Alimentary Pharmacology and Therapeutics
Emergence of spontaneous bacterial peritonitis due to enterococci – risk factors and outcome in a 12-year retrospective study P. A. Reuken*,†, M. W. Pletz*,†, M. Baier‡, W. Pfister‡, A. Stallmach*,† & T. Bruns*,†
*Division of Gastroenterology, Hepatology and Infectious Diseases, Department of Internal Medicine II, Jena University Hospital, Friedrich Schiller University, Jena, Germany. † Integrated Research and Treatment Center - Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University, Jena, Germany. ‡ Institute of Medical Microbiology, University Hospital of Jena, Jena, Germany.
Correspondence to: Dr T. Bruns, NIHR Biomedical Research Unit and Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail:
[email protected]
Publication data Submitted 14 January 2012 First decision 2 February 2012 Resubmitted 20 February 2012 Accepted 5 March 2012 EV Pub Online 26 March 2012
SUMMARY Background Third-generation cephalosporins (TGC) constitute the empirical first-line therapy for spontaneous bacterial peritonitis (SBP). Hospitalisation, invasive procedures and use of antibiotics may challenge this concept due to an increase in enterococci and other TGC-resistant microorganisms. Aim To determine prevalence, risk factors and outcome of ascitic fluid infections caused by enterococci. Methods All independent episodes of culture-positive ascitic fluid between 2000 and 2011 in a German tertiary centre were analysed retrospectively. Results Out of 244 positive ascitic fluid cultures, 90 episodes of monomicrobial SBP and 25 episodes of monomicrobial bacterascites (BA) in patients with decompensated cirrhosis were identified. Enterococcus spp. were isolated in 32 (28%) episodes. We noticed a profound increase in the frequency of enterococcal infection over the study period from 11% to 35% (P = 0.007). Univariate risk factors for enterococcal SBP/BA included nosocomial infection (OR = 4.56; 95% CI 1.90–10.97), previous use of antibiotics (OR = 5.63; 95% CI 1.81–17.49) and recent gastrointestinal endoscopy (OR = 3.17; 95% CI 1.33–7.54). Nosocomial infection (OR = 3.29; P = 0.011) and recent antibiotic therapy (OR = 3.88; P = 0.025) remained independent risk factors for enterococcal infection in multivariate logistic regression and these factors contributed also to the model when only SBP cases were considered. In subjects with monomicrobial SBP who were treated with TGC or ciprofloxacin, the probability of 90-day survival was 12% in enterococcal infection compared to 50% in non-enterococcal SBP (P = 0.022 in log-rank test). Conclusion Because of the increasing prevalence of enterococcal spontaneous bacterial peritonitis and its poor prognosis when treated inappropriately, clinicians should consider empirical therapy with anti-enterococcal antibiotics for patients with risk factors. Aliment Pharmacol Ther 2012; 35: 1199–1208
ª 2012 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2012.05076.x
1199
P. A. Reuken et al. INTRODUCTION Spontaneous bacterial peritonitis (SBP) is a common complication in cirrhotic patients with ascites with a prevalence of 9%–17% in hospitalised patients1, 2 and 1%–4% in out-patients.1, 3 The diagnosis is commonly based on the ascitic fluid (AF) neutrophil cell count of 250 cells/mm3 or more,4 since bacterial cultures fail to grow a causative microorganism from AF in more than 50% of SBP episodes.5–7 Third-generation cephalosporins (TGC) are the first-line therapy of SBP according to current guidelines, since Gram-negative Enterobacteriaceae comprise the majority causative organisms.8, 9 However, hospitalisation, increasing invasive procedures and antibiotic prophylaxis in cirrhotic patients change the bacterial spectrum and resistance profiles of causative pathogens and lead to an increase of SBP due to Grampositive and TGC-resistant bacteria.5, 10 In recent studies from Greece (1998–2002)6 and France (1998–1999)11 Gram-positive bacteria (GPB) were detected in 43% and 54% of positive AF cultures from patients with cirrhosis. In contrast, studies from Spain (1998–2000)5 and Korea (2000–2007)12 reported that only 20%–23% of culture-positive SBP were caused by GPB. Among GPB, Enterococcus spp. are of clinical importance, since they exhibit intrinsic resistance to cephalosporins, sulphonamides and low-level aminoglycosides.13 Enterococci have been isolated from AF in 2%–24%5, 6, 10–12, 14 and TGC-resistant Gram-negative bacteria (GNB) in 4%–23%5, 7, 11, 12 of all culture-positive episodes of SBP challenging the concept of empiric first-line therapy with TGC. Failure of first-line therapy for SBP is associated with poor survival,12, 14, 15 therefore, early identification of patients with SBP due to TGC-resistant bacteria is crucial. Since microbial strain distributions and antibiotic resistance profiles show huge regional variations and are rapidly changing,16 the aims of this study were to identify changes in microbial spectrum and resistance profiles in pathogens isolated from AF infections in a German centre over the last 12 years and to identify risk factors and prognosis in patients with enterococcal SBP. PATIENTS AND METHODS Study design Microbiology laboratory files were reviewed to identify all cases with a positive AF culture result in patients hospitalised in our department at a German tertiary centre during the period from 1 January 2000 until 31 November 2011. Only episodes that did not include repeated 1200
cultivation of the same microorganism(s) in the same patient within the same hospital stay were considered as independent episodes. Medical records including patients’ files, electronic health records, imaging data, laboratory data, and nursing documentation were used to identify patients with decompensated cirrhosis and secondary peritonitis. The following variables were collected from the medical records: age, gender, aetiology of liver disease, Child-Pugh score, co-morbidities, co-medication including antibiotics and changes in antibiotic therapy, treatment on intensive care unit, urinary or central venous catheterisation, gastrointestinal haemorrhage and endoscopic diagnostic procedures or interventions. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local ethics committee on 14 June 2011 (no. 314906/11).
Definitions Secondary peritonitis was defined as positive AF cultures in patients with an intra-abdominal surgically treatable source of infection (e.g. hollow organ perforation, abscess), after abdominal surgery, with transabdominal catheters (e.g. peritoneal dialysis catheter, percutaneous endoscopic gastrostomy tube) or with acute pancreatitis. To exclude episodes of traumatic paracentesis with bowel entry by the paracentesis needle17 and contamination by skin commensals, only monomicrobial episodes were considered for further analysis after exclusion of coagulase-negative staphylococci, corynebacteria, propionibacteria, and Bacillus spp. In these cases, monomicrobial SBP was defined by an elevated AF polymorphonuclear leucocyte (PMN) count of 250/lL or greater in one diagnostic paracentesis within the period of 7 days before to 2 days after the microbial culture result. Monomicrobial bacterascites (BA)18 was defined as AF PMN count 0.200) (Table 3). There was no significant association of enterococcal infection with hepatocellular carcinoma (13% vs. 12%; P = 1.000) or other malignant diseases, (16% vs. 7%; P = 0.177). However, enterococcal infection was associated with recent diagnostic or therapeutic gastrointestinal endoscopy (OR = 3.171; 95% CI 1.334–7.538; P = 0.009) and also associated with a trend towards a higher number of interventions, such as central venous catheterisation Aliment Pharmacol Ther 2012; 35: 1199-1208 ª 2012 Blackwell Publishing Ltd
Risk factors and outcome of enterococcal spontaneous bacterial peritonitis Table 1 | Bacteria isolated from ascitic fluid in SBP and bacterascites
Gram-negative bacteria Escherichia coli Klebsiella spp. Pseudomonas spp. Enterobacter spp. Acinetobacter spp. Citrobacter spp. Stenotrophomonas spp. Gram-negative anaerobes Other Gram-negative bacteria Gram-positive bacteria Enterococcus spp. Coagulase-negative Staphylococci Streptococcus spp. Staphylococcus aureus Gram-positive anaerobes Other Gram-positive bacteria Candida spp.
Microorganisms isolated from primary AF infections in cirrhosis†
Microorganisms isolated from monomicrobial episodes‡
PMN 250/ lL (N = 112)
PMN < 250/ lL (N = 48*)
P value
SBP (N = 90)
Bacterascites (N = 25*)
51 (46%) 31 6 3 3 1 0 0 9 1 65 (58%) 28 15 14 10 3 4 5 (5%)
12 (25%) 4 1 2 1 1 1 1 1 2 40 (83%) 11 15 9 0 3 6 1 (2%)
0.021
42 (47%) 28 5 2 1 1 0 0 5 0 45 (50%) 25 – 9 8 1 2 3 (3%)
6 (24%) 3 0 1 1 0 0 0 0 1 19 (76%) 7 – 8 0 2 2 0 (0%)
0.002
0.669
P value 0.065
0.024
1.000
AF, ascitic fluid; PMN, polymorphonuclear leucocyte; SBP, spontaneous bacterial peritonitis. P-values in Fisher’s exact test are indicated. * Including patients with unknown neutrophil count (N = 4 in primary AF infections and N = 1 for monocultural episodes). † Sum of episodes with Gram-negative bacteria, Gram-negative bacteria and fungi exceeds 100% due to the occurrence of polymicrobial episodes. ‡ Monomicrobial episodes after exclusion of skin commensals, i.e. coagulase-negative Staphylococci, Corynebacteria, Propionibacterium and Bacillus spp.
(OR = 2.296; 95% CI 0.976–5.405; P = 0.057) or indwelling urinary catheter (OR = 2.329; 95% CI 0.954–5.686; P = 0.063). In multivariate analysis, only the use of antibiotics (OR = 3.875; 95% CI 1.189–12.631; P = 0.025) and nosocomial infection (OR = 3.287; 95% CI 1.311– 8.243; P = 0.011) remained independent significant predictors for enterococcal infection. When patients with monomicrobial BA were excluded and only episodes of monomicrobial SBP were considered, the univariate odds ratios were 3.725 (95% CI 1.415–9.807; P = 0.008) for nosocomial SBP, 4.583 (95% CI 1.242– 16.913; P = 0.022) for recent use of antibiotics and 2.820 (95% CI 1.038–7.663; P = 0.042) for recent gastrointestinal endoscopy. When these three predictors were used in a backward stepwise model with probability for removal >0.05, only nosocomial SBP (OR = 2.985; 95% CI 1.098– 8.113; P = 0.032) and recent antibiotic treatment (OR = 3.498; 95% CI 0.912–13.414; P = 0.068) were contained within the model with a good fit of the logistic regression model (P = 0.947 in Hosmer and Lemeshow test). Aliment Pharmacol Ther 2012; 35: 1199-1208 ª 2012 Blackwell Publishing Ltd
Survival of patients with monomicrobial culturepositive Spontaneous bacterial peritonitis Seventy patients had one episode and 10 patients had two episodes of monomicrobial culture-positive SBP during the observation period. Of these, 24 (30%) patients had at least one enterococcal SBP episode whereas 56 (70%) patients never presented with an episode of monomicrobial enterococcal SBP. Within 90 days after positive AF culture result 50 (63%) patients died, 2 (3%) patients underwent liver transplantation after 59 and 76 days and one patient was lost to follow-up after 7 days. Median survival was 13 days (95% CI 5–21 days) in patients with enterococcal SBP and 21 days (95% CI 0–44 days) in patients with non-enterococcal SBP (P = 0.329 in log-rank test) (Figure 3a). Empiric therapy for patients with enterococcal SBP was ceftriaxone or ciprofloxacin in 15 (63%) patients with median time on treatment until result of AF cultures of 2 days (range 0–8 days). Seven of these 15 patients were switched to vancomycin (N = 3), linezo1203
50
P = 0.001
40 30 20 10 0
14 12 10 8 6 4 2 0
Enterococcal SBP Enterococcal BA
(c)
P = 0.008
Episodes (% of hospitalised cirrhotic patients with ascites) 20 00 – 20 200 02 1 – 20 200 04 3 – 20 200 06 5 – 20 200 08 7 – 20 200 10 9 –2 01 1
60
(b)
Episodes (absolute number) 20 00 – 20 200 1 02 –2 0 20 04 03 – 20 200 5 06 – 20 200 7 08 – 20 200 9 10 –2 01 1
(a)
20 00 – 20 200 1 02 –2 0 20 04 03 –2 0 20 06 05 – 20 200 7 08 – 20 200 9 10 –2 01 1
Episodes (% of culture-positive monomicrobial episodes)
P. A. Reuken et al.
10
8
P = 0.050
6
4
2
0
Figure 2 | Increasing prevalence of SBP/BA caused by Enterococcus spp. The frequency of monobacterial Enterococcal SBP/BA episodes are shown for the respective observation periods and plotted as (a) percentage of all culturepositive monomicrobial SBP periods in the respective 2-year periods, (b) absolute number of diagnosed episodes and (c) percentage of hospitalised patients with cirrhosis and ascites treated in our department in the respective 2-year periods. Only monobacterial episodes of SBP/BA after exclusion of skin commensals have been considered. P values are indicated for Linear-By-Linear Association test (a) or nonparametric Spearman’s correlation [(b) and (c)].
2000–2003 2004–2007 2008–2011 (N = 29) (N = 33) (N = 53) P value Episodes with TGC-resistance Enterococcus spp. ESBL-producing Enterobacteriaceae and Pseudomonas aeruginosa Episodes with Quinolone-resistance* Enterococcus spp. Enterobacteriacea and Pseudomonas aeruginosa Episodes with Ampicillin-resistance Enterococcus spp. ESBL-producing Enterobacteriaceae and Pseudomonas aeruginosa Episodes with Vancomycin-resistance Enterococcus spp.
2 (7%) 2 0
11 (33%) 10 1
23 (43%) 20 3
0.001
2 (7%) 1 1
7 (21%) 6 1
11 (21%) 8 3
0.137
1 (3%) 1 0
5 (15%) 4 1
18 (34%) 15 3
0.001
0 (0%) 0
0 (0%) 0
4 (8%) 4
0.048
Table 2 | Antibiotic resistance profiles in episodes of monomicrobial SBP/BA
BA, monomicrobial bacterascites; EBSL, extended spectrum beta-lactamase; SBP, spontaneous bacterial peritonitis; TGC, third-generation cephalosporins. P values according to Linear-by-linear association chi-square test. * Levofloxacin-resistant Enterococci or Ciprofloxacin-resistant Gram-negative bacteria, respectively.
lide (N = 2) or piperacillin/tazobactam (N = 2) after a median of 2 days (range 2–3 days). In the remaining eight patients that continued to receive TGC or ciprofloxacin, 90-days survival was 13% (1/8); seven patients died within 10 days and one patient after 21 days (Figure 3b). Compared to patients with enterococcal SBP who received a different initial empirical therapy or were switched to a different antibiotic regimen within 3 days (N = 16), median survival was shorter in patients remaining on TGC or ciprofloxacin (5 vs. 17 days; P = 0.039). Among patients treated with TGC 1204
or ciprofloxacin for SBP, survival was significantly shorter in patients with enterococcal SBP than with non-enterococcal SBP (P = 0.022 in log-rank test) (Figure 3b).
DISCUSSION In this study, we report an emergence of monomicrobial SBP and bacterascites by Enterococcus spp. comprising more than one third of culture-positive SBP in our centre over the last 6 years. We have identified nosocomial AF infection and recent antibiotic treatment as indepenAliment Pharmacol Ther 2012; 35: 1199-1208 ª 2012 Blackwell Publishing Ltd
Risk factors and outcome of enterococcal spontaneous bacterial peritonitis Table 3 | Risk factors for monomicrobial enterococcal SBP/BA
Age (years) Female gender Malignancies HCC other Alcoholic cirrhosis Diabetes mellitus Child-Pugh Score MELD Score SBP in history Nosocomial AF infection Gastrointestinal haemorrhage Prior gastrointestinal endoscopy† Indwelling urinary catheter† Central venous catheter† Admission to intensive care unit† Any antibiotic treatment† Cephalosporins Quinolones Penicillins Carbapenems other Long-term SBP prophylaxis Total serum bilirubin (lmol/L) International normalised ratio Creatinine (lmol/L) C–reactive protein (mg/L) White blood cell count (Gpt/L) Platelets (Gpt/L) Albumin (g/L) AF protein (g/L) AF PMN count (per lL)
Univariate analysis
Multivariate analysis*
Odds ratio (95% CI)
P value
Adjusted odds ratio (95% CI)
Enterococcal SBP/BA (N = 32)
Nonenterococcal SBP/BA (N = 83)
61 (52–70) 11 (34%)
56 (50–68) 26 (31%)
1.020 (0.984–1.057) 1.148 (0.484–2.726)
0.286 0.754
– –
– –
4 (13%) 5 (16%) 23 (78%) 16 (50%) 12 (11–13) 24 (18–27) 7 (22%) 22 (69%)
10 (12%) 6 (7%) 74 (89%) 39 (47%) 12 (10–13) 19 (14–28) 13 (16%) 27 (33%)
1.639 (0.637–4.212)
0.305
–
–
0.434 (0.147–1.228) 1.128 (0.499–2.552) 1.132 (0.886–1.446) 1.027 (0.976–1.081) 1.508 (0.540–4.207) 4.563 (1.898–10.971)
0.133 0.772 0.322 0.308 0.433 0.001
– – – – – 0.011
9 (28%) 22 (69%)
15 (18%) 34 (41%)
1.774 (0.685–4.596) 3.171 (1.334–7.538)
0.238 0.009
12 (38%) 14 (44%) 11 (34%)
17 (21%) 21 (25%) 17 (21%)
2.329 (0.954–5.686) 2.296 (0.976–5.405) 2.034 (0.824–5.019)
0.063 0.057 0.124
– – – – – 3.287 (1.311–8.243) – Removed from model – – –
28 (88%)
46 (55%)
5.630 (1.812–17.492)
0.003
3.875 (1.189–12.631)
0.025
15 (47%) 6 (19%) 5 (16%) 1 (3%) 2 (6%) 2 (6%) 59 (33–156) 1.6 (1.3–2.2) 152 (85–239) 68 (31–153) 12.9 (7.3–16.0) 108 (53–179) 22 (17–27) 13 (9–18) 0.74 (0.25–5.11)
25 (30%) 12 (15%) 2 (2%) 2 (2%) 5 (6%) 5 (6%) 63 (31–154) 1.5 (1.3–1.8) 124 (85–209) 56 (25–117) 7.5 (4.6–12.8) 115 (76–146) 23 (21–28) 15 (10–21) 0.97 (0.38–2.98)
1.040 (0.191–5.653) 1.000 (0.997–1.003) 1.579 (0.751–3.316) 1.000 (0.998–1.003) 1.002 (0.997–1.006) 1.027 (0.983–1.072) 1.003 (0.998–1.008) 0.930 (0.858–1.009) 0.987 (0.927–1.052) 1.014 (0.955–1.077)
0.964 0.943 0.228 0.717 0.523 0.234 0.260 0.081 0.698 0.651
– – – – – – – – – –
– – – – – – – – – –
P value
– n.s. – – –
AF, ascitic fluid; BA, monomicrobial bacterascites; PMN, polymorphonuclear leucocyte; SBP, spontaneous bacterial peritonitis. For continuous variables median and interquartiles are reported. * Including significant univariate predictors (0.05). † Within previous 14 days.
dent risk factors for enterococcal peritonitis in patients with cirrhosis and demonstrated that therapy of enterococcal SBP with the first-line empiric therapy for SBP (TGC or ciprofloxacin) was associated with a poor survival in this retrospective analysis. In earlier studies, it has been reported that 65–75% of culture-positive SBP episodes are due to Gram-negative bacilli, whereas Gram-positive cocci constitute only 25% Aliment Pharmacol Ther 2012; 35: 1199-1208 ª 2012 Blackwell Publishing Ltd
of all culture-positive SBP episodes with Streptococcus spp. as the most frequent Gram-positive pathogen.19, 20 Although this pattern still holds true in some current studies,12, 21 there have been reports about an increase of Gram-positive infections in cirrhosis associated with nosocomial peritonitis, norfloxacin prophylaxis and invasive procedures in Europe and in Asia.5, 10, 22 Fernández et al.5 reported that Gram-positive cocci were isolated in 1205
0
15
30
45
60
75
90 days
0
Patients with SBP EC: 24 11
9
8
7
7
7
Patients at risk
Standard treatment EC: 8
Non-EC: 56
26
24
23
22
20 Patients at risk
Non-EC: 39
34
15
30
45
60
75
P = 0.022
P = 0.329
(b)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
P = 0.039
(a)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Cumulative survival
Cumulative survival
P. A. Reuken et al.
90 days
2
1
1
1
1
1
25
21
20
19
19
17 Patients at risk
Patients at risk
EC: 16
9
8
7
6
6
6
Patients at risk
Non-EC: 17
9
5
4
4
3
3
Patients at risk
Different treatment
Figure 3 | Short-term survival in subjects with monomicrobial culture-positive SBP. Kaplan–Meier analysis of survival in subjects with culture-positive monomicrobial SBP (a) with respect to the growth of Enterococci (EC) in ascitic fluid and (b) with respect to the growth of Enterococci stratified for empirical treatment with Third-generation cephalosporins or ciprofloxacin (standard treatment) or different antibiotic treatments (different treatments). P values according to log-rank test are indicated.
more than 50% of nosocomial infections in patients with cirrhosis in a Spanish Liver Unit between 1998 and 2000. However, the majority of these infections were bloodstream infections and only 7% of communityacquired and 36% of nosocomial episodes of culturepositive SBP were caused by GPB. In contrast to these results and in agreement with our results, GPB are isolated from approximately 50% of culture-positive cases of SBP and bacterascites6, 11, 14, 22–24 and in up to 70% in nosocomial SBP25 according to studies from France, Greece, and Germany. Enterococcus spp. comprise approximately 5%–40% of GPB isolated from neutrocytic AF with broad regional differences: 4% in China (1996–2010),22 7%–19% in Korea (1995–2007),7, 12, 21 11%–35% in France (1996– 2003),11, 23, 25 35% in the US (1991–2001) and 38% in Greece (1998–2002).6 We herein report that Enterococcus spp. were isolated in 50% (32/64) of Gram-positive episodes of SBP or bacterascites in our centre, whereas TGC-resistant GNB were far less frequent. Similar results were reported from another German tertiary centre, where Enterococcus faecium was isolated in 10 of 19 (53%) patients with Gram-positive SBP between 2002 and 2006.14 Despite an increasing awareness of enterococcal infections and the identification of risk factors for enterococcal bacteremia,26–29 risk factors for enterococcal SBP are less well understood. Lee et al.30 described recent gastrointestinal haemorrhage as a risk factor in 1206
their case-control study of 13 cases with enterococcal SBP. We only observed nonsignificant association of recent gastrointestinal haemorrhage with enterococcal SBP (28% vs. 18%), but observed that recent gastrointestinal endoscopy was associated with enterococcal AF infection in univariate analysis (69% vs. 41%; P = 0.009). In agreement with our results, recent use of antibiotics has also been identified as a risk factor for postoperative peritonitis and peritoneal dialysis-related peritonitis by enterococci.31, 32 Since Enterococci are of low virulence and are often found as a secondary invader in polymicrobial infections, the clinical relevance of enterococcal peritonitis is subject of debate.33 Early animal studies questioned the ability of Enterococcus spp. to cause mortality and abscess formation after intraperitoneal inoculation34 but enterococci impair phagocytosis and killing of other intraperitoneal pathogens, facilitate a prolonged peritoneal inflammatory response and may therefore aggravate SBP.35 On the other hand, there is some evidence that enterococcal infections may be associated with increased mortality in secondary peritonitis.36 We limited our analysis to patients with monomicrobial AF infections and excluded patients with skin contaminants. The increasing number of monomicrobial SBP episodes and the fact that subjects with monomicrobial enterococcal SBP treated with TGC or ciprofloxacin had a poorer prognosis than differently treated patients and patients with non-enterococcal SBP Aliment Pharmacol Ther 2012; 35: 1199-1208 ª 2012 Blackwell Publishing Ltd
Risk factors and outcome of enterococcal spontaneous bacterial peritonitis indicates a pathogenic relevance and prognostic significance of enterococci in SBP. Since our data have shown not only an increase in enterococcal AF infection but also in ampicillin-resistant episodes, recommending an appropriate empiric treatment becomes sophisticated. Since vancomycin carries the risk of nephrotoxicity in this highly vulnerable patient population and, in addition, imposes a risk for selection of vancomycin-resistant enterococci, novel substances might be more appropriate. Linezolid, daptomycin, tigecyclin and the novel lipoglycopeptides like telavancin or old substances like fosfomycin are options based on in vitro susceptibility data and case reports.37–39 Randomised clinical studies for most of these novel substances in SBP are lacking. Tigecycline is the only one of the above mentioned novel antibiotics that has been studied in and licensed for intra-abdominal infections.40, 41 However, the recommended dosage of tigecycline may be insufficient in critically ill patients: In a recent study for nosocomial pneumonia the failure rate for tigecycline was higher in ICU patients compared to imipenem and a pharmacokinetic analysis revealed significantly lower AUC values for ventilated compared to non-ventilated patients.42, 43 This study has prompted the FDA to issue a warning that tigecycline should not be used in critically ill patients. In contrast, the European Medical Agency has stated that tigecycline should not be set in nosocomial pneumonia but can still be applied in patients with intra-abdominal infections.44 Unfortunately, studies with tigecycline using higher dosages are lacking.
The increasing prevalence of enterococci and the identification of risk factors for enterococcal SBP in this retrospective study set the stage for a prospective study on the efficacy and safety of anti-enterococcal antibiotic regimens for the empiric treatment of SBP. Until then, empiric therapy should be selected according to a patient-based approach45 considering current guidelines as well as patient’s previous antibiotic exposure, comorbidities and local antibiotic susceptibility. Based on our observations, clinicians should consider empirical therapy with anti-enterococcal antibiotics for patients with nosocomial SBP and/or previous antibiotic treatment.
ACKNOWLEDGEMENTS Declaration of personal interests: MWP has served as a speaker for Pfizer, Novartis, Bayer, Astra Zeneca, Gilead and Thermo Fisher, and has served as an advisory board member for Pfizer and MSD. MP has received research funding from Pfizer. WP has served as a speaker for Pfizer and an advisory board member for Rosen Pharma, and has received research funding from Rosen Pharma. AS has served as a speaker, a consultant and an advisory board member for Pfizer and Astellas. Declaration of funding interests: This study was funded in part by the Federal Ministry of Education and Research (BMBF), Germany (FKZ: 01 E0 1002) to PAR and TB. TB has received research funding by the German Research Foundation (BR 4182/1-1).
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