Background
Methods
Setting, study design and patient eligibility
Decolonization treatment
Patient follow-up and definition of success
Microbiology
Statistical analysis
Literature search
Results
Patient characteristics and microbiology
Parameter | Total | Decolonization success | Decolonization failure |
---|---|---|---|
(n = 45) | (n = 19) | (n = 26) | |
Median age (range), yrs | 57 (19–86) | 56 (19–84) | 60 (20–86) |
Male, n (%) | 20 (44 %) | 9 (47 %) | 11 (42 %) |
Underlying diseases, n (%) | |||
▪ Renal transplant | 12 (27 %) | 5 (26 %) | 7 (27 %) |
▪ Other solid organ transplant | 1 (2 %) | 1 (5 %) | - |
▪ Autoimmune/collagen vascular disease | 4 (9 %) | 1 (5 %) | 3 (12 %) |
▪ Obstructive uropathy | 16 (36 %) | 5 (26 %) | 11 (42 %) |
▪ Nephrolithiasis | 1 (2 %) | 1 (5 %) | - |
▪ Lymphoma or cancer | 6 (13 %) | 4 (21 %) | 2 (8 %) |
▪ CVID | 2 (4 %) | 1 (5 %) | 1 (4 %) |
▪ Other | 11 (24 %) | 4 (21 %) | 7 (27 %) |
Previous infections, n (%) | |||
▪ Urinary tract infection | 38 (84 %) | 16 (84 %) | 22 (85 %) |
▪ Bloodstream | 9 (20 %) | 4 (21 %) | 5 (19 %) |
▪ Wound infection | 5 (11 %) | 3 (16 %) | 2 (8 %) |
▪ Respiratory tract infection | 2 (4 %) | 1 (5 %) | 1 (4 %) |
▪ other sites | 2 (4 %) | 1 (5 %) | 1 (4 %) |
Microorganisms, n (%) | |||
▪ E.coli | 29 (64 %) | 11 (58 %) | 18 (69 %) |
▪ E.coli plus other | 9 (20 %) | 5 (26 %) | 4 (15 %) |
▪ Klebsiella pneumoniae | 6 (13 %) | 2 (11 %) | 4 (15 %) |
▪ Enterobacter aerogenes | 1 (2 %) | 1 (5 %) | - |
In vitro resistance (E.coli) (n = 38), n (%) | |||
▪ Ciprofloxacin | 33 (87 %) | 13 (81 %) | 20 (91 %) |
▪ Trimethoprim-sulfamethoxazole | 35 (92 %) | 14 (88 %) | 21 (95 %) |
▪ Gentamicin | 21 (55 %) | 7 (50 %) | 14 (64 %) |
▪ Tetracycline | 33 (87 %) | 14 (88 %) | 19 (86 %) |
▪ Fosfomycin | - | - | - |
▪ Nitrofurantoin | 2 (5 %) | - | 2 (9 %) |
Decolonization regimen, n (%) | |||
▪ Colistin 4 × 1 | 18 (40 %) | 7 (37 %) | 11 (42 %) |
▪ Colistin 4 × 2 | 12 (27 %) | 3 (16 %) | 9 (35 %) |
▪ Rifaximin | 15 (33 %) | 9 (47 %) | 6 (23 %) |
Initial additional UTI treatment, n (%) | 26 (58 %) | 8 (42 %) | 18 (69 %) |
▪ Oral fosfomycin | 9 (20 %) | 2 (11 %) | 7 (27 %) |
▪ Oral nitrofurantoin | 3 (7 %) | 1 (5 %) | 2 (8 %) |
▪ Oral cefpodoxime + amoxi-clav | 7 (16 %) | 4 (21 %) | 3 (12 %) |
▪ Parenteral carbapenem | 7 (16 %) | 1 (5 %) | 6 (23 %) |
Outcomes of initial treatment
Salvage regimens and late follow-up
Review of the literature
Author, year; study type | Patients included | Pathogen | Decolonization regimena [duration] | Decolonization efficacy [definition, methods to detect] | Follow-up period | Resistance development | Remarks |
---|---|---|---|---|---|---|---|
Prospective ‘decolonization’ studies | |||||||
Huttner et al., 2013; randomized, double-blind, placebo-controlled study [8] | Hospitalized carriers (n = 54) | ESBL-E (E. coli ~80 %, K. pneumoniae ~20 %) | Colistin 1,26 MU, neomycin 250 mg [10d] (plus nitrofurantoin 3 × 100 mg/d [5d] in urinary tract colonization) (n = 27) vs. placebo (n = 27) | 52 % vs. 37 %; no significant difference [≥1 neg. rectal swab culture] | 28 ± 7 days | No significant change in colistin or neomycin MICs | Extraintestinal colonization 50 % at baseline; systemic antibiotic treatment in 4 % of patients (vs. 19 % in placebo group) |
Oren et al., 2013; prospective, controlled study [10] | Hospitalized carriers (n = 152), ~40 % of which with clinical infection | CR-E (K. pneumoniae ~90 %) | Colistin 2,5 MU (n = 16) or gentamicin 80 mg (n = 26) or combination (n = 8) [until decolonization, max. 60 d] vs. spontaneous eradication (n = 102) | 44 % (42 %, 50 %, 37.5 %) vs. 7 %; significant difference [3 neg. consecutive rectal swabs cultures, neg. PCR testing of third swab] | Median f/u 33 days vs. 140 days | Gentamicin resistance 23 %; colistin resistance 6 %, combination 0 % | Systemic antibiotic treatment in ~40 % of patients in both groups |
Saidel-Odes et al., 2012; randomized, double-blind, placebo-controlled study [9] | Hospitalized carriers (n = 40) | CR-E (K. pneumoniae) | Colistin 1 MU, gentamicin 80 mg, plus SOD [7d] (n = 20) vs. placebo (n = 20) | 59 % vs. 33 %; no significant difference [neg. rectal swab culture] | 42 days | None, gentamicin MIC remained ≤2 mg/ml and colistin MIC ≤0.094 mg/ml | Efficacy 61 % vs. 16 % at week 2; no impact on extraintestinal colonization (groin cultures 60 % positive) |
Buehlmann et al., 2011; prospective, controlled study [11] | Infected patients (n = 83) or hospitalized carriers (n = 17) | ESBL-E (E. coli 71 %, K. pneumoniae 25 %) | Paromomycin 1 g (intestinal colonisation) [4d], diverse oral antibiotics (urinary tract colonization) [5d], chlorhexidine mouth rinse [5d] (n = 39) vs. spontaneous eradication (n = 61) | 63 % (ITT analysis)/83 % (on treatment analysis) vs. 55 % [≥1 neg. throat and rectal swab and neg. urine culture] | Median f/u 24 months | n.d. | 55 % of patients eliminated ESBL-E without decolonization regimen by systemic antibiotic treatment or surgery |
SDD studies with ESBL-E or CR-E decolonization efficacy subgroup analysis or retrospective observational studies | |||||||
Lübbert et al., 2013; retrospective, observational SDD study [12] | Hospitalized carriers (n = 52) or infected patients (n = 38) | CR-E (K. pneumoniae) | Colistin 1 MU, gentamicin 80 mg plus SOD [7d] (n = 14) vs. non SDD-control (n = 76) | 43 % vs. 30 %; no significant difference [≥3 consecutive negative rectal swab PCRs separated by ≥48 h from one another] | Median f/u 48 days vs. 53 days | 2/6 previous sensitive isolates acquired colistin resistance; 5/11 acquired gentamicin resistance | Systemic antibiotic treatment in 43 % of SDD group vs. 29 % non-SDD group |
Oostdijk et al., 2012; post hoc subgroup analysis of prospective, randomized SDD study [13] | Hospitalized (ICU) carriers (n = 507) | 3CR-E or AGR-Eb | Colistin 2,5 MU, tobramycin 80 mg, amphotericin B 500 mg plus SOD [until discharge]; no control group | 73 % in 3CR-E (vs. 80 % in cephalosporin-sensitive isolates), 62 % in AGR-E(vs. 81 % in aminoglycoside-sensitive isolates) [2 consecutive rectal swab cultures] | Until ICU discharge | No significant resistance development in patients with decolonization failure | Decolonization after median duration of 5 days in 3CR-E, 5.5 days in AGR-E (vs. 4 days in respective sensitive isolates) |
Abecasis et al., 2011; post hoc subgroup analysis of prospective SDD study [14] | Hospitalized (pediatric ICU) carriers (n = 28) or infected patients (n = 11) | ESBL-E | Colistin, tobramycin, parenteral cefotaxime [until ICU discharge, dose and duration not specified]; no control group | Overall 54 % (21/39), with follow-up 21/27 (78 %) [negative rectal swab culture] | Until ICU discharge | No tobramycin resistence development | In 9/23 patients with tobramycin-resistent isolates decolonization failed (vs. 0/16 with tobramycin-sensitive isolates) |
Troché et al., 2005; post hoc subgroup analysis of prospective SDD study [15] | Hospitalized (ICU) carriers (n = 27) or infected patients (n = 10) | ESBL-E | Colistin 1.5 MU plus neomycin 500 mg or plus erythromycin 500 mg [until two negative rectal swabs or ICU discharge]; no control group | 46 % [2 consecutive negative rectal swab cultures] | Until ICU discharge | n.d. | Systemic antibiotic treatment in ten infected patients |
Nitschke et al., 2012; retrospective observational cohort studyc [16] | Patients with intestinal carriage of STEC with or without HUS (n = 65) | STEC O104:H4 | Azithromycin [cumulative 3 g in 14 days] (n = 22) vs. spontaneous eradication (n = 43) | 95 % vs. 19 %; significant difference [≥2 neg. stool cultures over a period of at least 6 days] | Mean f/u 41 days vs. 45 days | n.d. | Subsequently, 15 long term STEC carriers were treated with 3 days azithromycin with 100 % decolonization efficacy |
Paterson et al., 2001; retrospective observational cohort studyc [17] | Hospitalized carriers (n = 7) or infected patients (n = 2) | ESBL-E (E. coli 67 %, K. pneumoniae 33 %) | Norfloxacin 2 × 400 mg/d [5d]; no control group | 44 % [≥1 neg. stool culture] | 28 days | n.d. | Transient ESBL-E suppression at day 2–3 after completion of norfloxacin in 9/9 patients |
Discussion
Methodological heterogeneities in previous studies |
▪ Different ESBL-E sampling (perianal vs. rectal swab vs. fecal sample) and detection (culture vs. PCR-based technology vs. combined) |
▪ Diverse definitions of decolonization success (number of negative samples, duration of follow-up period) |
▪ In- or exclusion of patients with concomitant ESBL-E infection |
▪ Intestinal decolonization with or without systemic antibiotic treatment |
▪ Availability of pre-decolonization antibiotic susceptibility tests and variable impact on decolonization regimen |
Open questions that need to be addressed in future studies |
▪ Are there effective decolonization strategies leading to sustained clearance of ESBL-E? |
▪ What is the optimal regimen (combination regimen?), dose and duration? |
▪ Will we observe resistance development (and risk to lose important last resort antibiotics e.g. colistin)? |
▪ Which patients may have the greatest benefit of decolonization? |
▪ What is the impact of extraintestinal colonization (perianal region, groin)? Should decolonization strategies address this? |
▪ Does relapse represent intestinal ‘outgrowth’ of suppressed ESBL-E or re-colonization from extraintestinal sites or other patients, food sources or the environment? |
▪ Do pathogens differ with respect to the decolonization success rate (e.g. Klebsiella spp. vs. Escherichia coli vs. Enterobacter spp.)? |
▪ How robust is the intestinal microbiome under antibiotic treatment? What is its impact on ESBL-E colonization resistance? |