but less to metronidazole (12.5%; Table 1 ).

Empiric antibiotics and treatment responses of the patients are shown in Table 2 . The most frequent empiric antibiotics were ceftriaxone plus metronidazole (36, 31.3%) and cefuroxime plus metronidazole (28, 24.3%). Most (92, 80%) of the patients received appropriate empiric antibiotics, whereas the remaining 23 (20%) were deemed inappropriate. The majority (83, 90.2%) of the patients in the appropriate empiric antibiotics group demonstrated successful treatment responses. Ceftriaxone plus metronidazole, although the most frequent antibiotic combination used, also appeared to be highly effective. The only failure was found in the inappropriate treatment group, with one of the etiologic agents, E. coli , being resistant to the ceftriaxone used. Thus, if only the appropriate empiric antibiotics were considered, this antibiotic combination actually reached a full success treatment rate of 100%. Some other antibiotics, such as cefazolin, flomoxef, and doripenem also demonstrated a full success rate of 100%, although these were only used in five or fewer patients. Among the nine patients whose treatment failed, six (3 cases of cefuroxime plus metronidazole, 1 case of cefmetazole, 1 case of cefazolin plus metronidazole, and 1 case of ceftazidime plus metronidazole) were subsequently treated successfully with ceftriaxone plus metronidazole. Another case of treatment failure with levofloxacin also demonstrated successful responses when ceftriaxone was used subsequently. Three patients died despite all receiving appropriate empiric antibiotics. The cause of death in the patient treated with ceftazidime plus metronidazole was other underlying diseases rather than uncontrolled infections, whereas the remaining two were due to septic shock complicated with multiple organ failure.

Table 2. Empiric antibiotics administered and the corresponding treatment responses among the 115 patients studied.
Empiric antibiotics No. of cases Evaluation of appropriateness Treatment response Mortality
Appropriate Inappropriate Success Failure
CXM + M 28 22 (78.6) 6 (21.4) 23 (82.1) 5 (17.9) 0 (0.0)
CXM 4 2 (50.0) 2 (50.0) 3 (75.0) 1 (25.0) 0 (0.0)
CRO + M 36 32 (88.9) 4 (11.1) 35 (97.2) 1 (2.8) 0 (0.0)
CRO 5 4 (80.0) 1 (20.0) 4 (80.0) 1 (20.0) 0 (0.0)
CZ + M 8 5 (62.5) 3 (37.5) 6 (75.0) 2 (25.0) 0 (0.0)
CZ 5 4 (80.0) 1 (20.0) 5 (100.0) 0 (0.0) 0 (0.0)
CAZ + M 2 2 (100.0) 0 (0.0) 1 (50.0) 1 (50.0) 1 (50.0)
LEV 4 4 (100.0) 0 (0.0) 2 (50.0) 2 (50.0) 1 (50.0)
MOX 6 4 (66.7) 2 (33.3) 5 (83.3) 1 (16.7) 0 (0.0)
CMZ 7 4 (57.1) 3 (42.9) 6 (85.7) 1 (14.3) 0 (0.0)
FLO 4 3 (75.0) 1 (25.0) 4 (100.0) 0 (0.0) 0 (0.0)
DOR 5 5 (100.0) 0 (0.0) 5 (100.0) 0 (0.0) 0 (0.0)
IMP 1 1 (100.0) 0 (0.0) 0 (0.0) 1 (100.0) 1 (100.0)
Total 115 92 (80.0) 23 (20.0) 99 (86.1) 16 (13.9) 3 (2.6)
Appropriate empiric antibiotics (n  = 92) 83 (90.2) 9 (9.8) 3 (3.3)
Inappropriate empiric antibiotics (n  = 23) 16 (69.6) 7 (30.4) 0 (0.0)

Data are presented as n (%).

CAZ = ceftazidime; CMZ = cefmetazole; CRO = ceftriaxone; CXM = cefuroxime; CZ = cefazolin; DOR = doripenem; FLO = flomoxef; IMP = imipenem; LEV = levofloxacin; M = metronidazole; MOX = moxifloxacin.

Among the 23 patients receiving inappropriate empiric antibiotics, 16 (69.6%) were still treated successfully. These empiric antibiotics were ceftriaxone plus metronidazole (n  = 3), ceftriaxone (n  = 1), cefuroxime plus metronidazole (n  = 4), cefuroxime (n  = 1), cefmetazole (n  = 2), cefazolin plus metronidazole (n  = 2), cefazolin (n  = 1), moxifloxacin (n  = 1), and flomoxef (n  = 1). Of the seven patients with treatment failure, three received cefmetazole, cefuroxime plus metronidazole, and cefuroxime, respectively, and were subsequently treated successfully with ceftriaxone plus metronidazole, the appropriate empiric antibiotics in two of the patients.

In the 29 patients with positive bile cultures for enterococci, 27 received empiric antibiotics without antienterococcal activities, but 26 (96.3%) demonstrated successful responses. In the only case of treatment failure, the bile culture also grew E. coli , which was resistant to the empiric antibiotics used. Overall, the treatment success rate of appropriate empiric antibiotics was significantly higher than that of inappropriate empiric antibiotics (83 of 92 vs. 16 of 23, p  < 0.05, χ2 test).

Discussion

From the standpoint of medical treatment, the selection of empiric antibiotics has to consider two important factors. First, >80% of the suspected etiologic microorganisms should be susceptible to the antibiotics, and, for patients with septic shock, the susceptibility rates should even reach 100% to obtain favorable treatment responses [15] . Second, the antibiotics should yield sufficient concentrations at the sites of infection to produce the expected antimicrobial effect [13]  ;  [14] . Hence, both the susceptibility rates and the ability of biliary penetration should be considered when selecting empiric antibiotics for the treatment of BTI. The antibiotics usually used to treat BTI and their biliary penetration ability (indicated as the ratio of bile to serum concentrations) are listed in Table 3[16] ; [17] ; [18]  ;  [19] . According to the criteria mentioned above, only those with a satisfactory ratio (≥1) of bile to serum concentrations (Table 3 ) could be the candidate of empiric antibiotics for BTI. Appropriate empiric antibiotics should further consider the local antimicrobial susceptibility patterns of the usual etiologic agents for BTI. Only those with resistance rates of <20% should be used as empiric antibiotics to ensure a favorable outcome.

Table 3. The antibiotics usually used to treat biliary tract infections and their biliary penetration ability (indicated as the ratio of bile to serum concentrations) [16] ; [17] ; [18]  ;  [19] .
Good penetration efficiency (≥1) Low penetration efficiency (<1)
Antibiotics Bile/serum Antibiotics Bile/serum
Tazocin 60 Cefotaxime 0.75
Tigecycline 38 Meropenem 0.75
Augmentin 30 Ceftazidime 0.5
Ciprofloxacin 30 Vancomycin 0.5
Unasyn 9 Amikacin 0.3
Ceftriaxone 5 Gentamicin 0.3
Levofloxacin 5 Cefepime 0.1
Penicillin G 5 Imipenem 0.01
Cefazolin 3
Clindamycin 3
Doripenem 1.17
Cefuroxime 1
Metronidazole 1

Augmentin = amoxicillin–clavulanate; Bile/serum = bile concentration/serum concentration; Tazocin = piperacillin–tazobactam; Unasyn = ampicillin–sulbactam.

Previous reports have indicated that the common etiologic agents for BTI usually include E. coli , Klebsiella spp., enterococci, and Bacteroides spp. [5] ; [6] ; [7] ; [8] ; [9]  ;  [10] . Similar results were also noted in the present study. Furthermore, although anaerobes were identified from only 15 (13%) patients, they were usually associated with polymicrobial infections, especially with GNBs. Hence, the empiric antibiotics used should be effective against both groups of microorganisms, regardless whether anaerobes are isolated [20] . In the present study, metronidazole was found to be the preferred option with a much lower resistance rate (12.5%) compared to that (37.5%) of clindamycin.

Whether to treat enterococci remains controversial when the organisms are isolated from bile specimens. In most conditions, enterococci do not need antimicrobial treatment [21]  ;  [22] . In the present study, most of the patients with positive bile cultures for enterococci did not receive antibiotics with known antienterococcal activity. However, only one treatment failure was subsequently found, probably due to the antimicrobial resistance of the other organism that concomitantly caused the BTI. It appears that antienterococcal activity is not important when empiric antibiotics are to be selected for treating CA-BTI.

Cefazolin (to treat GNBs and streptococci) plus metronidazole (to treat anaerobes) has long been regarded as the first-line empiric antibiotic combination for CA-BTI. However, our data did not support this recommendation due to the high resistance rate observed. Even cefuroxime and ampicillin–sulbactam were inappropriate with resistance rates of both being >20%. Therefore, third-generation cephalosporins (such as ceftriaxone and ceftazidime) and fluoroquinolones (such as levofloxacin and ciprofloxacin) may serve as the preferred options due to the lower resistance rates (<20%).

According to the above analysis, metronidazole plus ceftriaxone or levofloxacin may be the most appropriate empiric antibiotics to treat CA-BTI. When the resistance rates and medical cost are further considered, ceftriaxone appears to be superior to levofloxacin. Hence, we suggest that ceftriaxone plus metronidazole is the most appropriate empiric antibiotic combination to treat CA-BTI at this hospital. The suggestion also could be supported by the high treatment success rate (97.2%) of ceftriaxone plus metronidazole observed in the present study. Moreover, some of the treatment failures with other antibiotics were subsequently treated successfully with ceftriaxone plus metronidazole. However, if antibiotics are necessary for outpatient treatment, oral levofloxacin (or ciprofloxacin) plus metronidazole may still serve as the appropriate alternative antibiotics.

In this study, 26 (22.6%) patients also developed bacteremia. Hence, antibiotics with lower serum concentrations cannot be used as empiric antibiotics to treat BTI. For example, tigecycline is effective against GPCs, GNBs, and anaerobes. It is also recommended as an empiric antibiotic for treating BTI due to the low resistance rates and high biliary penetration abilities [23] . However, none of the patients was administered with the antibiotic in the present study. Moreover, we disagree with this recommendation because tigecycline was known to be associated with lower serum concentrations and thus may result in treatment failure if bacteremia is simultaneously present [24] ; [25]  ;  [26] .

Biliary drainage and administration of appropriate antibiotics are two most important approaches to treat BTI, especially for cholangitis. More precisely, biliary drainage is even more important than the administration of appropriate antibiotics. Biliary drainage is a method of primary source control and can allow antibiotics to penetrate effectively into the biliary tract where the infection occurs. However, administration of appropriate empiric antibiotics is also important. Based on results from the present study, we recommend that ceftriaxone plus metronidazole may be the appropriate empiric antibiotic combination to treat CA-BTI at this hospital. In addition, we also suggest that every hospital should have its own guideline in this regard because different etiologic organisms with various antimicrobial susceptibility patterns may be present [5] , especially in areas where multidrug-resistant infections have been increasing.

Conflicts of interest

All authors declare no conflicts of interest.

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