1
Oral gentamicin gut decontamination for prevention of KPC-producing Klebsiella 1 pneumoniae infections: the relevance of concomitant systemic antibiotic therapy 2 3 Running title: Gut decontamination from KPC-Kp. 4 5 Carlo Tascini 1, Francesco Sbrana 2, Sarah Flammini 1, Enrico Tagliaferri 1, Fabio Arena 3, 6 Alessandro Leonildi 1, Ilaria Ciullo 1, Francesco Amadori 1, Antonello Di Paolo 4, Andrea Ripoli 7 2, Russell Lewis 5, Gian Maria Rossolini 3, 6, 7, Francesco Menichetti 1#, and the GENGUT 8 study group 9 10 (1) Infectious Diseases Unit, Cisanello Hospital, Pisa, Italy 11 (2) Fondazione Toscana Gabriele Monasterio, Pisa, Italy 12 (3) Dipartimento di Biotecnologie Mediche, Università di Siena, Siena, Italy 13 (4) Division of Pharmacology, Dep. of Clinical and Experimental Medicine, Un. of Pisa, Italy 14 (5) Infectious Diseases Unit, S’Orsola-Malpighi Hospital. Department of Medical Sciences 15 and Surgery, Un. of Bologna, Bologna, Italy 16 (6) Dipartimento di Medicina Sperimentale e Clinica, Sezione di Medicina Critica e Medicine 17 Specialistiche, Università di Firenze, Florence, Italy 18 (7) S.O.D. Microbiologia e Virologia, Azienda Ospedaliera Universitaria Careggi, Florence, 19 Italy 20 21 22 Corresponding author: Francesco Menichetti, MD 23
Infectious Diseases Unit - Cisanello Hospital 24 Via Paradisa 2 25
56100 Pisa, Italy 26 Phone: +39 050 996739 27 Fax: +39 050 571021 28 E-mail: [email protected] 29
30
AAC Accepts, published online ahead of print on 13 January 2014Antimicrob. Agents Chemother. doi:10.1128/AAC.02283-13Copyright © 2014, American Society for Microbiology. All Rights Reserved.
2
Abstract 31
Gut colonization represents the main source for KPC-producing Klebsiella pneumoniae 32
(KPC-Kp) epidemic dissemination. Oral gentamicin, 80 mg four-times daily, was administered 33
to 50 consecutive patients with gut colonization by gentamicin susceptible KPC-Kp in case of 34
planned surgery, major medical intervention, or need for patient transferral. The overall 35
decontamination rate was 68% (34/50). The median duration of gentamicin treatment was 9 36
days (interquartile range 7-15) in decontaminated patients as compared to 24 days 37
(interquartile range 20-30) in those with persistent colonization (p<0.001). In the six-months 38
period of follow-up, KPC-Kp infections were documented in 5/34 (15%) successfully 39
decontaminated patients as compared to 12/16 (73%) persistent carriers (p<0.001). The 40
decontamination rate was 96% (22/23) in patients receiving oral gentamicin only as 41
compared to 44% (12/27) of those treated with oral gentamicin and concomitant systemic 42
antibiotic therapy (CSAT) (p<0.001). The multivariate analysis confirmed CSAT and a KPC-43
Kp infection as the variables associated with gut decontamination. In the follow-up period, 44
KPC-Kp infections were documented in 2/23 (9%) of patients treated with oral gentamicin 45
only and in 15/27 (56%) of those receiving also CSAT (p=0.003). No difference in overall 46
death rate was documented between different groups. Gentamicin-resistant KPC-Kp strains 47
were isolated from stools of 4/16 persistent carriers. Peak gentamicin blood levels were 48
below 1 mg/L in 12/14 tested patients. Oral gentamicin showed to be potentially useful for gut 49
decontamination and prevention of infection due to KPC-Kp, especially in patients not 50
receiving CSAT. The risk of emergence of gentamicin-resistant KPC-Kp should be 51
considered. 52
53
Keywords: KPC-producing K. pneumoniae; Infection prevention; Oral gentamicin gut 54 decontamination. 55 56
3
Introduction 57
Carbapenem-resistant Klebsiella pneumoniae producing KPC-type beta-lactamase (KPC-Kp) 58
are multi-drug resistant Gram-negative bacilli with limited therapeutic options and high 59
associated mortality rates (> 40%) [1-4]. Gut colonization represents the main human 60
reservoir for epidemic dissemination in hospitals and requires active surveillance for prompt 61
carrier identification and infection control measures such as isolation or cohorting with 62
dedicated staff [5, 6]. Furthermore, gut colonization seems to be associated with a 63
substantial risk (around 10%) of developing subsequent KPC-Kp infection [7, 8] and may be 64
a contraindication for some surgical procedures, organ transplantation and other major 65
medical interventions. Gut colonization by KPC-Kp may last for months, even in the absence 66
of hospital readmission [9]. Therefore, gut decontamination for KPC-Kp colonization could be 67
of interest as a complementary approach for removing patient from isolation, reducing 68
transmission, and preventing subsequent infectious episodes in already colonized patients. 69
In fact, various regimens for KPC-Kp gut decontamination have been investigated. Using an 70
oral gentamicin regimen of 80 mg qid, Zuckerman et al. reported decontamination of KPC-Kp 71
from 10/15 (66%) haematological patients without selecting gentamicin-resistant strains [10]. 72
Oren et al., using oral gentamicin 80 mg qid, reported decontamination of carbapenem-73
resistant K. pneumoniae from 11/26 (42%) patients [11]. In a randomized double-blind 74
placebo-controlled trial in 40 patients with KPC-Kp positive rectal swab, Saidel-Odes et al., 75
reported that administration of an oral gentamicin/polymyxin E combination cleared KPC-Kp 76
colonization in 12/20 patients (60%) without selecting gentamicin or colistin-resistant KPC-Kp 77
strains [12]. However, Brink et al. found that use of colistin for selective digestive tract 78
decontamination was associated with the emergence of a colistin-resistant OXA -181-79
producing K. pneumoniae strain [13]. 80
Oral gentamicin may be an ideal agent for gut decontamination from KPC-Kp for several 81
reasons, including: i) gentamicin is rapidly bactericidal "in vitro" against gentamicin-82
susceptible KPC-Kp strains; ii) the oral formulation is virtually non-absorbable, without 83
systemic activity and toxicity; iii) the drug has a limited spectrum and no activity against 84
4
anaerobes, being less disruptive to the gastrointestinal flora; and iv) gentamicin is not 85
typically administered as part of combination regimens for serious KPC-Kp infections [1]. 86
The aim of our pilot study was to describe the microbiological and clinical response of gut 87
decontamination with oral gentamicin in 50 consecutive patients colonized by KPC-Kp, 88
receiving or not concomitant systemic antibiotic therapy (CSAT). 89
90
Materials and Methods 91
We performed a pilot, non-blinded prospective study in three Italian hospitals to assess the 92
feasibility of administering oral gentamicin for KPC-Kp gut decontamination. Because no 93
published data were available regarding the possible treatment efficacy of oral 94
decontamination therapy for KPC-Kp, we did not attempt to estimate a priori the required 95
sample size for this pilot study. In a eight-months period consecutive adult patients with a 96
rectal swab culture positive for KPC-Kp within the previous 7 days were considered eligible 97
for the study if they had: i) planned surgery; ii) need for major medical intervention that could 98
predispose to serious infection (e. g., cancer chemotherapy or immunosuppression); or iii) 99
need for transferral outside the hospital. All patients provided written informed consent to 100
participate in the study. Patients who met the inclusion criteria were administered oral 101
gentamicin (80 mg four times daily) for at least 8 days. The need for continued oral 102
decontamination therapy beyond 8 days was determined by the physicians caring for the 103
patient, who were not blinded to follow-up rectal swab culture results. Infection control 104
procedures for patients with KPC-Kp gut colonization were similar at all participating 105
institutions, consisting of patient isolation or cohorting, with strict contact precautions, and 106
dedicated caregivers and equipment as described in CDC guidelines [14]. 107
We used a validated direct screening method on rectal swab culture to identify patients with 108
KPC-Kp gut colonization [15]. Rectal swab cultures were performed at the time of hospital 109
admission and every 4 days thereafter. K. pneumoniae stool isolates were identified with the 110
mini-API system (bioMérieux, Mercy L’Etoile, France) or MALDI-TOF mass spectrometry 111
(Vitek MS, bioMérieux). Detection of blaKPC genes was confirmed by PCR as previously 112
5
described [16]. Antimicrobial susceptibility testing was performed using a disk diffusion 113
method according to EUCAST version 3.1 guidelines [17], and MIC of gentamicin, colistin 114
and fosfomycin were determined with E-test, according to the manufacturer’s instruction (AB 115
Biodisk, Solno, Sweden). Interpretation of susceptibility data was according to EUCAST 116
breakpoints (version 3.1) [17]. Pulsed-field gel electrophoresis (PFGE) of XbaI-digested 117
genomic DNA of KPC-Kp to compare isolates longitudinal isolates from patients who failed 118
decontamination was performed and interpreted as described previously [18]. 119
Gentamicin peak plasma concentration was determined with a fluorescent immunoassay 120
method (Abbott, Abbott Park, IL) on day three of treatment on samples obtained 2 hours after 121
drug administration. 122
Study endpoints: The primary study outcome was decontamination of KPC-Kp gut 123
colonization defined by at least two consecutive negative rectal swab cultures. Patients with 124
two or more consecutive positive rectal swabs were considered to have failed oral 125
decontamination and were considered persistent carriers. We also evaluated clinical 126
outcomes of patients administered oral gentamicin for KPC-Kp decontamination, including 127
infectious episodes caused by KPC-Kp and death for any cause during a six-months period 128
after oral gentamicin therapy, in decontaminated and persistent carrier groups. A separate 129
analysis was performed with the 23 patients receiving oral gentamicin alone and with the 27 130
patients who received CSAT. 131
Statistical analysis: Data were expressed as mean +/- standard deviation, median and 132
interquartile range or proportions, as appropriate. Comparisons were performed with 133
unpaired t-test, Mann-Whitney test or chi-square test with continuity correction, as 134
appropriate. Gut decontamination events during oral gentamicin therapy were analysed by 135
the Kaplan–Meier method, with log-rank test for curve comparison in patients treated or not 136
with CSAT. To evaluate the influence of CSAT on gut decontamination we performed a 137
univariate logistic regression analysis adjusting for several potential confounders (KPC-Kp 138
infection, ICU stay, days of gentamicin treatment, gender and age). Predictors found to be 139
statistically significant (p<0.05) at the univariate logistic regression were then included in a 140
6
multivariate logistic model. All computations were done with R statistical software (R, version 141
2.11.1, 2010; R Development Core Team 2006, R Foundation for Statistical Computing, 142
Vienna, Austria). A value of p < 0.05 was considered significant. 143
144
Results 145
Fifty consecutive patients with KPC-Kp positive rectal swab cultures were enrolled in the 146
study over 8 months. All the KPC-Kp isolates from rectal swabs showed susceptibility to 147
gentamicin (MIC50 1.5 mg/L; MIC90 2 mg/L; range 0.125 - 2 mg/L). All strains were resistant to 148
carbapenems; 27/50 (54%) were resistant to colistin, 24/50 (48%) to tigecycline and 7/50 149
(14%) to fosfomycin. 150
CSAT was administered in 27/50 of the study patients due to clinically documented 151
pneumonia (n=1) and 26 microbiologically and clinically documented infections due to: 18 152
KPC-Kp (bloodstream infection-BSI, n=14; ventilator-associated pneumonia, n= 2; peritonitis 153
n=1, urinary tract infection-UTI n=1), 2 P. aeruginosa (BSI n=1, cellulitis n=1), 3 E. coli (BSI 154
n=2, UTI n=1), 2 S. aureus (BSI n=1, cellulitis n=1), and 1 S. epidermidis BSI. The majority of 155
patients (22/27) received combinations of two or more antibiotics, whereas five patients 156
received monotherapy regimens. The prescribed antibiotics were: tigecycline (n=15 patients), 157
meropenem (n=12), colistin (n=12), gentamicin (n=8), fosfomycin (n=4), imipenem (n=4), 158
cotrimoxazole (n=3), piperacillin/tazobactam (n=3), rifampin (n=2), teicoplanin (n=1). 159
The enrolled patients were treated with oral gentamicin for a median of 16 days (interquartile 160
range 10-27), and the overall decontamination rate in the entire study population 161
administered oral gentamicin was 68% (34/50). The median duration of gentamicin therapy 162
was 9 days (interquartile range 7-15) in decontaminated patients, versus 24 days 163
(interquartile range 20-30) in those with persistent colonization (p <0.001). At 6 months 164
follow-up, KPC-Kp infections were documented in 5/34 (15%) patients successfully 165
decontaminated, compared to 12/16 (73%) of patients with persistent colonization (p <0.001). 166
7
No difference in overall mortality was observed between decontaminated and persistently 167
colonized patients. Patient characteristics and clinical outcomes in successfully 168
decontaminated patients and persistent carriers are summarized in Table 1. 169
The probability of a persistent carriage status during oral gentamicin therapy was statistically 170
lower in patients treated with gentamicin only as compared to those receiving CSAT (p 171
=0.007) (Figure 1). The decontamination rate was 96% (22/23) in patients receiving oral 172
gentamicin only versus 44% (12/27) in those also treated with CSAT (p <0.001). In the follow-173
up period, KPC-Kp infection were documented in 2/23 (9%) of patients treated with oral 174
gentamicin only and in 15/27 (56%) of those receiving also CSAT (p = 0.003). No difference 175
in overall mortality rate was documented between the two treatment groups. Patient 176
characteristics, microbiological and clinical outcomes in patients receiving gentamicin only 177
and those also treated with CSAT are summarized in Table 2. 178
The univariate analysis identified CSAT, KPC-Kp infection and ICU stay as significant 179
variables (Table 3). The multivariate analysis confirmed CSAT and KPC-Kp infection as the 180
variables associated with gut decontamination (Table 4). 181
Genotype analysis performed with PFGE on strains of 5/17 patients who failed gut 182
decontamination with gentamicin showed that KPC-Kp strains were genetically related 183
(Correlation index > 90%). 184
Gentamicin-resistant KPC-Kp strains were isolated during oral gentamicin therapy in 4/16 185
failed patients (25%). 186
Mean of gentamicin peak blood concentrations, measured in 14/16 patients, were 0.7 ± 1.1 187
mg/L (range: 0 – 3.1 mg/L). Only two patients showed a gentamicin blood level above 1 188
mg/L. No drug treatment was interrupted for any reason and no documented side effects 189
attributable to gentamicin oral therapy were observed. 190
191
Discussion 192
Gut colonization with KPC-Kp represents the main source for the epidemic dissemination of 193
carbapenem-resistant Enterobacteriaceae, and is associated with a substantial risk of 194
8
developing subsequent infection [7, 8]. Selective gut decontamination of KPC-Kp, therefore 195
could be an important complementary approach for reducing a colonized patient’s risk for 196
spreading or developing severe infection with Multi-drug resistant (MDR) Enterobacteriaceae 197
[10, 11, 12]. 198
In our population of 50 KPC-Kp colonized patients treated with oral gentamicin, we observed 199
a favourable microbiological outcome (overall gut decontamination rate: 34/50; 68%). 200
Our results are similar to those reported in a small group of haematological patients treated 201
with the same regimen (10/15; 66%) [10], and in a cohort of medical and surgical population 202
receiving oral gentamicin in combination with polymyxin E (12/20; 60%) [12]. Recently, 203
Feldman et al. reported that spontaneous resolution of carriage may occur in the majority of 204
patients with remote (> 4 months) versus recent acquisition [19]. However, Oren et al. 205
reported a spontaneous eradication of carbapenem-resistant enterobacteriaceae from stools 206
in only 7/102 patients (7%) after a median follow-up period of 140 days (range 20-737) [11]; 207
furthermore, some patients (such as those represented in our study) may benefit from more 208
rapid clearance of KPC-Kp colonization due to planned major therapeutic interventions. 209
It is noteworthy that infectious episodes due to KPC-Kp documented in the six-months follow-210
up period were significantly lower in the group of successfully decontaminated patients (5/34; 211
15%) with respect to the group of persistently colonized patients (12/16; 73%). Interestingly, 212
Zuckerman et al. reported that 5/15 patients who failed gentamicin decontamination 213
subsequently died, with three of these deaths due to KPC-Kp BSI [10]. Our experience 214
seems to support the relevant role of gut decontamination in preventing subsequent 215
infectious episodes due to KPC-Kp. 216
In our study we observed a significant difference in decontamination rate in the group of 217
patients receiving oral gentamicin only (22/23; 96%) compared to patients also receiving oral 218
gentamicin during CSAT (12/27; 44%). Selective pressure of CSAT on gut microbiota may 219
favour the persistent carriage of KPC-Kp, thereby contributing to the higher failure rates 220
observed versus monotherapy. This hypothesis is supported by the reports of Schwaber [20] 221
suggesting the role of antibiotics use as predictors for KPC-Kp acquisition and Ben-David 222
9
[21] identifying antibiotic exposure during the prior three months as one of the risk factor for 223
persistent carriage. In our experience 16/27 (59%) patients treated with CSAT received a 224
carbapenem antibiotic. The specific role of carbapenems in favouring selective pressure and 225
the acquisition of KPC-Kp has also been reported [22, 23]. However, we cannot exclude the 226
possibility that CSAT was a marker for more severely-ill, debilitated patients who are more 227
likely to have a natural history of persistent KPC-Kp colonization. 228
The genotype analysis, although performed on few strains isolated from 5/17 patients who 229
failed gut decontamination with gentamicin, show a high correlation rate and no acquisition of 230
new clones. 231
It is noteworthy that patients treated with gentamicin only suffered for less KPC-Kp infectious 232
episodes (2/23, 9%) as compared to the group receiving also CSAT (15/27, 56%). This 233
significant difference suggests that gut decontamination for asymptomatic KPC-Kp carriers 234
may be an effective strategy worthy of evaluation in prospective randomized trials, especially 235
among patients who do not require immediate additional systemic antimicrobial therapy. 236
Considering the small sample size, it was also not surprising we were unable to detect an 237
overall survival difference between successfully and non-successfully decontaminated 238
patients who did not receive CSAT (22% vs. 37%, p = 0.406 ). Detection of such a difference 239
would likely require a prospective randomized trial with several hundred patients per 240
treatment arm. 241
According to the multivariate analysis results CSAT and KPC-Kp infections are the variables 242
associated with gut decontamination; these variables might identify a sub-group of more 243
critically ill patients less responsive to gentamicin oral therapy. 244
Oral gut decontamination is associated with some risks. Gentamicin oral therapy may favour 245
the emergence of resistant KPC-Kp, especially in patients who failed to respond to gut 246
decontamination regimen. Gentamicin-resistant KPC-Kp strains were in fact isolated in our 247
study from 4/16 (25%) persistent carriers. Although previous experience with oral gentamicin 248
did not mention the emergence of resistant strains [10, 12], this potential risk should be 249
considered and gut decontamination should be interrupted as soon as patients fail. 250
10
The virtual lack of any systemic activity of oral gentamicin (only 2 patients had blood levels > 251
1 mg/L) underscored why the oral regimen was associated with a good safety profile in our 252
study, with no evidence of nephrotoxicity, ototoxicity, or drug interruption due to adverse 253
effects. 254
Finally, a limitation of this pilot study was the lack of a control group and blinding by 255
physicians caring for patients. 256
An additional limitation was the potential overestimation of gut decontamination due to the 257
lower sensitivity of the culture method as compared to PCR [15]. Low-level carriage may not 258
be detectable with culture-based methods, but two consecutive negative results are certainly 259
suggestive either of true decontamination or of significant reduction of the gut colonization 260
burden, and have been used as the basis for relaxation of strict contact precautions in 261
infection control programs [14]. 262
However, given our experience that suggests selective oral decontamination therapy of KPC-263
Kp with oral gentamicin is safe and possibly effective, we believe larger scale, prospective 264
randomized trials should be considered to evaluate the promising, complementary approach 265
for reducing risk of severe infection with these notoriously difficult to treat MDR 266
Enterobacteriaceae. 267
268
269
11
Acknowledgements: 270
Partial data related to this study have been presented in ECCMID meeting in April 2013 271
(ECCMID R2812). 272
Funding: This work was supported in part by a grant from FP7 project EvoTAR 273
(no.HEALTH-F3-2011-2011-282004) to G.M.R. 274
Disclosures: No conflict of interest for each authors. 275
In the past 2 years, C.T. has been paid for lectures on behalf of Pfizer, Novartis, Merck, and 276
Astellas. 277
278
The GENGUT study group: Paola Lambelet - Viareggio, Francesco Forfori - Pisa, Bruno 279
Viaggi - Pisa, Francesca Papini - Pisa, Lucio Urbani - Pisa, Paolo Malacarne – Pisa. 280
281
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366
367
368
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TABLE 1. Patient characteristics and clinical outcomes in decontaminated patients vs. 369
persistent carriers. 370
371
Decontaminated Patients (n= 34)
Persistent Carriers (n= 16)
p
Male 23 (68%) 12 (75%) 0.843
Mean age, years ± SD
66 ± 11 59 ± 15 0.141
ICU’s patients 2 (6%) 8 (50%) 0.001
Median duration of treatment, days (range)
9 [7 – 15] 21 [15 – 30] < 0.001
KPC-Kp infection a 5/34 (15%) 12/16 (73%) < 0.001
Overall death a 10/34 (29%) 5/16 (31%) 0.843
372 a in the 6-month follow-up period 373
374
17
TABLE 2. Patient characteristics, microbiological and clinical outcomes in patients treated 376
with gentamicin only vs. those receiving concomitant systemic antibiotic therapy (CSAT). 377
378
Oral gentamicin only
(n= 23)
Oral gentamicin plus CSAT
(n= 27) p
Male 15 (65%) 20 (74%) 0.710
Mean age, years ± SD 67 ± 12 61 ± 15 0.108
ICU’s patients 1 (4%) 9 (33%) < 0.001
Median duration of treatment, days (range)
14 [11 – 19] 18 [12 – 29] 0.311
Gut decontamination 22/23 (96%) 12/27 (44%) < 0.001
KPC-Kp infection a 2/23 (9%) 15/27 (56%) 0.003
Overall death a 5/23 (22%) 10/27 (37%) 0.406
379 a in the 6-month follow-up period 380
18
TABLE 3. Univariate logistic regression for gut decontamination event. Odds Ratio, 95% 381 Confidence Interval for Odds Ratio and p-value of each predictor. 382
383
OR 95% CI OR p
CSAT 0.036 0.002 – 0.213 0.002
KPC-Kp infection 0.057 0.011 – 0.231 <0.001
ICU’s patients 0.062 0.008 – 0.305 0.002
Male gender 0.697 0.165 – 2.548 0.598
Age (years) 1.028 0.985 – 1.076 0.200
Duration of Gentamicin treatment (days) 0.966 0.913 – 1.015 0.198
384
19
TABLE 4. Multivariate logistic regression for gut decontamination event. Odds Ratio, 95% 385
Confidence Interval for Odds Ratio and p-value of each predictor. 386
387
OR 95% CI OR p
CSAT 0.105 0.005 – 0.801 0.048
KPC-Kp infection 0.139 0.021 – 0.754 < 0.001
ICU’s patients 0.132 0.011 – 0.992 0.066
388
20
FIGURE 1. Probability of persistent carriage in patients treated with oral gentamicin only 389
[SOLID LINE] vs. those receiving also concomitant systemic antibiotic therapy [DOT LINE] (p 390
= 0.007). 391
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