Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: A prospective study

Authors

  • Javier Fernández,

    Corresponding author
    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    • Liver Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona. Spain
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    • fax: 34-93-4515522

  • Juan Acevedo,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Miriam Castro,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Orlando Garcia,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Carlos Rodríguez de Lope,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Daria Roca,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Marco Pavesi,

    1. Statistical Department, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Elsa Sola,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Leticia Moreira,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Anibal Silva,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Tiago Seva-Pereira,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Francesco Corradi,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Jose Mensa,

    1. Infectious Disease Department, Hospital Clínic, University of Barcelona, Barcelona, Spain
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  • Pere Ginès,

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Vicente Arroyo

    1. Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Barcelona, Spain
    3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Potential conflict of interest: Nothing to report.

Abstract

Epidemiology, risk factors, and clinical effect of infections by multiresistant bacteria in cirrhosis are poorly known. This work was a prospective evaluation in two series of cirrhotic patients admitted with infection or developing infection during hospitalization. The first series was studied between 2005 and 2007 (507 bacterial infections in 223 patients) and the second between 2010 and 2011 (162 bacterial infections in 110 patients). In the first series, 32% of infections were community acquired (CA), 32% healthcare associated (HCA), and 36% nosocomial. Multiresistant bacteria (92 infections; 18%) were isolated in 4%, 14%, and 35% of these infections, respectively (P < 0.001). Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E; n = 43) was the main multiresistant organism identified, followed by Pseudomonas aeruginosa (n = 17), methicillin-resistant Staphylococcus aureus (n = 14), and Enterococcus faecium (n = 14). The efficacy of currently recommended empirical antibiotic therapy was very low in nosocomial infections (40%), compared to HCA and CA episodes (73% and 83%, respectively; P < 0.0001), particularly in spontaneous bacterial peritonitis, urinary tract infection, and pneumonia (26%, 29%, and 44%, respectively). Septic shock (26% versus 10%; P < 0.0001) and mortality rate (25% versus 12%; P = 0.001) were significantly higher in infections caused by multiresistant strains. Nosocomial origin of infection (hazard ratio [HR], 4.43), long-term norfloxacin prophylaxis (HR, 2.69), recent infection by multiresistant bacteria (HR, 2.45), and recent use of β-lactams (HR, 2.39) were independently associated with the development of multiresistant infections. Results in the second series were similar to those observed in the first series. Conclusions: Multiresistant bacteria, especially ESBL-producing Enterobacteriaceae, are frequently isolated in nosocomial and, to a lesser extent, HCA infections in cirrhosis, rendering third-generation cephalosporins clinically ineffective. New antibiotic strategies tailored according to the local epidemiological patterns are needed for the empirical treatment of nosocomial infections in cirrhosis. (HEPATOLOGY 2012)

Bacterial infections are frequent in advanced cirrhosis and are associated with poor prognosis.1-5 According to International Ascites Club (IAC), American Association for the Study of Liver Diseases, and European Association for the Study of the Liver guidelines, the treatment of choice of the most common infections occurring in cirrhosis are third-generation cephalosporins because they are active against Enterobacteriaceae and nonenterococcal streptococci and are well tolerated.6-9 Patients with cirrhosis, low-protein ascites, and severe circulatory dysfunction are at high risk of developing spontaneous bacterial peritonitis (SBP).10 Bacterial infections are also common in patients with variceal bleeding.3, 11 Finally, SBP is a recurrent infection.12 Primary and secondary prophylaxis with norfloxacin reduces dramatically the prevalence of bacterial infections and improves survival in these selected subpopulations.7-11, 13-15 Norfloxacin is therefore widely used in the management of patients with decompensated cirrhosis.

In 2002, we reported the first prospective investigation assessing changes in the epidemiology of bacterial infections in patients with decompensated cirrhosis.1 The main findings of the study were an increase in the rate of infections caused by Gram-positive cocci (GPC) associated with invasive procedures during hospitalization and the emergence of SBP by quinolone-resistant (QR) bacteria in patients on long-term norfloxacin prophylaxis. Only 1.2% of infections caused by Enterobacteriaceae were resistant to cefotaxime.1

Recent investigations suggest that the prevalence of infections caused by multiresistant bacteria is increasing in cirrhosis,16-22 as in the general population (23-25).23-25 Multiresistant bacteria are strains resistant to at least three of the main antibiotic families, including β-lactams.26 In our area, the most frequent are extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E), nonfermentable Gram-negative bacilli (GNB) as Pseudomonas aeruginosa or Acinetobacter baumanii, methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus faecium. Because the prevalence of infections by these organisms was low in our previous study,1 we decided to perform a second prospective evaluation aimed at assessing the prevalence, epidemiology, risk factors, and effect on empirical antibiotic treatment response and hospital survival of multiresistant bacterial infection in decompensated cirrhosis.

Abbreviations

CA, community acquired; CI, confidence interval; ESBL-E, extended-spectrum β-lactamase-producing Enterobacteriaceae; GNB, Gram-negative bacilli; GPC, Gram-positive cocci; HCA, healthcare associated; HCV, hepatitis C virus; HR, hazard ratio; HRS, hepatorenal syndrome; IAC, International Ascites Club; ICU, intensive care unit; IV, intravenous; MELD, Model for End-Stage Liver Disease; MRSA, methicillin-resistant Staphylococcus aureus; QR, quinolone resistant; SB, spontaneous bacteremia; SBP, spontaneous bacterial peritonitis; SE, spontaneous bacterial empyema; SIRS, systemic inflammatory response syndrome; UTI, urinary tract infection.

Patients and Methods

We performed a prospective evaluation of all bacterial infections occurring in cirrhotic patients admitted to our unit during two different periods. The evaluation protocol has been previously described.1 The first series was studied from September 2005 to September 2007 to assess the prevalence, epidemiology, risk factors, and clinical effect of multiresistant bacterial infection in cirrhosis. The second series was studied to assess new potential epidemiological changes (September 2010-April 2011). Exclusion criteria were human immunodeficiency virus infection, previous transplantation, and any other type of immunodeficiency. Diagnosis of cirrhosis was established by histology or by clinical, analytical, and ultrasonographic findings. Criteria for the diagnosis of infections were the following: SBP and spontaneous empyema (SE; polymorphonuclear cell count in ascitic and pleural fluid ≥250/mm3, respectively)7-9; secondary peritonitis according to conventional criteria27; spontaneous bacteremia (SB; positive blood cultures with no cause of bacteremia)1; catheter-related infection (positive blood and catheter cultures); urinary infections (UTI; more than 10 leukocytes per high-power field in urine and positive urine cultures)28; or uncountable leukocytes per field without positive cultures. Diagnosis of other infections was made according to conventional criteria.29 Infections diagnosed at admission or within 2 days after admission were classified as healthcare associated (HCA) in those patients with a previous contact with a healthcare environment (e.g., hospitalization or short-term admission for at least 2 days in the previous 90 days, residence in a nursing home or a long-term care facility, or chronic hemodialysis).30 We selected 90, and not 180, days22 as criteria to define HCA infections because it related better with the development of multiresistant infections. The remaining infections were considered community acquired (CA) when they were present at admission or developed within the first 48 hours after hospitalization and nosocomial when the diagnosis was made thereafter.31

Isolated organisms were tested for antimicrobial susceptibility through both the disk-diffusion method and minimum inhibitory concentration testing using the VITEK2 system (BioMérieux, Marcy l'Etoile, France) or the Etest system (AB Biodisk, Solna, Sweden), according to the recommendations of the Clinical and Laboratory Standards Institute.32 The following bacteria were considered multiresistant in the current study: ESBL (e.g., Escherichia coli and Klebsiella pneumonia) or desrepressed chromosomic AmpC β-lactamase-producing Enterobacteriaceae (e.g., Enterobacter or Citrobacter spp.), described as ESBL-E, P. aeruginosa, Stenotrophomonas maltophilia, A. baumanii, Achromobacter spp., MRSA, and E. faecium.

The clinical course (i.e., efficacy of the currently recommended empirical antibiotic therapy, complications related to infection, final resolution, and hospital mortality) was assessed in the first series and was restricted to the most common infections of cirrhosis. Infrequent infections were not evaluated (e.g., meningitis, endocarditis, arthritis, dental infection, pseudomembranous colitis, gastroenteritis, acute cholecystitis, cholangitis, and secondary peritonitis). The empirical antibiotic regimen used in this series was as follows: (1) intravenous (IV) ceftriaxone for SBP, SE, SB, UTI, and sepsis of unknown origin; (2) IV ceftriaxone plus cloxacillin or amoxicillin/clavulanic acid for cellulitis; (3) IV ceftriaxone and a macrolide or levofloxacin (plus clindamycin in the case of aspiration) in patients with CA pneumonia3; (4) ceftazidime plus ciprofloxacin in nosocomial pneumonia, as adapted from a previous work33; and (5) catheter withdrawal and one dose of vancomycin (in patients without systemic inflammatory response syndrome; SIRS) and vancomycin plus ceftazidime (in patients with SIRS) in suspected catheter infections.

Criteria used to consider an infection cured were the following: (1) no clinical signs of infection; (2) SBP and SE (cell count in ascitic or pleural fluid polymorphonuclear cells <250/mm3); and (3) SB and UTI (negative control cultures after antibiotic treatment). Resolution of the remaining infections was established by conventional criteria.29 Septic shock was diagnosed by the presence of data compatible with SIRS,34 mean arterial pressure below 60 mmHg during more than 1 hour despite adequate fluid resuscitation (increase in central venous pressure to 8-10 mmHg), and need of vasopressor drugs.35 Hepatorenal syndrome (HRS) was diagnosed according to the IAC criteria.36 In patients with two or more infections at the same admission, complications related to infection and hospital mortality were attributed according to the severity of the infection.

Clinical and laboratory data (e.g., sex, age, active alcoholism, diabetes, presence of ascites or hepatic encephalopathy, Child-Pugh and Model for End-Stage Liver Disease [MELD] scores, catheter insertion, mechanical ventilation, and intensive care unit [ICU] admission) and epidemiological data related to the development of multiresistant infections in the general population (e.g., site of acquisition of the infection, previous infection by multiresistant bacteria [within 6 months], recent treatment with oral and/or IV β-lactams, and hospitalization within 3 months before infection)37-41 were evaluated to identify risk factors of multiresistant bacterial infections in our two series of patients. Long-term norfloxacin prophylaxis was also included in this analysis. The study was approved by the ethics committee of the hospital.

Statistical Analysis.

Statistical analysis was performed using the unpaired Student's t test for continuous variables with parametric distribution, Mann-Witney's U test for those with nonparametric distribution, and the chi-sqaure test for qualitative variables, applying Yate's correction when required. Differences were considered significant at the level of 0.05. Multivariate analysis was performed using Cox's proportional hazards model for recurrent events (per infection analysis). This statistical test is the only test that allows the analysis of multiple observations (in this case, infection) in different episodes that occur in the same patient. Analyses were done with the SPSS (version 16.0; SPSS, Inc., Chicago, IL) and the SAS (version 9.1; SAS Institute Inc., Cary, NC) statistical packages.

Results

Patients, Admissions, and Infections.

The first series of patients was obtained from a total of 946 patients who were admitted for the treatment of an acute complication of cirrhosis between 2005 and 2007 (Fig. 1). Bacterial infections were present at entry into the hospital and/or developed during hospitalization in 223 patients (390 admissions; 25%). Ninety-eight patients had received β-lactams within 3 months before infection, 95 had a history of hospitalization in the previous 3 months, and 70 were receiving long-term norfloxacin prophylaxis. In total, 507 bacterial infections were detected: 163 (32%) were CA, 164 were HCA (32%), and 180 (36%) were nosocomial. In 53 infectious episodes, there was history of infection by multiresistant bacteria in the previous 6 months (ESBL-E in 24, P. aeruginosa in 12, E. faecium in 9, and MRSA in 8).

Figure 1.

Flow chart of the first series of patients (2005-2007). Two different analyses were performed. The epidemiological analysis evaluated all the infections occurring during this study period. The analysis on the efficacy of the currently recommended empirical antibiotic treatment was restricted to the most frequent infections (e.g., SBP, UTI, cellulitis, pneumonia, purulent bronchitis, SB, SE, catheter sepsis, and infections of unknown origin). *Meningitis, endocarditis, arthritis, dental infection, pseudomembranous colitis, gastroenteritis, acute cholecystitis, cholangitis, and secondary peritonitis were excluded. **Antibiotics different to those recommended in the guidelines.

Clinical Characteristics of Patients and Types of Infection.

In the first series, 63% of patients were men. Mean age was 60±13 years. Cause of cirrhosis was alcoholism in 86 cases, hepatitis C virus (HCV) in 82, HCV plus alcohol in 27, and other causes in 28. Most patients were severely ill, as indicated by a high incidence of decompensations (ascites in 271 admissions, hepatic encephalopathy in 148, and gastrointestinal hemorrhage in 55) and poor hepatic and renal function. Median Child-Pugh and MELD scores were 9.26 ± 2.16 and 17.83 ± 6.91, respectively. Patients had HRS in 62 admissions.

The most common infection in the first series was SBP (126), followed by UTI (98), cellulitis (66), pneumonia (46), SB (30), purulent bronchitis (27), catheter infection (23), secondary peritonitis (5), SE (4), endocarditis (4), and other (16). Sixty-two patients presented sepsis of unknown origin (e.g., culture-negative fever and leukocytosis).

Isolated Bacteria and Site of Infection Acquisition.

In the first series, a total of 312 bacteria were isolated in 271 culture-positive infections (53%). Bacterial isolation was more frequent in nosocomial than in HCA and CA infections (70% versus 50% versus 39%; p = 0.0001). The rate of positive cultures was 91% in UTI, 47% in cellulitis, 41% in SBP, and 37% in pneumonia. GNB were isolated in 65% of culture-positive CA infections and GPC in 46%. Similar figures were observed in HCA infections (60% and 43%). Both GNB and GPC caused a similar rate of hospital-acquired infections (46% and 44%, respectively). SBP, SB, and UTI were mainly caused by GNB (56%, 60%, and 62%, respectively). GPC predominated in cellulitis and catheter infection (55% and 65%, respectively). GPC were also frequent in CA pneumonia.

E. coli was the most frequently isolated organism (28%), followed by S. aureus (13%), K. pneumoniae (12%), Streptococcus viridans and Enterococcus faecalis (10% each), P. aeruginosa (5%), and E. faecium (5%). Bacteria isolated in the study are shown in Supporting Table 1. The main organisms isolated were as follows: E. coli and K. pneumoniae in SBP and SB; E. coli in UTI, and nonenterococal streptococci in CA pneumonia. Legionella urinary antigen was determined in 85% of pneumonia (negative in all). Cellulitis and catheter sepsis were mainly caused by Staphylococci.

Isolated Multiresistant Bacteria.

Ninety-eight of the 312 organisms isolated in the first series (31%) were multiresistant. They were isolated in 92 infections (18%) from 62 patients (28%). Multiresistant bacteria were more frequently isolated in nosocomial infections (35%), as compared with HCA and CA episodes (14% and 4%, respectively; Table 1). The prevalence of multiresistant bacteria was extremely high in UTI (39%), especially when acquired during hospitalization (57%) and in HCA episodes (35%). A high prevalence of multiresistant bacteria was also observed in hospital-acquired SBP (22% versus 5% in HCA and 2% in CA SBP), cellulitis (27% versus 8% and 7%), pneumonia (32% versus 14% and 9%), and other infections (25% versus 4% and 2%).

Table 2 shows the type of multiresistant bacteria isolated in the different infections according to the site of acquisition. ESBL-E were the most frequent multiresistant strains isolated (28 E. coli and 17 K. pneumoniae), followed by P. aeruginosa (n = 17), MRSA (n = 14), and E. faecium (n = 14). ESBL-E was the most frequent multiresistant bacteria isolated in SBP (73%), UTI (60%), and SB (64%), MRSA predominated in cellulitis (57%) and catheter infection (50%), and P. aeruginosa in nosocomial pneumonia (60%).

Table 1. Prevalence of CA, HCA, and Nosocomial Infections Caused by Multiresistant Bacteria in the First Series (2005-2007)
 CA (n = 163)HCA (n = 164)Nosocomial (n = 180)Total (n = 507)P Value
  • Abbreviation: NS, nonsignificant.

  • *

    Other multiresistant bacteria included A. baumanii, S. maltophilia, and Achromobacter spp.

  • One nosocomial SBP and 2 nosocomial UTIs were caused by 2 ESBL-producing Enterobacteriaceae.

  • One HCA UTI was caused by E. faecium + ESBL-producing Enterobacteriaceae and 1 nosocomial UTI was caused by E. faecium + P. aeruginosa.

  • §

    One nosocomial pneumonia was caused by P. aeruginosa + S. maltophilia.

  • Other infections included purulent bronchitis, catheter sepsis, secondary peritonitis, SE, endocarditis, dental infection, arthritis, gastroenteritis, meningitis, pseudomembranous colitis, cholangitis, and sepsis of unknown origin.

Overall infections (n/%)6 (4)23 (14)63 (35)92 (18)<0.001
 ESBL-producing Enterobacteriaceae1 (1)15 (9)28 (16)44 (8.7)<0.001
 P. aeruginosa3 (2)14 (8)17 (3.4)<0.001
 MRSA4 (2.5)1 (1)9 (5)14 (2.8)ns
 E. faecium1 (0.6)4 (2)9 (5)14 (2.8)0.013
 Other multiresistant bacteria*1 (1)5 (2.8)6 (1.2)0.017
SBP (n/%)1 (2)2 (5)7 (22)10 (8)0.002
 ESBL-producing Enterobacteriaceae1 (2)1 (2)5 (16)7 (5.6)0.013
 P. aeruginosa1 (2)2 (6)3 (2.4)NS
UTI (n/%)1 (5)12 (35)25 (57)38 (39)<0.001
 ESBL-producing Enterobacteriaceae10 (29)13 (30)23 (23)0.023
 P. aeruginosa3 (7)3 (3)NS
 MRSA1 (2)1 (1)NS
 E. faecium1 (5)3 (9)8 (18)12 (12)NS
 Other multiresistant bacteria1 (2)1 (1)NS
Cellulitis (n/%)2 (7)2 (8)3 (27)7 (11)NS
 ESBL-producing Enterobacteriaceae1 (4)1 (1.5)NS
 P. aeruginosa1 (9)1 (1.5)NS
 MRSA2 (7)2 (18)4 (6)NS
 E. faecium1 (4)1 (1.5)NS
Pneumonia (n/%)1 (9)1 (14)9 (32)11 (24)NS
 ESBL-producing Enterobacteriaceae1 (4)1 (2.2)NS
 P. aeruginosa1 (14)6 (21)7 (15.2)NS
 MRSA1 (9)1 (2.2)NS
 Other multiresistant bacteria§3 (11)3 (6.5)NS
Spontaneous bacteremia (n/%)0 (0)4 (40)7 (41)11 (37)NS
 ESBL-producing Enterobacteriaceae3 (30)4 (24)7 (23.3)NS
 MRSA1 (6)1 (3.3)NS
 E. faecium1 (6)1 (3.3)NS
 Other multiresistant bacteria1 (10)1 (6)2 (7)NS
Other infections (n/%)1 (2)2 (4)12 (25)15 (10.5)<0.001
 ESBL-producing Enterobacteriaceae5 (10.5)5 (3.5)0.006
 P. aeruginosa1 (2)2 (4)3 (2)NS
 MRSA1 (2)1 (2)5 (10.5)7 (5)NS
Table 2. Multiresistant Bacteria Isolated in CA, HCA, and Nosocomial Infections in the First Series (2005-2007)
 SBPUTICellulitisPneumoniaSpontaneous BacteremiaCatheter SepsisOther*All Infections
 (Nos/HCA/ C-acq)(Nos/HCA/ C-acq)(Nos/HCA/ C-acq)(Nos/HCA/ C-acq)(Nos/HCA/ C-acq)(Nos/HCA/ C-acq)(Nos/HCA/ C-acq)
  • Abbreviations: Nos, nosocomial; C-acq, community acquired; Amp-C, AmpC β-lactamase.

  • *

    Other infections included purulent bronchitis, secondary peritonitis, SE, endocarditis, dental infection, arthritis, gastroenteritis, meningitis, pseudomembranous colitis, cholangitis, and sepsis of unknown origin.

Total isolated mutiresistant GNB8/2/119/10/—1/1/—10/1/—5/4—52/1/—50/19/1
 ESBL-producing E. coli2/1/18/7/——/1/—3/2/—12/—/—16/11/1
 ESBL-producing K. pneumoniae4/—/—6/3/—1/—/—1/1/—113/4/—
 ESBL-producing Proteus mirabilis1/—/—1/—/—
 Amp-C-producing Citrobacter spp.11/—/—
 P. aeruginosa2/1/—3/—/—1/—/—6/1/—2—/1/—14/3/—
 S. maltophilia1/—/—2/—/—3/—/—
 Acromobacter spp.1/—/—1/—/—
 A. baumanii1/1/—1/1/—
Total isolated multiresistant GPC9/3/12/1/2—/—/12/—/—5—/1/118/5/5
 MRSA1/—/—2/-/2—/—/11/—/—5—/1/19/1/4
 E. faecium8/3/1—/1/—1/—/—9/4/1

QR Bacteria.

QR GNB were isolated in 97 infections (first series). Isolation was more frequent in patients receiving long-term norfloxacin prophylaxis (85% versus 47%; P = 0.0001). SBP by QR GNB were more frequent in these patients (85% versus 19%; P = 0.001).

Efficacy of Empirical Antibiotic Therapy.

Only the most frequent and characteristic infections (n = 482) in the first series were considered for assessing the efficacy of empirical antibiotic therapy, including SBP, UTI, cellulitis, pneumonia, purulent bronchitis, SB, SE, catheter infection, and sepsis of unknown origin (Fig. 1). Analysis was performed in the 404 infections (84%) treated, according to the empirical antibiotic schedules previously described. The currently recommended empirical antibiotic regimen was more effective in CA than in nosocomial infections (Table 3). The low efficacy of empirical antibiotic therapy in hospital-acquired infections was observed across the different types of infections analyzed. Clinical efficacy of empirical antibiotic treatment was also lower in HCA infections, compared to CA episodes, particularly in pneumonia and UTI.

Table 3. Efficacy of Currently Recommended Empirical Antibiotic Therapy* in CA, HCA, and Nosocomial Infections in the First Series (2005-2007)
 CAHCANosocomialTotalP Value
  • Abbreviation: NS, nonsignificant.

  • *

    Empirical antibiotic therapy was as follows: SBP, SE, SB, UTI, and sepsis of unkown origin were treated with IV ceftriaxone; cellulitis was treated with IV ceftriaxone plus cloxacillin or amoxicillin/clavulanic acid; patients with CA pneumonia received IV ceftriaxone plus a macrolide or levofloxacin, and clindamycin was added in the case of aspiration; HCA or nosocomial pneumonia were treated with ceftazidime plus ciprofloxacin, catheter-related infection with vancomycin, and catheter withdrawal and purulent bronchitis with ceftriaxone or amoxicillin/clavulanic acid.

  • Other infections included catheter sepsis, purulent bronchitis, SE, and sepsis of unknown origin.

Overall infections (n)144136124404 
 Resolution rate (%)83734066<0.0001
SBP (n)513819108 
 Resolution rate (%)78712667<0.0001
UTI (n)19323889 
 Resolution rate (%)90592953<0.0001
Cellulitis (n)2821655 
 Resolution rate (%)82815078NS
Pneumonia (n)931628 
 Resolution rate (%)67334450NS
Spontaneous bacteremia (n)3101124 
 Resolution rate (%)67601842=0.05
Other infections (n)343234100 
 Resolution rate (%)91916582=0.005

Clinical Outcome and Mortality Rate.

Table 4 shows the clinical outcome and hospital mortality rates of infections caused or not by multiresistant bacteria. Final resolution of infection was significantly lower in infections caused by multiresistant strains (70% versus 92%; P < 0.0001), particularly in SBP and pneumonia (50% and 55%, respectively). Septic shock was more frequently observed in multiresistant infections (26% versus 10%; P < 0.0001), being extremely frequent in pneumonia (82%), SBP (40%), and SB (36%). Hospital mortality was also higher in infections by multiresistant bacteria (25% versus 12%; P = 0.001). Mortality was particularly high in SBP (50%), pneumonia (46%), and SB (27%).

Table 4. Clinical Outcome and Hospital Mortality Rate of Infections According to the Antibiotic-Resistant Profile of the Responsible Bacteria (First Series)
 No Isolation/Susceptible BacteriaMultiresistant Bacteria*TotalP Value
  • Abbreviation: ns, nonsignificant.

  • *

    Multiresistant bacteria: extended-spectrum β-lactamase or desrepressed chromosomic AmpC β-lactamase-producing Enterobacteriaceae, P. aeruginosa, S. maltophilia, A. baumanii, Achromobacter spp., MRSA, and E. faecium.

Overall Infections (n)41592507 
 Final resolution (n/%)381 (92)64 (70)445 (88)<0.0001
 Septic shock42 (10)24 (26)66 (13)<0.0001
 Hospital mortality48 (12)23 (25)71 (14)0.001
SBP (n)11610126 
 Final resolution (n/%)104 (90)5 (50)109 (87)0.004
 Septic shock18 (16)4 (40)22 (18)0.07
 Hospital mortality17 (15)5 (50)22 (18)0.01
UTI (n)603898 
 Final resolution (n/%)58 (97)30 (79)88 (90)0.01
 Septic shock2 (3)2 (5)4 (4)NS
 Hospital mortality4 (7)7 (18)11 (11)NS
Cellulitis (n)59766 
 Final resolution (n/%)56 (95)5 (71)61 (92)0.08
 Septic shock2 (3)1 (14)3 (4)NS
 Hospital mortality2 (3)02 (3)NS
Pneumonia (n)351146 
 Final resolution (n/%)25 (71)6 (55)31 (67)NS
 Septic shock10 (29)9 (82)19 (41)0.004
 Hospital mortality12 (34)5 (46)17 (37)NS
Spontaneous bacteremia (n)191130 
 Final resolution (n/%)19 (100)7 (64)26 (87)0.01
 Septic shock04 (36)4 (13)0.01
 Hospital mortality2 (10)3 (27)5 (17)NS

Epidemiology of Infections in the Second Series (2010-2011).

In the second series, a total of 110 patients developed infection in 115 admissions. In total, 162 bacterial infections were detected: 48 (30%) were CA, 40 were HCA (25%), and 74 (45%) were nosocomial. Thirty-seven patients had a history of hospitalization in the previous 3 months, 33 had received β-lactams within 3 months before infection, and 16 were receiving long-term norfloxacin prophylaxis. In 25 infectious episodes, there was history of recent infection by multiresistant bacteria. UTI was the main infection observed (41), followed by SBP (33), pneumonia (21), cellulitis (20), SB (15), catheter infection (7), and others (25) (Table 5).

Table 5. Prevalence of CA, HCA, and Nosocomial Infections Caused by Multiresistant Bacteria in the Second Series (2010-2011)
 CA (n = 48)HCA (n = 40)Nosocomial (n = 74)Total (n = 162)P Value
  • Abbreviation: NS, nonsignificant.

  • *

    Other multiresistant bacteria included Acinetobacter spp. (5) and S. maltophilia (2). No carbapenemase-producing Enterobacteriaceae or vancomycin-resistant Enterococcus or S. aureus were isolated.

  • One nosocomial UTI was caused by E. faecium + S. maltophilia, 1 nosocomial catheter sepsis was caused by MRSA and ESBL-producing Enterobacteriaceae, and 1 HCA arthritis was caused by MRSA + A. baumanii.

  • Other infections included catheter sepsis (7), pseudomembranous colitis (5), sepsis of unknown origin (5), purulent bronchitis (4), endocarditis (3), arthritis (2), cholangitis (2), perianal infection (1), SE (1), secondary peritonitis (1), and mediastinitis (1).

Overall infections (n/%)0 (0)8 (20)29 (39)37 (23)0.002
 ESBL-producing Enterobacteriaceae2 (5)10 (13.5)12 (7.5)0.02
 P. aeruginosa4 (5.5)4 (2.5)0.09
 MRSA2 (5)4 (5.5)6 (4)NS
 E. faecium2 (5)9 (12)11 (7)0.03
 Other multiresistant bacteria*3 (7.5)4 (5)7 (4)NS
SBP (n/%)0 (0)1 (11)2 (29)3 (9)0.08
 ESBL-producing Enterobacteriaceae2 (29)2 (6)0.02
 MRSA1 (11)1 (3)NS
UTI (n/%)0 (0)3 (27)10 (59)13 (32)0.003
 ESBL-producing Enterobacteriaceae2 (18)3 (18)5 (12)NS
 P. aeruginosa1 (6)1 (2.5)NS
 E. faecium1 (9)6 (35)7 (17)0.03
 Other multiresistant bacteria1 (6)1 (2.5)NS
Cellulitis (n/%)0 (0)1 (11)1 (5)NS
 Other multiresistant bacteria1 (11)1 (5)NS
Pneumonia (n/%)0 (0)1 (33)5 (33)6 (29)NS
 P. aeruginosa2 (13)2 (9.5)NS
 MRSA2 (13)2 (9.5)NS
 Other multiresistant bacteria1 (33)1 (6.5)2 (9.5)NS
Spontaneous bacteremia (n/%)0 (0)1 (25)6 (67)7 (47)NS
 ESBL-producing Enterobacteriaceae4 (44)4 (27)NS
 E. faecium1 (25)2 (22)3 (20)NS
Other infections (n/%)0 (0)1 (25)6 (29)7 (22)NS
 ESBL-producing Enterobacteriaceae1 (5)1 (3)NS
 P. aeruginosa1 (5)1 (3)NS
 MRSA1 (25)2 (9.5)3 (9.5)NS
 E. faecium1 (5)1 (3)NS
 Other multiresistant bacteria1 (25)2 (9.5)3 (9.5)NS

During this study period, a total of 140 bacteria were isolated in 110 culture-positive infections (68%). Bacterial isolation was more frequent in nosocomial than in HCA or CA infections (77% versus 63% versus 58%, respectively; P = 0.06). E. coli was the most frequently isolated organism (29%), followed by S. aureus (12%), K. pneumoniae and E. faecalis (11% each), and E. faecium (9%).

Thirty-eight of the 137 organisms isolated (28%) were multiresistant. They were isolated in 37 infections from 25 patients (23%). Multiresistant bacteria were more frequently isolated in nosocomial than in HCA infections (39% versus 20%; P = 0.04). No multiresistant bacteria were isolated in CA infections. Table 5 shows the type of multiresistant bacteria isolated in the different infections according to the type of infection and site of acquisition. ESBL-E was the most frequent multiresistant strain isolated (n = 12), followed by E. faecium (n = 11), MRSA (n = 6), Acinetobacter spp. (n = 5), and P. aeruginosa (n = 4).

Risk Factors for the Development of Infections Caused by Multiresistant Bacteria.

Table 6 shows factors associated with the development of infections by multiresistant bacteria in the univariate analysis in the first series (n = 507). In the multivariate analysis, only the nosocomial acquisition of infection (hazard ratio [HR], 4.43; 95% confidence interval [CI]: 2.29-8.59; P < 0.0001), long-term norfloxacin prophylaxis (HR, 2.69; 95% CI: 1.36-5.30; P = 0.004), use of β-lactams within the last 3 months (HR, 2.39; 95% CI: 1.18-4.85; P = 0.02), and infection by multiresistant bacteria in the last 6 months (HR, 2.45; 95% CI: 1.04-5.81; P = 0.04) were independent predictors of infection by multiresistant bacteria. Nosocomial acquisition of infection (HR, 5.22; 95% CI: 2.10-12.98; P = 0.0004) and previous infection by multiresistant bacteria in the last 6 months (HR, 7.62; 95% CI: 2.81-20.64; P < 0.0001) were confirmed as independent predictors in the second series.

Table 6. Risk Factors for the Development of Infections by Multiresistant Bacteria in the Univariate Analysis (First Series)
 Multiresistant Bacteria* (n = 92)No Multiresistant Isolation (n = 415)P Value
  • Abbreviation: NS, nonsignificant.

  • *

    Multiresistant bacteria: extended-spectrum β-lactamase or desrepressed chromosomic AmpC β-lactamase-producing Enterobacteriaceae, P. aeruginosa, S. maltophilia, A. baumanii, Achromobacter spp, MRSA, and E. faecium.

  • HCA infection: previous admission in hospital or in a short term-admission center for invasive procedures within the previous 3 months.

  • Within the previous 3 months.

  • §

    Within the previous 6 months.

  • Within the previous month.

  • Mean value of MELD score at infection diagnosis.

Nosocomial infection (%)6928<0.0001
HCA infection (%)14200.0900
Recent hospitalization (%)55370.0020
Recent use of β-lactams (%)7133<0.0001
Long-term norfloxacin prophylaxis (%)47290.0020
Previous isolation of multiresistant bacteria§ (%)257<0.0001
Central line insertion (%)33140.0001
Urinary catheterization (%)32100.0001
ICU admission (%)1770.0080
Mechanical ventilation (%)920.0020
Female sex (%)3938NS
Ascites at inclusion (%)7973NS
Hepatic encephalopathy at inclusion (%)59400.0030
MELD score ≥19 points (%)52420.0900
Active alcoholism (%)2824NS
Diabetes mellitus (%)2425NS

Long-term norfloxacin prophylaxis (HR, 3.46; 95% CI: 1.21-9.92; P = 0.02) and infection by multiresistant bacteria within the previous 6 months (HR, 2.88; 95% CI: 1.02-8.16; P = 0.04) in HCA infections and the use of β-lactams within the previous 3 months (HR, 4.11; 95% CI: 2.07-8.13; P < 0.0001) in nosocomial infections were identified as independent predictors of infections by multiresistant strains after classifying infections according to their site of acquisition.

Multivariate analysis of infections caused by ESBL-E in the first series identified infection by ESBL-E within the previous 6 months (HR, 10.24; 95% CI: 3.04-34.58; P < 0.0001), nosocomial acquisition of infection (HR, 5.41; 95% CI: 2.21-13.22; P < 0.0001), long-term norfloxacin prophylaxis (HR, 3.88; 95% CI: 1.54-9.76; P < 0.0001), and treatment with β-lactams within the previous 3 months (HR, 3.09; 95% CI: 1.18-8.15; P = 0.02) as independent risk factors. Infection by ESBL-E within the previous 6 months (HR, 7.94; 95% CI: 2.04-30.84; P = 0.003) was the only independent predictor identified in the second series. The same results were obtained when AmpC β-lactamase-producing Enterobacteriaceae were not included in the analysis.

Discussion

Three major changes in the epidemiology of bacterial infections in cirrhosis have been observed within the last few decades. The first change consisted of a rapid development of QR bacteria in the fecal flora of cirrhotic patients receiving oral long-term norfloxacin prophylaxis.42, 43 The clinical effect of this feature was limited. Although infections caused by Enterobacteriaceae in patients receiving norfloxacin are usually caused by QR organisms,1, 44 selective intestinal decontamination with norfloxacin continues to be highly effective in preventing Gram-negative infection.10 On the other hand, most QR bacteria isolated in previous studies were susceptible to third-generation cephalosporins, the accepted empirical treatment of SBP, and of other infections in cirrhosis.3, 7-9, 11

The second change was detected in a previous prospective study published in 2002 by our group. We reported a high rate of infections caused by GPC related to the increasing use of invasive procedures and treatments in the ICU.1 The traditional preponderance of infections caused by GNB characteristic of cirrhosis was shifted to a higher prevalence of infection by GPC in hospitalized patients. In CA infections, GNB continued to be the main cause of infection. This second epidemiological change did not have a major clinical effect either because the prevalence of infections resulting from multiresistant bacteria in this series was <10%.

The current study, however, indicates that a major change that may have important clinical implications is occurring in the epidemiology of bacterial infections in cirrhosis. The prevalence of infections caused by multiresistant bacteria (18% in the first series studied between 2005 and 2007 and 23% in the second series) has increased by nearly 100% and this is mainly the result of the emergence of infections caused by ESBL-E and E. faecium. Frequency of infections caused by ESBL-E has increased from 1.2% in our previous series published in 2002 to 7.5%-8.7% and that of infections caused by E. faecium from 1% to 3%-7%. The main risk factors of infections caused by multiresistant bacteria identified in the first series were similar to those observed in the general population, including nosocomial origin of infection and previous treatment with β-lactams or quinolones.37-41 Previous infection by ESBL-E, nosocomial acquisition of the infection, and previous treatment with β-lactams or norfloxacin were also independent predictors of ESBL-E infection.

Another relevant finding of the current study is the decrease in the rate of nosocomial infections caused by GPC, compared to our previous work (60% in 2002 versus 44% in 2005-2007). This feature is probably a consequence of the increased rate of infections caused by multiresistant GNB.

As expected, infections caused by multiresistant bacteria were associated with a higher incidence of treatment failure, septic shock, and hospital mortality. This was related to the lack of efficacy of the currently recommended empirical antibiotic therapy, which is mainly based on third-generation cephalosporins and amoxicillin/clavulanic acid, which is what delayed the initiation of an effective treatment. These antibiotic regimens were clearly ineffective in nosocomial infections (60% of treatment failure).

The results of the current investigation have determined major changes in our current guidelines on the first-line treatment of nosocomial infections in cirrhosis. Because the prevalence of multiresistant bacteria in nosocomial infections was very high (35%-39% when considering all patients and 50% in culture-positive infections), no other risk factors were taken into account to design the new treatment protocol. Nosocomial SBP and SB are now empirically treated with carbapenems or with tigecycline to cover ESBL-E, UTI associated with SIRS with the combination of a carbapenem plus a glycopeptide (to cover ESBL-E and E. faecium), uncomplicated UTI with oral nitrofurantoin or fosfomycin, and cellulitis with ceftazidime plus a glycopeptide (to cover MRSA and P. aeruginosa). HCA and nosocomial pneumonia are now treated according to our local guidelines (carbapenems or ceftazidime plus levofloxacin plus a glycopeptide).

The results of the current study, which derive from a single-center experience with a specific epidemiological pattern of multiresistance, cannot be generalized to any hospital. However, several reports and unpublished observations from other groups indicate that the increased rate of infections by multiresistant bacteria,16-22 and the failure of the currently recommended empirical antibiotic schedules observed in our hospital,45-47 is not a single-center issue, but an emerging problem in cirrhosis. The use of third-generation cephalosporins and long-term norfloxacin prophylaxis are probably important factors in its pathogenesis. Its prevention is, however, difficult. Currently, we have no drugs to prevent bacterial translocation other than oral antibiotics. On the other hand, the diagnostic capacity of the current markers of bacterial infection in cirrhosis is low,48 and many noninfected patients receive antibiotics, thereby increasing antibiotic pressure over the endogenous flora and inducing the emergence of resistant strains. Isolation of patients infected by multiresistant bacteria is another important measure to prevent the spread of these organisms in the hospital setting.24, 49

In summary, our results indicate that the epidemiology of bacterial infections in cirrhosis has experienced a new, important change with the emergence of infections caused by ESBL-E and other multiresistant bacteria. These infections, which are especially frequent in the hospital setting, are associated with a high incidence of septic shock and/or rapid deterioration of liver function and death. The current guidelines of empiric antibiotic therapy in cirrhosis do not take into account this feature. Susceptibility of bacteria causing infections in cirrhosis should therefore be periodically tested in each hospital, and the empirical antibiotic schedules should be properly adapted.

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