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Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial
Clinical Microbiology and Infection xxx (2018) 1e6
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Original article
Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial C. Pallotto 1, *, M. Fiorio 1, V. De Angelis 2, A. Ripoli 3, E. Franciosini 4, L. Quondam Girolamo 5, F. Volpi 5, P. Iorio 4, D. Francisci 1, C. Tascini 6, F. Baldelli 1 1)
Infectious Diseases Unit, University Hospital of Perugia, Perugia, Italy Medical Oncology Unit, University Hospital of Perugia, Perugia, Italy Fondazione CNR Regione Toscana ‘G. Monasterio’, Pisa, Italy 4) Intensive Care Unit, University Hospital of Perugia, Perugia, Italy 5) Post-operative Cardiosurgical Intensive Care Unit, University Hospital of Perugia, Perugia, Italy 6) First Division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, Naples, Italy 2) 3)
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 January 2018 Received in revised form 21 August 2018 Accepted 16 September 2018 Available online xxx
Objectives: To investigate whether daily bathing with a soap-like solution of 4% chlorhexidine (CHG) followed by water rinsing (CHGwr) would decrease the incidence of hospital-acquired infections (HAI) in intensive care settings. Methods: Randomized, controlled trial; infectious diseases specialists were blinded to the intervention status. All patients admitted to the Intensive Care Unit (ICU) and to the Post-operative Cardiosurgical Intensive Care Unit (PC-ICU) of the University Hospital of Perugia were enrolled and randomized to the intervention arm (daily bathing with 4% CHGwr) or to the control arm (daily bathing with standard soap). The incidence rate of acquisition of HAI was compared between the two arms as primary outcome. We also evaluated the incidence of bloodstream infections (BSI), central-line-associated BSI (CLABSI), ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI), and 4% CHGwr safety. Results: In all, 449 individuals were enrolled, 226 in treatment arm and 223 in control arm. Thirty-four individuals of the 226 (15%) and 57 (25.6%) suffered from at least an HAI in the intervention and control arms, respectively (p 0.008); 23.2 and 40.9 infections/1000 patient-days were detected in the intervention arm and control arm, respectively (p 0.037). The incidence of all bloodstream infections (BSI plus CABSI) was significantly reduced in the intervention arm (9.2 versus 22.6 infections/1000 patient-days, p 0.027); no differences were observed in the mortality between the two arms. Conclusions: Daily bathing with 4% CHGwr significantly reduced HAI incidence in intensive care settings. ClinicalTrial.gov registration: NCT03639363. C. Pallotto, Clin Microbiol Infect 2018;▪:1 © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Editor: M. Paul Keywords: 4% chlorhexidine gluconate Daily bathing Hospital-acquired infections Infection control Intensive care
Introduction Hospital-acquired infections (HAI)dand especially bloodstream infections (BSI) and central-line-associated BSI (CLABSI)dare responsible for increased morbidity, mortality and healthcare costs [1,2]. Skin and its microbial flora represent the most important pathogen reservoir for BSI and CLABSI [3]. Several infection control
* Corresponding author. C. Pallotto, Infectious Diseases Unit, University Hospital of Perugia, ‘Santa Maria della Misericordia’ Hospital, Piazzale Menghini, 1, 06129 Perugia, Italy. E-mail address: [email protected] (C. Pallotto).
strategies were investigated to reduce the incidence of HAI. Daily bathing with 2% chlorhexidine gluconate (CHG) seemed to be one of the most promising. However, a large cluster randomized trial of more than 10 000 patients showed that bathing with 2% CHG did not reduce the incidence of healthcare-associated infections including CLABSI, catheter-related urinary tract infections (CAUTI), ventilator-associated pneumonias (VAP) and Clostridium difficile colitis [2]. Moreover, some papers recently showed that prolonged exposure to 2% CHG can induce resistance to this antiseptic agent [4e6]. We hypothesized that 4% CHG could be useful in preventing inducible resistance to CHG but, to our knowledge, there is no evidence for its efficacy. Therefore, we conducted a randomized
https://doi.org/10.1016/j.cmi.2018.09.012 1198-743X/© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
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C. Pallotto et al. / Clinical Microbiology and Infection xxx (2018) 1e6
controlled trial to evaluate the effect of daily bathing with a soaplike solution of 4% CHG followed by water rinsing (CHGwr) on the acquisition rate of HAI in intensive care settings as primary outcome. Materials and methods Trial design and participants We conducted a single-centre, single-blind, controlled, parallel group, 1:1, two-arm, investigator-initiated, randomized trial at the University Hospital of Perugia, Italy. All patients who were consecutively admitted to the Intensive Care Unit (ICU) and to the Post-operative Cardiosurgical Intensive Care Unit (PC-ICU) between 10 August 2015 and 27 January 2016 and 10 August 2015 and 14 April 2016, respectively, were considered for enrolment. Inclusion criteria were: (i) admission to the ICU or to the PC-ICU, (ii) ICU/PCICU stay for at least one night, and (iii) age >18 years. Exclusion criteria were: (i) known allergy to chlorhexidine, (ii) burns, toxic epidermal necrolysis or StevenseJohnson syndrome as admission diagnosis, (iii) pregnancy, and (iv) age <18 years. Interventions Individuals who were randomized to the intervention arm (arm A) were daily bathed with a soap-like solution of 4% CHG (Neoxidina mani 4%, Nuova Farmec, Settimo di Pescantina (VR), Italy) followed by water rinsing according to the manufacturer's instructions for preoperative bathing; bathing was performed every day from admission to discharge. In brief, the whole body surface with the exception of the face was (i) humidified by waterimpregnated washcloths, (ii) bathed with 4% CHG-impregnated washcloths (at least 30 mL) and, after at least 30 seconds, (iii) rinsed with water-impregnated washcloths. In contrast, individuals randomized to the control arm (arm B) were bathed with water and standard soap following the same procedure. Bathing was performed every morning by nurses who had been trained in the proper techniques for bathing before the trial was initiated. Bathing procedures are described in detail in Supplementary material (Appendix A). This infection control intervention was the only one in progress during the study period. Outcomes The primary end point was HAI incidence defined as cumulative incidence of BSI, CLABSI, UTI, CAUTI and VAP. The secondary end points were defined as the incidence of: (i) VAP, (ii) BSI, (iii) CLABSI, (iv) UTI and (v) CAUTI. Moreover, we decided to evaluate (vi) 4% CHGwr safety, reporting adverse events and mortality during the ICU/PC-ICU stay and (vii) time till infection. As a post-hoc analysis, we report data about microbiological isolates related to diagnosed VAP, BSI, CLABSI, UTI or CAUTI. HAI were prospectively diagnosed at the bed-side by an Infectious Diseases specialist or a fellow during the individuals' ICU or PC-ICU stay and was confirmed by a different Infectious Diseases specialist. All these physicians were blind to the intervention. All infections occurred >48 h after admission to the ICU or to the PCICU were considered as HAI [7]. Diagnosis of primary BSI, CLABSI, UTI, CAUTI and VAP were in agreement with the National Healthcare Safety Network (NHSN)/Centre for Disease Control and Prevention (CDC) definitions [7]. Multidrug-resistant (MDR), extended drug resistant and pandrug resistant microorganisms were defined
according to the European Centre for Disease Prevention and Control (ECDC) and the CDC e-Prevention guidelines [8]. Data collection Demographic and clinical data (co-morbidities, blood and microbiological tests) were collected by an Infectious Diseases specialist or a fellow using a case report form that had been specifically prepared for this trial. Co-morbidities were evaluated using the Charlson co-morbidity index [9]. Sample size determination and randomization To calculate the sample size, we retrospectively measured the pre-trial incidence of HAI in the ICU and PC-ICU (patients admitted to the ICU and PC-ICU between 1 January and 31 January 2015). Twenty patients out of 66 had from at least one HAI (incidence 30.3%). By adopting an a error tolerance (false-positive risk) equal to 0.05, b error tolerance (false-negative risk) equal to 0.1, power equal to 0.9, a potential reduction of HAI incidence by 10% and a percentage between 5% and 8% of potential dropouts, we calculated that a sample size of at least 410e420 participants would be required to provide sufficient power to detect significant differences. A simple randomization was performed at patient-level; group assignment was based on a computer-generated randomization list prepared by the Random.org program (Random.org, Randomness and Integrity Services Ltd, Dublin, Ireland). At admission, an ICU/PCICU physician verified the presence of inclusion and exclusion criteria and established the recruitment. In case of eligibility for enrolment, the participant was assigned to the proper arm according to the randomized allocation sequence. Physicians and nurses of the ICU and the PC-ICU were not blinded to the intervention. Infectious Diseases specialists and fellows were daily involved in the ICU/PC-ICU clinical round as consultants and they were responsible for infection diagnosis and treatment. They worked both as caretakers and as outcome assessors for the study. Infectious Diseases specialists and fellows were blinded to the intervention. Statistical analysis Distribution of variables was assessed by KolmogoroveSmirnov test. Normal variables were represented as mean ± standard deviation, continuous non Gaussian variables were represented as median and interquartile range, categorical variables were represented as frequency and percentage. Comparisons between groups were performed with twotailed unpaired t test, ManneWhitney test or chi-squared test with Yate's correction, depending on variable distribution. Time till infection was analysed creating a KaplaneMeier surviving curve. All analyses were executed with R statistical software. A value of p less than 0.05 was considered statistically significant. Ethical considerations Enrolment and patient data management were made in agreement with the declaration of Helsinki. All patients gave their written consent at admission. Unconscious patients were enrolled by an ICU/PC-ICU physician at admission. In these cases, a waiver of consent at randomization until the regaining of consciousness was approved by the local Ethics Committee. At consciousness restoration, these participants received an ad hoc consent form to sign to remain or leave the trial. The trial was approved by the local Ethics Committee (CEAS Umbria).
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
C. Pallotto et al. / Clinical Microbiology and Infection xxx (2018) 1e6
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Fig. 1. Study design and enrolment. Abbreviations: ICU, Intensive Care Unit; PC-ICU, Post-operative Cardiosurgical Intensive Care Unit. Notes: a, 11 patients <18 years, 3 patients suffered from burns; b, 3 patient <18 years.
Results Enrolment and patient baseline characteristics A total of 519 individuals were admitted to the participating wards during the study period. Seventeen did not meet inclusion criteria and 53 declined to participate. Therefore, 449 were enrolled, 189 at the ICU and 260 at the PC-ICU. Two-hundred and twenty-six (50.3%) patients were randomized to the intervention arm and 223 (49.7%) to the control arm (Fig. 1). Table 1 describes baseline demographic and clinical characteristics of the study population and of each arm. As a consequence of the randomization, the intervention arm and control arm were homogeneous for sex, age and co-morbidities at admission.
Moreover, median length of stay from ICU/PC-ICU admission to ICU/ PC-ICU discharge was 4 days in the two arms (p >0.05). Overall, we detected 108 HAI in 91/449 (20.3%) patients; 76/449 (16.9%) and 15/449 (2.7%) individuals suffered from one HAI and more than one HAI, respectively. Bloodstream infections (BSI and CLABSI) were the most frequently diagnosed HAI (15.4 infections/ 1000 patient-days). VAP and CAUTI were as frequent as 11 and 4.9 infection/1000 patient-days, respectively. No UTI were detected. Moreover, we did not observe any differences between the incidence of HAI in ICU and PC-ICU. Aetiology was determined in 82/108 (75.9%) HAI and 13/108 (12%) were polymicrobial infections. Ninety-five strains were isolated; 31/95 (32.6%), 62/95 (65.3%) and 2/95 (2.1%) isolates were Gram-positive bacteria, Gram-negative bacteria and fungi,
Table 1 Baseline demographic and clinical characteristics
Patients, n (%) Male, n (%) Age, mean years ± SD Reason for admission Surgical, n (%) Medical, n (%) Trauma, n (%) Charlson Co-morbidity Index, mean ± SD Diabetes, n (%) Immunodepression, n (%) Previous admission 3 months, n (%) Surgery during the admission, n (%) Oro-tracheal intubation, n (%) Urinary catheter, n (%) Central venous catheter, n (%) Patients in ICU, n (%) Patients in PC-ICU, n Length of stay* median days (IQR
Study population
Treatment arm
Control arm
449 (100%) 273 (60.8%) 67.4 ± 14.7
226 (50.3%) 136 (60.2%) 67.2 ± 13.8
223 (49.7%) 137 (61.4%) 67.5 ± 15.6
233 (51.9%) 173 (38.5%) 43 (9.6%) 6.12 ± 2.61 89 (19.8%) 65 (14.5%) 236 (52.6%) 375 (83.5%) 448 (99.8%) 448 (99.8%) 448 (99.8%) 189 (42.1%) 260 (57.9%) 4 (2e7.25)
115 (50.9%) 87 (38.5%) 24 (10.6%) 6.15 ± 2.65 38 (16.8%) 34 (15%) 116 (51.3%) 190 (84.1%) 225 (99.6%) 225 (99.6%) 225 (99.6%) 97 (42.9%) 129 (57.1%) 4 (2e8)
118 (52.9%) 86 (38.6%) 19 (8.5%) 6.09 ± 2.57 51 (22.9%) 31 (13.9%) 120 (53.8%) 185 (83%) 223 (100%) 223 (100%) 223 (100%) 92 (41.3%) 131 (58.7%) 4 (2e7)
Abbreviation: SD, standard deviation; IQR, interquartile range; ICU, intensive care unit; PC-ICU, postoperative cardiosurgical intensive care unit. Note: *, from ICU/PC-ICU admission to ICU/PC-ICU discharge.
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
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Table 2 Incidence of infections per 1000 patient-days and mortality
Total infections, n/1000 pd (95% CI) VAP, n/1000 pd (95% CI) BSI, n/1000 pd (95% CI) CLABSI, n/1000 pd (95% CI) CAUTI n/1000 pd (95% CI) BSIþCLABSI, n/1000 pd (95% CI) Mortality, n (%)
Study population n ¼ 449 (3444 patient-days)
Intervention arm n ¼ 226 (1857 patient-days)
Control arm n ¼ 223 (1587 patient-days)
p
31.3 (25.9e37.9) 11 (7.9e15.3) 9 (6.2e12.9) 6.4 (4.1e9.8) 4.9 (3e8.1) 15.4 (11.6e20.2) 61 (13.6%)
23.2 (17e31.3) 11.3 (7.2e17.5) 5.4 (2.7e10.2) 3.8 (1.6e8.1) 2.7 (0.9e6.7) 9.2 (5.5e14.9) 29 (12.8%)
40.9 (32e52.2) 10.7 (6.4e17.5) 13.2 (8.4e20.5) 9.4 (5.5e15.9) 7.6 (4.1e13.6) 22.6 (16.2e31.6) 32 (14.3%)
0.034 1 0.113 0.204 0.223 0.027 0.74
Abbreviations: BSI, bloodstream infection; CAUTI, community-acquired urinary tract infection; CLABSI, central-line-associated BSI; pd, patient-days; VAP, ventilatorassociated pneumonia.
Fig. 2. Infection-free time in intervention and control arms.
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
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respectively. The most frequently isolated microorganism was Klebsiella pneumoniae (18/95, 18.9%); 42/95 (44.2%) isolates were MDR and no pandrug-resistant strains were detected. Primary outcome We detected at least one HAI in 34/226 (15%) and 57/223 (25.6%) patients in the intervention arm and control arm, respectively (p 0.008). HAI incidence was 23.2 infections/1000 patient-days in intervention arm and 40.9 infections/1000 patient-days in the control arm (Table 2). Secondary outcomes Incidence of VAP, BSI, CLABSI, UTI and CAUTI is shown in Table 2. No statistically significant differences were detected between the two arms; BSI plus CLABSI in the control arm was significantly more than in the intervention arm (p 0.027). Twenty-nine out of 226 (12.8%) and 32/223 (14.3%) patients died (all-cause mortality) during the study period in the intervention arm and control arm, respectively (p 0.74, RR 0.89, 95% CI 0.56e1.43) (Table 2). Fig. 2 shows the infection-free time in the intervention arm and control arm. Mean time to infection in the intervention arm was 21.77 days (median 19 days) whereas in the control arm it was 12.17 days (median 10 days) with p <0.0001. Gram-negative bacteria were the most frequently isolated microorganisms both in the intervention arm and in the control arm; a significant reduction of Gram-positive isolates was detected with 4% CHGwr bathing (7/39, 17.9% in intervention arm; 24/56, 42.9% in control arm, p 0.02). On the other hand, Gram-negative microorganism incidence was not different in the two arms (Table 3). MDR microorganisms were isolated with a similar frequency in the two arms (17/39, 43.6% in intervention arm, 25/56, 44.6% in control arm, p >0.1) (Table 3). We observed just one adverse event in the intervention arm. A patient suffered from a mild skin rash that promptly disappeared after 4% CHGwr bathing discontinuation. No adverse event was observed in the control arm.
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Discussion Daily bathing with 2% CHG is now one of the most investigated infection control strategies, especially in intensive care settings. A recent meta-analysis found evidence of its effectiveness in reducing the incidence of CLABSI and methicillin-resistant Staphylococcus aureus infections [10]. Nevertheless, there are some studies that do not support these findings [1,2,11] and new warnings about possible emergence of resistance to chlorhexidine were recently published [4e6]. In our study, we evaluated the effectiveness of 4% CHG bathing followed by rinsing with water. We found that HAI are 40.4% less frequent in the intervention arm than in the control arm. Climo et al.dusing 2% CHG daily bathingdreported a reduction by only 28%, assessing only BSIs [1]. On the other hand, Bleasdale et al. [12] and Munoz-Price et al. [13] showed consistent results to ours, but they analysed only BSIs. Globally, data from the literature show that CHG daily bathing could be more effective in preventing BSI and CLABSI than other HAI [10]das also underlined in our study. In fact, only the cumulative incidence of BSI and CLABSI reached a statistically significant difference between the two arms (9.2 infections/ 1000 patient-days in intervention arm versus 22.6 infections/1000 patient-days in control arm, p 0.027)dwhereas other HAI did not, probably due to the relatively small number of events. A specific consideration is needed for VAP. It is well known that most aetiological agents of VAP come from the upper respiratory and gastrointestinal tracts [14]. As a consequence, CHG daily bathing should not consistently influence VAP acquisition rate. However, as already pointed out by Frost et al. [10], CHG daily bathing could also have a role in VAP prevention. Despite 4% CHGwr daily bathing, 34 patients in the intervention arm were diagnosed with an HAI. Obviously HAI cannot be completely eliminated. However, we found that HAI are at least postponed by 4% CHGwr daily bathing so that, performing this infection control strategy, infection-free time is significantly increased. CHG daily bathing appears to be associated with greater effect against Gram-positive microorganisms than against Gram-negative
Table 3 Microbiological isolates
Gram-positive bacteria, n (%) MSSA MRSA CoNS Enterococcus spp. other Gram-negative bacteria, n (%) Acinetobacter baumannii Klebsiella pneumoniae Escherichia coli Enterobacter spp. Pseudomonas aeruginosa Serratia marcescens other MDR bacteria, n (%) Gram-positive Gram-negative Fungi, n (%)
All isolates n ¼ 95
Treatment arm isolates n ¼ 39
Control arm isolates n ¼ 56
p
31 (32.6%) 3 (3.2%) 8 (8.4%) 13 (13.7%) 4 (4.2%) 3 (3.2%) 62 (65.3%) 2 (2.1%) 18 (18.9%) 8 (8.4%) 5 (5.3%) 14 (14.7%) 8 (8.4%) 7 (7.4%) 42 (44.2%) 20 (21.1%) 22 (23.2%) 2 (2.1%)
7 (17.9%) 1 (2.6%) 2 (5.1%) 3 (7.7%)a 1 (2.6%)c 0 30 (76.9%) 2 (5.1%) 11 (28.2%) 2 (5.1%) 1 (2.6%)f 9 (23.1%) 3 (7.7%) 2 (5.1%)h 17 (43.6%) 5 (12.8%)l 12 (30.8%)n 2 (5.1%)p
24 (42.9%) 2 (3.6%) 6 (10.7%) 10 (17.9%)b 3 (5.4%)d 3 (5.4%)e 32 (57.1%) 0 7 (12.5%) 6 (10.7%) 4 (7.1%)g 5 (8.9%) 5 (8.9%) 5 (8.9%)i 25 (44.6%) 15 (26.8%)m 10 (17.9%)o 0 (0%)
0.02
0.076
>0.1 >0.1 >0.1 0.324
Notes: a, 3 S. epidermidis; b, 7 S. epidermidis, 1 S. capitis, 1 S. haemolyticus and 1 S. hominis; c, 1 E. faecalis; d, 1 E. faecalis and 2 E. faecium; e, 1 Corynebacterium striatum, 1 Streptococcus mitis and 1 Streptococcus disgalactiae; f, 1 E. cloacae; g, 3 E. cloacae and 1 E. aerogenes; h, 1 Stenotrophomonas maltophilia and 1 Morganella morganii; i, 1 M. morganii, 2 Citrobacter freundii, 1 Proteus mirabilis and 1 Proteus vulgaris; l, 2 MRSA and 3 methicillin-resistant Staphylococcus epidermidis; m, 6 MRSA and 9 coagulase-negative staphylococci; n, 1 ESBL producing E. cloacae, 1 ESBL producing E. coli, 6 KPC producing K. pneumoniae, 2 ESBL producing K. pneumoniae and 2 P. aeruginosa MDR; o, 1 ESBL producing E. cloacae, 3 ESBL producing E. coli, 4 KPC producing K. pneumoniae and 2 ESBL producing K. pneumoniae; p, 1 Candida albicans and 1 Candida glabrata. Abbreviations: MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; CoNS, coagulase-negative staphylococci; MDR, multidrug-resistant; ESBL, expanded spectrum b-lactamases; KPC, Klebsiella pneumoniae-like carbapenemase.
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
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C. Pallotto et al. / Clinical Microbiology and Infection xxx (2018) 1e6
ones [11,15e17]. Our study confirmed this finding: Gram-positive isolates decreased by 58% (p 0.02), whereas Gram-negative ones did not reach the threshold of significance. Recently, the US Food and Drug Administration issued a warning about CHG after having identified 52 cases of anaphylaxis [18]. Moreover, Price et al. showed an increased mortality after use of chlorhexidine as oropharyngeal decontaminant for VAP prevention [19]. On the contrary, several authors described daily bathing with 2% CHG as a safe procedure with rare and mild cutaneous adverse events [12,20,21]. Although in the present study a double concentration of chlorhexidine was used, we observed a single adverse eventda mild skin rash that promptly disappeared after 4% CHGwr bathing discontinuationdand all-cause mortality rate during the study period was the same in the two arms. However, more studies are necessary to determine whether 4% CHGwr daily bathing is a completely safe infection control strategy. This study has some limitations. Although it is randomized, this trial is monocentric and single-blind. We were not able to blind staff that performed bathing, patients and ICU and PC-ICU personnel; however, physicians responsible for infection diagnosis were blinded to the intervention. Second, this is a patientlevel randomized study and it is possible that 4% CHGwr daily bathing can have an ecological effect (decreasing crosstransmission of pathogens between neighbouring patients). In addition to this, we used an open printed randomization list to determine patients' allocation and it can represent a selection bias. Moreover, there are some limitations for the generalization of our findings such as the high level of HAI incidence in our hospital. Finally, it was not possible to assess bathing adherence and chlorhexidine-resistance development was not monitored. In conclusion, daily bathing with a soap-like solution of 4% CHG followed by water rinsing significantly reduced HAI incidence in intensive care settingsdespecially when Gram-positive microorganisms were involveddand without increasing all-cause mortality rate and adverse events. In addition to this, infection-free time significantly increased. It could be interesting and useful to compare 4% CHGwr and 2% CHG. Transparency declaration The authors have no conflicts of interest to declare for the present study. No external funding was received for the present study. Acknowledgement We are grateful to the nursing staff of the Intensive Care Unit and the Post-operative Cardiosurgical Intensive Care Unit. Preliminary results of the present study were presented at the 26th ECCMID (Amsterdam, the Netherlands, 9e12 April 2016) as a poster presentation; full study results were presented at the 15th Annual National Congress of the Italian Society of Infectious and Tropical Diseases (SIMIT 2016, PaviadBaveno, 16e19 October 2016) as an oral presentation. All authors had full access to the data. Authors contribution CP and MF conceived the study, elaborated the study protocol and interpreted data, CP, FV, PI, LQG and EF enrolled patients and collected data, VDA and AR made the statistical analysis, CP drafted the article, MF, CT, DF and FB revised the article and MF and FB supervised the whole study. All the authors approved the final version of the article to be submitted. CP and MF are the guarantors of data.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2018.09.012.
References [1] Climo MW, Yokoe DS, Warren DK, Perl TM, Bolon M, Herwaldt LA, et al. Effect of daily chlorhexidine bathing on hospital.acquired infection. N Engl J Med 2013;368:533e42. [2] Noto JM, Domenico HJ, Byrne DW, Talbot T, Rice TW, Bernard GR, et al. Chlorhexidine bathing and health care-associated infections: a randomized clinical trial. JAMA 2015;313:369e78. [3] O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. Healthcare Infection Control Practices Advisory Committee (HICPAC). Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 2011;52:e162e93. [4] Pittet D, Angus DC. Daily chlorhexidine bathing for critically ill patients: a note of cautions. JAMA 2015;313:365e6. [5] Horner C, Mawer D, Wilcox M. Reduced susceptibility to chlorhexidine in staphylococci: is it increasing and does it matter? J Antimicrob Chemother 2012;67:2547e59. [6] Stickler DJ. Susceptibility of antibiotic-resistant gram-negative bacteria to biocides: a perspective from the study of catheter biofilms. J Appl Microbiol 2002;92:163Se70S. [7] Centers for Diseases Control and Prevention. CDC/NHSN surveillance definitions for specific types of infections; Available at: http://www.cdc.gov/nhsn. (27 April 2015). [8] Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resi stance. Clin Microbiol Infect 2012;18:268e81. [9] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying progrostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373e83. [10] Frost SA, Alogso MC, Metcalfe L, Lynch JM, Hunt L, Sanghavi R, et al. Chlorhexidine bathing and health care-associated infections among adult intensive care patients: a systematic review and meta-analysis. Crit Care 2016;20:379. [11] Tacconelli E, Cataldo MA, Dancer SJ, De Angelis G, Falcone M, Frank U, et al. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant gram negative bacteria in hospitalized patients. Clin Microbiol Infect 2014;20:1e55. [12] Bleasdale SC, Trick WE, Gonzalez IM, Lyles RD, Hayden MK, Weinstein RA. Effectiveness of chlorhexidine bathing to reduce catheter-associated bloodstream infections in medical intensive care unit patients. Arch Intern Med 2007;167:2073e9. [13] Munoz-Price LS, Hota B, Stremer A, Weinstein RA. Prevention of bloodstream infections by use of daily chlorhexidine baths for patients at a long-term acute care hospital. Infect Control Hosp Epidemiol 2009;30: 1031e5. [14] Klompas M. Nosocomial pneumonia. In: Bennett JE, Dolin R, Blaser MJ, Mandell, editors. Douglas and Bennett’s principles and practise of infectious diseases. 8th ed. Philadelphia: Elsevier; 2015. 3325e3333.e4. [15] Lowe CF, Lloyd-Smith E, Sidhu B, Ritchie G, Sharma A, Jang W, et al. Reduction in hospital-associated methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus with daily chlorhexidine gluconate bathing for medical inpatients. Am J Infect Control 2016. S0196e6553(16) 30911e7. [Epub ahead of print]. [16] Huang HP, Chen B, Wang HY, He M. The efficacy of daily chlorhexidine bathing for preventing healthcare-associated infections in adult intensive care units. Kor J Intern Med 2016;31:1159e70. [17] Afonso E, Blot K, Blot S. Prevention of hospital-acquired bloodstream infections through chlorhexidine gluconate-impregnated washcloth bathing in intensive care units: a systematic review and meta-analysis of randomised crossover trials. Euro Surveill 2016;21. pii: 30400. [18] U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns about rare but serious allergic reactions with the skin antiseptic chlorhexidine gluconate. Published on 2 February 2017. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm530975.htm (28 February 2017). [19] Price R, McLennan G. Glen J on the behalf of the SUDDICU collaboration. Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis. BMJ 2014;348: g2197. [20] Evans HL, Dellit TH, Chan J, Nathens AB, Maier RV, Cuschieri J. Effect of chlorhexidine whole-body bathing on hospital-acquired infections among trauma patients. Arch Surg 2010;145:240e6. [21] Petlin A, Schallom M, Prentice D, Sona C, Mantia P, McMullen K, et al. Chlorhexidine gluconate bathing to reduce methicillin-resistant Staphylococcus aureus acquisition. Crit Care Nurse 2014;34:17e25.
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Original article
Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial C. Pallotto 1, *, M. Fiorio 1, V. De Angelis 2, A. Ripoli 3, E. Franciosini 4, L. Quondam Girolamo 5, F. Volpi 5, P. Iorio 4, D. Francisci 1, C. Tascini 6, F. Baldelli 1 1)
Infectious Diseases Unit, University Hospital of Perugia, Perugia, Italy Medical Oncology Unit, University Hospital of Perugia, Perugia, Italy Fondazione CNR Regione Toscana ‘G. Monasterio’, Pisa, Italy 4) Intensive Care Unit, University Hospital of Perugia, Perugia, Italy 5) Post-operative Cardiosurgical Intensive Care Unit, University Hospital of Perugia, Perugia, Italy 6) First Division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, Naples, Italy 2) 3)
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 January 2018 Received in revised form 21 August 2018 Accepted 16 September 2018 Available online xxx
Objectives: To investigate whether daily bathing with a soap-like solution of 4% chlorhexidine (CHG) followed by water rinsing (CHGwr) would decrease the incidence of hospital-acquired infections (HAI) in intensive care settings. Methods: Randomized, controlled trial; infectious diseases specialists were blinded to the intervention status. All patients admitted to the Intensive Care Unit (ICU) and to the Post-operative Cardiosurgical Intensive Care Unit (PC-ICU) of the University Hospital of Perugia were enrolled and randomized to the intervention arm (daily bathing with 4% CHGwr) or to the control arm (daily bathing with standard soap). The incidence rate of acquisition of HAI was compared between the two arms as primary outcome. We also evaluated the incidence of bloodstream infections (BSI), central-line-associated BSI (CLABSI), ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI), and 4% CHGwr safety. Results: In all, 449 individuals were enrolled, 226 in treatment arm and 223 in control arm. Thirty-four individuals of the 226 (15%) and 57 (25.6%) suffered from at least an HAI in the intervention and control arms, respectively (p 0.008); 23.2 and 40.9 infections/1000 patient-days were detected in the intervention arm and control arm, respectively (p 0.037). The incidence of all bloodstream infections (BSI plus CABSI) was significantly reduced in the intervention arm (9.2 versus 22.6 infections/1000 patient-days, p 0.027); no differences were observed in the mortality between the two arms. Conclusions: Daily bathing with 4% CHGwr significantly reduced HAI incidence in intensive care settings. ClinicalTrial.gov registration: NCT03639363. C. Pallotto, Clin Microbiol Infect 2018;▪:1 © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Editor: M. Paul Keywords: 4% chlorhexidine gluconate Daily bathing Hospital-acquired infections Infection control Intensive care
Introduction Hospital-acquired infections (HAI)dand especially bloodstream infections (BSI) and central-line-associated BSI (CLABSI)dare responsible for increased morbidity, mortality and healthcare costs [1,2]. Skin and its microbial flora represent the most important pathogen reservoir for BSI and CLABSI [3]. Several infection control
* Corresponding author. C. Pallotto, Infectious Diseases Unit, University Hospital of Perugia, ‘Santa Maria della Misericordia’ Hospital, Piazzale Menghini, 1, 06129 Perugia, Italy. E-mail address: [email protected] (C. Pallotto).
strategies were investigated to reduce the incidence of HAI. Daily bathing with 2% chlorhexidine gluconate (CHG) seemed to be one of the most promising. However, a large cluster randomized trial of more than 10 000 patients showed that bathing with 2% CHG did not reduce the incidence of healthcare-associated infections including CLABSI, catheter-related urinary tract infections (CAUTI), ventilator-associated pneumonias (VAP) and Clostridium difficile colitis [2]. Moreover, some papers recently showed that prolonged exposure to 2% CHG can induce resistance to this antiseptic agent [4e6]. We hypothesized that 4% CHG could be useful in preventing inducible resistance to CHG but, to our knowledge, there is no evidence for its efficacy. Therefore, we conducted a randomized
https://doi.org/10.1016/j.cmi.2018.09.012 1198-743X/© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
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C. Pallotto et al. / Clinical Microbiology and Infection xxx (2018) 1e6
controlled trial to evaluate the effect of daily bathing with a soaplike solution of 4% CHG followed by water rinsing (CHGwr) on the acquisition rate of HAI in intensive care settings as primary outcome. Materials and methods Trial design and participants We conducted a single-centre, single-blind, controlled, parallel group, 1:1, two-arm, investigator-initiated, randomized trial at the University Hospital of Perugia, Italy. All patients who were consecutively admitted to the Intensive Care Unit (ICU) and to the Post-operative Cardiosurgical Intensive Care Unit (PC-ICU) between 10 August 2015 and 27 January 2016 and 10 August 2015 and 14 April 2016, respectively, were considered for enrolment. Inclusion criteria were: (i) admission to the ICU or to the PC-ICU, (ii) ICU/PCICU stay for at least one night, and (iii) age >18 years. Exclusion criteria were: (i) known allergy to chlorhexidine, (ii) burns, toxic epidermal necrolysis or StevenseJohnson syndrome as admission diagnosis, (iii) pregnancy, and (iv) age <18 years. Interventions Individuals who were randomized to the intervention arm (arm A) were daily bathed with a soap-like solution of 4% CHG (Neoxidina mani 4%, Nuova Farmec, Settimo di Pescantina (VR), Italy) followed by water rinsing according to the manufacturer's instructions for preoperative bathing; bathing was performed every day from admission to discharge. In brief, the whole body surface with the exception of the face was (i) humidified by waterimpregnated washcloths, (ii) bathed with 4% CHG-impregnated washcloths (at least 30 mL) and, after at least 30 seconds, (iii) rinsed with water-impregnated washcloths. In contrast, individuals randomized to the control arm (arm B) were bathed with water and standard soap following the same procedure. Bathing was performed every morning by nurses who had been trained in the proper techniques for bathing before the trial was initiated. Bathing procedures are described in detail in Supplementary material (Appendix A). This infection control intervention was the only one in progress during the study period. Outcomes The primary end point was HAI incidence defined as cumulative incidence of BSI, CLABSI, UTI, CAUTI and VAP. The secondary end points were defined as the incidence of: (i) VAP, (ii) BSI, (iii) CLABSI, (iv) UTI and (v) CAUTI. Moreover, we decided to evaluate (vi) 4% CHGwr safety, reporting adverse events and mortality during the ICU/PC-ICU stay and (vii) time till infection. As a post-hoc analysis, we report data about microbiological isolates related to diagnosed VAP, BSI, CLABSI, UTI or CAUTI. HAI were prospectively diagnosed at the bed-side by an Infectious Diseases specialist or a fellow during the individuals' ICU or PC-ICU stay and was confirmed by a different Infectious Diseases specialist. All these physicians were blind to the intervention. All infections occurred >48 h after admission to the ICU or to the PCICU were considered as HAI [7]. Diagnosis of primary BSI, CLABSI, UTI, CAUTI and VAP were in agreement with the National Healthcare Safety Network (NHSN)/Centre for Disease Control and Prevention (CDC) definitions [7]. Multidrug-resistant (MDR), extended drug resistant and pandrug resistant microorganisms were defined
according to the European Centre for Disease Prevention and Control (ECDC) and the CDC e-Prevention guidelines [8]. Data collection Demographic and clinical data (co-morbidities, blood and microbiological tests) were collected by an Infectious Diseases specialist or a fellow using a case report form that had been specifically prepared for this trial. Co-morbidities were evaluated using the Charlson co-morbidity index [9]. Sample size determination and randomization To calculate the sample size, we retrospectively measured the pre-trial incidence of HAI in the ICU and PC-ICU (patients admitted to the ICU and PC-ICU between 1 January and 31 January 2015). Twenty patients out of 66 had from at least one HAI (incidence 30.3%). By adopting an a error tolerance (false-positive risk) equal to 0.05, b error tolerance (false-negative risk) equal to 0.1, power equal to 0.9, a potential reduction of HAI incidence by 10% and a percentage between 5% and 8% of potential dropouts, we calculated that a sample size of at least 410e420 participants would be required to provide sufficient power to detect significant differences. A simple randomization was performed at patient-level; group assignment was based on a computer-generated randomization list prepared by the Random.org program (Random.org, Randomness and Integrity Services Ltd, Dublin, Ireland). At admission, an ICU/PCICU physician verified the presence of inclusion and exclusion criteria and established the recruitment. In case of eligibility for enrolment, the participant was assigned to the proper arm according to the randomized allocation sequence. Physicians and nurses of the ICU and the PC-ICU were not blinded to the intervention. Infectious Diseases specialists and fellows were daily involved in the ICU/PC-ICU clinical round as consultants and they were responsible for infection diagnosis and treatment. They worked both as caretakers and as outcome assessors for the study. Infectious Diseases specialists and fellows were blinded to the intervention. Statistical analysis Distribution of variables was assessed by KolmogoroveSmirnov test. Normal variables were represented as mean ± standard deviation, continuous non Gaussian variables were represented as median and interquartile range, categorical variables were represented as frequency and percentage. Comparisons between groups were performed with twotailed unpaired t test, ManneWhitney test or chi-squared test with Yate's correction, depending on variable distribution. Time till infection was analysed creating a KaplaneMeier surviving curve. All analyses were executed with R statistical software. A value of p less than 0.05 was considered statistically significant. Ethical considerations Enrolment and patient data management were made in agreement with the declaration of Helsinki. All patients gave their written consent at admission. Unconscious patients were enrolled by an ICU/PC-ICU physician at admission. In these cases, a waiver of consent at randomization until the regaining of consciousness was approved by the local Ethics Committee. At consciousness restoration, these participants received an ad hoc consent form to sign to remain or leave the trial. The trial was approved by the local Ethics Committee (CEAS Umbria).
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Fig. 1. Study design and enrolment. Abbreviations: ICU, Intensive Care Unit; PC-ICU, Post-operative Cardiosurgical Intensive Care Unit. Notes: a, 11 patients <18 years, 3 patients suffered from burns; b, 3 patient <18 years.
Results Enrolment and patient baseline characteristics A total of 519 individuals were admitted to the participating wards during the study period. Seventeen did not meet inclusion criteria and 53 declined to participate. Therefore, 449 were enrolled, 189 at the ICU and 260 at the PC-ICU. Two-hundred and twenty-six (50.3%) patients were randomized to the intervention arm and 223 (49.7%) to the control arm (Fig. 1). Table 1 describes baseline demographic and clinical characteristics of the study population and of each arm. As a consequence of the randomization, the intervention arm and control arm were homogeneous for sex, age and co-morbidities at admission.
Moreover, median length of stay from ICU/PC-ICU admission to ICU/ PC-ICU discharge was 4 days in the two arms (p >0.05). Overall, we detected 108 HAI in 91/449 (20.3%) patients; 76/449 (16.9%) and 15/449 (2.7%) individuals suffered from one HAI and more than one HAI, respectively. Bloodstream infections (BSI and CLABSI) were the most frequently diagnosed HAI (15.4 infections/ 1000 patient-days). VAP and CAUTI were as frequent as 11 and 4.9 infection/1000 patient-days, respectively. No UTI were detected. Moreover, we did not observe any differences between the incidence of HAI in ICU and PC-ICU. Aetiology was determined in 82/108 (75.9%) HAI and 13/108 (12%) were polymicrobial infections. Ninety-five strains were isolated; 31/95 (32.6%), 62/95 (65.3%) and 2/95 (2.1%) isolates were Gram-positive bacteria, Gram-negative bacteria and fungi,
Table 1 Baseline demographic and clinical characteristics
Patients, n (%) Male, n (%) Age, mean years ± SD Reason for admission Surgical, n (%) Medical, n (%) Trauma, n (%) Charlson Co-morbidity Index, mean ± SD Diabetes, n (%) Immunodepression, n (%) Previous admission 3 months, n (%) Surgery during the admission, n (%) Oro-tracheal intubation, n (%) Urinary catheter, n (%) Central venous catheter, n (%) Patients in ICU, n (%) Patients in PC-ICU, n Length of stay* median days (IQR
Study population
Treatment arm
Control arm
449 (100%) 273 (60.8%) 67.4 ± 14.7
226 (50.3%) 136 (60.2%) 67.2 ± 13.8
223 (49.7%) 137 (61.4%) 67.5 ± 15.6
233 (51.9%) 173 (38.5%) 43 (9.6%) 6.12 ± 2.61 89 (19.8%) 65 (14.5%) 236 (52.6%) 375 (83.5%) 448 (99.8%) 448 (99.8%) 448 (99.8%) 189 (42.1%) 260 (57.9%) 4 (2e7.25)
115 (50.9%) 87 (38.5%) 24 (10.6%) 6.15 ± 2.65 38 (16.8%) 34 (15%) 116 (51.3%) 190 (84.1%) 225 (99.6%) 225 (99.6%) 225 (99.6%) 97 (42.9%) 129 (57.1%) 4 (2e8)
118 (52.9%) 86 (38.6%) 19 (8.5%) 6.09 ± 2.57 51 (22.9%) 31 (13.9%) 120 (53.8%) 185 (83%) 223 (100%) 223 (100%) 223 (100%) 92 (41.3%) 131 (58.7%) 4 (2e7)
Abbreviation: SD, standard deviation; IQR, interquartile range; ICU, intensive care unit; PC-ICU, postoperative cardiosurgical intensive care unit. Note: *, from ICU/PC-ICU admission to ICU/PC-ICU discharge.
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Table 2 Incidence of infections per 1000 patient-days and mortality
Total infections, n/1000 pd (95% CI) VAP, n/1000 pd (95% CI) BSI, n/1000 pd (95% CI) CLABSI, n/1000 pd (95% CI) CAUTI n/1000 pd (95% CI) BSIþCLABSI, n/1000 pd (95% CI) Mortality, n (%)
Study population n ¼ 449 (3444 patient-days)
Intervention arm n ¼ 226 (1857 patient-days)
Control arm n ¼ 223 (1587 patient-days)
p
31.3 (25.9e37.9) 11 (7.9e15.3) 9 (6.2e12.9) 6.4 (4.1e9.8) 4.9 (3e8.1) 15.4 (11.6e20.2) 61 (13.6%)
23.2 (17e31.3) 11.3 (7.2e17.5) 5.4 (2.7e10.2) 3.8 (1.6e8.1) 2.7 (0.9e6.7) 9.2 (5.5e14.9) 29 (12.8%)
40.9 (32e52.2) 10.7 (6.4e17.5) 13.2 (8.4e20.5) 9.4 (5.5e15.9) 7.6 (4.1e13.6) 22.6 (16.2e31.6) 32 (14.3%)
0.034 1 0.113 0.204 0.223 0.027 0.74
Abbreviations: BSI, bloodstream infection; CAUTI, community-acquired urinary tract infection; CLABSI, central-line-associated BSI; pd, patient-days; VAP, ventilatorassociated pneumonia.
Fig. 2. Infection-free time in intervention and control arms.
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C. Pallotto et al. / Clinical Microbiology and Infection xxx (2018) 1e6
respectively. The most frequently isolated microorganism was Klebsiella pneumoniae (18/95, 18.9%); 42/95 (44.2%) isolates were MDR and no pandrug-resistant strains were detected. Primary outcome We detected at least one HAI in 34/226 (15%) and 57/223 (25.6%) patients in the intervention arm and control arm, respectively (p 0.008). HAI incidence was 23.2 infections/1000 patient-days in intervention arm and 40.9 infections/1000 patient-days in the control arm (Table 2). Secondary outcomes Incidence of VAP, BSI, CLABSI, UTI and CAUTI is shown in Table 2. No statistically significant differences were detected between the two arms; BSI plus CLABSI in the control arm was significantly more than in the intervention arm (p 0.027). Twenty-nine out of 226 (12.8%) and 32/223 (14.3%) patients died (all-cause mortality) during the study period in the intervention arm and control arm, respectively (p 0.74, RR 0.89, 95% CI 0.56e1.43) (Table 2). Fig. 2 shows the infection-free time in the intervention arm and control arm. Mean time to infection in the intervention arm was 21.77 days (median 19 days) whereas in the control arm it was 12.17 days (median 10 days) with p <0.0001. Gram-negative bacteria were the most frequently isolated microorganisms both in the intervention arm and in the control arm; a significant reduction of Gram-positive isolates was detected with 4% CHGwr bathing (7/39, 17.9% in intervention arm; 24/56, 42.9% in control arm, p 0.02). On the other hand, Gram-negative microorganism incidence was not different in the two arms (Table 3). MDR microorganisms were isolated with a similar frequency in the two arms (17/39, 43.6% in intervention arm, 25/56, 44.6% in control arm, p >0.1) (Table 3). We observed just one adverse event in the intervention arm. A patient suffered from a mild skin rash that promptly disappeared after 4% CHGwr bathing discontinuation. No adverse event was observed in the control arm.
5
Discussion Daily bathing with 2% CHG is now one of the most investigated infection control strategies, especially in intensive care settings. A recent meta-analysis found evidence of its effectiveness in reducing the incidence of CLABSI and methicillin-resistant Staphylococcus aureus infections [10]. Nevertheless, there are some studies that do not support these findings [1,2,11] and new warnings about possible emergence of resistance to chlorhexidine were recently published [4e6]. In our study, we evaluated the effectiveness of 4% CHG bathing followed by rinsing with water. We found that HAI are 40.4% less frequent in the intervention arm than in the control arm. Climo et al.dusing 2% CHG daily bathingdreported a reduction by only 28%, assessing only BSIs [1]. On the other hand, Bleasdale et al. [12] and Munoz-Price et al. [13] showed consistent results to ours, but they analysed only BSIs. Globally, data from the literature show that CHG daily bathing could be more effective in preventing BSI and CLABSI than other HAI [10]das also underlined in our study. In fact, only the cumulative incidence of BSI and CLABSI reached a statistically significant difference between the two arms (9.2 infections/ 1000 patient-days in intervention arm versus 22.6 infections/1000 patient-days in control arm, p 0.027)dwhereas other HAI did not, probably due to the relatively small number of events. A specific consideration is needed for VAP. It is well known that most aetiological agents of VAP come from the upper respiratory and gastrointestinal tracts [14]. As a consequence, CHG daily bathing should not consistently influence VAP acquisition rate. However, as already pointed out by Frost et al. [10], CHG daily bathing could also have a role in VAP prevention. Despite 4% CHGwr daily bathing, 34 patients in the intervention arm were diagnosed with an HAI. Obviously HAI cannot be completely eliminated. However, we found that HAI are at least postponed by 4% CHGwr daily bathing so that, performing this infection control strategy, infection-free time is significantly increased. CHG daily bathing appears to be associated with greater effect against Gram-positive microorganisms than against Gram-negative
Table 3 Microbiological isolates
Gram-positive bacteria, n (%) MSSA MRSA CoNS Enterococcus spp. other Gram-negative bacteria, n (%) Acinetobacter baumannii Klebsiella pneumoniae Escherichia coli Enterobacter spp. Pseudomonas aeruginosa Serratia marcescens other MDR bacteria, n (%) Gram-positive Gram-negative Fungi, n (%)
All isolates n ¼ 95
Treatment arm isolates n ¼ 39
Control arm isolates n ¼ 56
p
31 (32.6%) 3 (3.2%) 8 (8.4%) 13 (13.7%) 4 (4.2%) 3 (3.2%) 62 (65.3%) 2 (2.1%) 18 (18.9%) 8 (8.4%) 5 (5.3%) 14 (14.7%) 8 (8.4%) 7 (7.4%) 42 (44.2%) 20 (21.1%) 22 (23.2%) 2 (2.1%)
7 (17.9%) 1 (2.6%) 2 (5.1%) 3 (7.7%)a 1 (2.6%)c 0 30 (76.9%) 2 (5.1%) 11 (28.2%) 2 (5.1%) 1 (2.6%)f 9 (23.1%) 3 (7.7%) 2 (5.1%)h 17 (43.6%) 5 (12.8%)l 12 (30.8%)n 2 (5.1%)p
24 (42.9%) 2 (3.6%) 6 (10.7%) 10 (17.9%)b 3 (5.4%)d 3 (5.4%)e 32 (57.1%) 0 7 (12.5%) 6 (10.7%) 4 (7.1%)g 5 (8.9%) 5 (8.9%) 5 (8.9%)i 25 (44.6%) 15 (26.8%)m 10 (17.9%)o 0 (0%)
0.02
0.076
>0.1 >0.1 >0.1 0.324
Notes: a, 3 S. epidermidis; b, 7 S. epidermidis, 1 S. capitis, 1 S. haemolyticus and 1 S. hominis; c, 1 E. faecalis; d, 1 E. faecalis and 2 E. faecium; e, 1 Corynebacterium striatum, 1 Streptococcus mitis and 1 Streptococcus disgalactiae; f, 1 E. cloacae; g, 3 E. cloacae and 1 E. aerogenes; h, 1 Stenotrophomonas maltophilia and 1 Morganella morganii; i, 1 M. morganii, 2 Citrobacter freundii, 1 Proteus mirabilis and 1 Proteus vulgaris; l, 2 MRSA and 3 methicillin-resistant Staphylococcus epidermidis; m, 6 MRSA and 9 coagulase-negative staphylococci; n, 1 ESBL producing E. cloacae, 1 ESBL producing E. coli, 6 KPC producing K. pneumoniae, 2 ESBL producing K. pneumoniae and 2 P. aeruginosa MDR; o, 1 ESBL producing E. cloacae, 3 ESBL producing E. coli, 4 KPC producing K. pneumoniae and 2 ESBL producing K. pneumoniae; p, 1 Candida albicans and 1 Candida glabrata. Abbreviations: MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; CoNS, coagulase-negative staphylococci; MDR, multidrug-resistant; ESBL, expanded spectrum b-lactamases; KPC, Klebsiella pneumoniae-like carbapenemase.
Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012
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C. Pallotto et al. / Clinical Microbiology and Infection xxx (2018) 1e6
ones [11,15e17]. Our study confirmed this finding: Gram-positive isolates decreased by 58% (p 0.02), whereas Gram-negative ones did not reach the threshold of significance. Recently, the US Food and Drug Administration issued a warning about CHG after having identified 52 cases of anaphylaxis [18]. Moreover, Price et al. showed an increased mortality after use of chlorhexidine as oropharyngeal decontaminant for VAP prevention [19]. On the contrary, several authors described daily bathing with 2% CHG as a safe procedure with rare and mild cutaneous adverse events [12,20,21]. Although in the present study a double concentration of chlorhexidine was used, we observed a single adverse eventda mild skin rash that promptly disappeared after 4% CHGwr bathing discontinuationdand all-cause mortality rate during the study period was the same in the two arms. However, more studies are necessary to determine whether 4% CHGwr daily bathing is a completely safe infection control strategy. This study has some limitations. Although it is randomized, this trial is monocentric and single-blind. We were not able to blind staff that performed bathing, patients and ICU and PC-ICU personnel; however, physicians responsible for infection diagnosis were blinded to the intervention. Second, this is a patientlevel randomized study and it is possible that 4% CHGwr daily bathing can have an ecological effect (decreasing crosstransmission of pathogens between neighbouring patients). In addition to this, we used an open printed randomization list to determine patients' allocation and it can represent a selection bias. Moreover, there are some limitations for the generalization of our findings such as the high level of HAI incidence in our hospital. Finally, it was not possible to assess bathing adherence and chlorhexidine-resistance development was not monitored. In conclusion, daily bathing with a soap-like solution of 4% CHG followed by water rinsing significantly reduced HAI incidence in intensive care settingsdespecially when Gram-positive microorganisms were involveddand without increasing all-cause mortality rate and adverse events. In addition to this, infection-free time significantly increased. It could be interesting and useful to compare 4% CHGwr and 2% CHG. Transparency declaration The authors have no conflicts of interest to declare for the present study. No external funding was received for the present study. Acknowledgement We are grateful to the nursing staff of the Intensive Care Unit and the Post-operative Cardiosurgical Intensive Care Unit. Preliminary results of the present study were presented at the 26th ECCMID (Amsterdam, the Netherlands, 9e12 April 2016) as a poster presentation; full study results were presented at the 15th Annual National Congress of the Italian Society of Infectious and Tropical Diseases (SIMIT 2016, PaviadBaveno, 16e19 October 2016) as an oral presentation. All authors had full access to the data. Authors contribution CP and MF conceived the study, elaborated the study protocol and interpreted data, CP, FV, PI, LQG and EF enrolled patients and collected data, VDA and AR made the statistical analysis, CP drafted the article, MF, CT, DF and FB revised the article and MF and FB supervised the whole study. All the authors approved the final version of the article to be submitted. CP and MF are the guarantors of data.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2018.09.012.
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Please cite this article in press as: Pallotto C, et al., Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial, Clinical Microbiology and Infection (2018), https://doi.org/10.1016/j.cmi.2018.09.012