- Email: [email protected]
Eradication of MRSA throat carriage - a randomized trial comparing topical treatment with rifampicin-based systemic therapy
Accepted Manuscript Title: Eradication of MRSA throat carriage - a randomized trial comparing topical treatment with rifampicin-based systemic therapy Author: Anna-Karin Lindgren, Anna C. Nilsson, Per Åkesson, Eva Gustafsson, Eva Melander PII: DOI: Reference:
S0924-8579(17)30313-8 http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.08.021 ANTAGE 5245
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
28-3-2017 15-8-2017
Please cite this article as: Anna-Karin Lindgren, Anna C. Nilsson, Per Åkesson, Eva Gustafsson, Eva Melander, Eradication of MRSA throat carriage - a randomized trial comparing topical treatment with rifampicin-based systemic therapy, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.08.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Version 2017-05-29
2
Eradication of MRSA throat carriage - a randomized trial comparing
3
topical treatment with rifampicin-based systemic therapy
4 5
Anna-Karin Lindgren1,2, Anna C. Nilsson2, Per Åkesson3, Eva Gustafsson4, and Eva
6
Melander2,4
7 8
1. Department of Infectious Diseases, Helsingborg Hospital, Helsingborg, Sweden
9
2. Infectious Disease Research Unit, Department of Translational Medicine, Lund University,
10
Malmö, Sweden
11
3. Department of Clinical Sciences, Division of Infection Medicine, Skåne University
12
Hospital, Lund, Sweden
13
4. Regional Centre for Communicable Disease Control, Skåne County Malmö, Sweden
14
Word count: 1560, Abstract: 217 Keywords: MRSA, eradication 15
Abbreviations: Methicillin-resistant Staphylococcus aureus (MRSA)
16
Running title: Eradication of MRSA
17
Corresponding author: Anna-Karin Lindgren: Department of Infectious Diseases,
18
Helsingborg Hospital, Södra Vallgatan 5, SE-25187 Helsingborg, Sweden.
19
Mail: anna-karin.a,[email protected], phone: +46-424062950, fax: +46-424062362
20
Alternative corresponding author: Eva Melander: Department of Communicable Diseases,
21
Skåne University Hospital, SE-20501 Malmö, Sweden. Mail: [email protected],
22
phone: +46-40337181, fax +46-40337188
Page 1 of 15
23
Highlights
24
The major findings were:
25
1) Rifampicin-based systemic antibiotics in addition to topical treatment decolonized 61% of the
26
study subjects. The follow-up time was six months. For eradication of an extra-nasal site, this
27
success rate is considered high.
28
2) Study subjects that only received topical mupirocin were not decolonized. Only 12% were
29
negative at the 6-month follow-up. Based on previous studies this might reflect spontaneous
30
decolonization. This indicates that throat carriers should not receive mupirocin treatment,
31
which is the standard protocol in many institutions.
32 33
Abstract
34
Objectives: Eradication of MRSA colonization may prevent transmission of strains between
35
patients and reduces the risk of clinical infection. Colonization of the throat is associated with
36
prolonged carriage and is more difficult to eradicate.
37
Methods: An open randomized study was conducted to evaluate two eradication protocols.
38
Patients with pharyngeal carriage of MRSA were enrolled at six Swedish centers during four
39
years. One treatment group received oral rifampicin and clindamycin or trimethoprim-
40
sulfamethoxazole for seven days, in combination with nasal mupirocin. Patients in the other
41
group were treated with nasal mupirocin, only. Patients in the same household were
42
randomized together. Both groups followed a hygiene protocol including chlorhexidine
43
washings. Cultures from the nares, perineum and throat were taken at baseline, and then two
44
weeks, two months and six months after the end of treatment.
45
Results: A total of 28 patients received rifampicin-based systemic antibiotics. The mupirocin
46
only group contained 24 subjects. At follow-up six months after the end of treatment, 61% of
47
the patients and 50% of the households in the systemic antibiotics group had culture results
48
negative for MRSA. Significantly less patients (12%) and households (10%) became
49
decolonized in the group receiving topical treatment only.
Page 2 of 15
50
Conclusions:
51
sulfamethoxazole was more effective in eliminating pharyngeal MRSA carriage compared to
52
topical treatment with mupirocin.
A
combination
of
rifampicin
and
clindamycin
or
trimethoprim-
Page 3 of 15
53
Introduction
54
In many countries, methicillin-resistant Staphylococcus aureus (MRSA) has become endemic
55
and a major challenge to the treatment of S. aureus infections. Preventing transmission of
56
MRSA is important. Infections with this pathogen are associated with considerable mortality
57
and excess hospital costs (1). Most of the patients with MRSA infections are colonized prior
58
to infection (2) and carriage of S. aureus is a risk factor of acquiring S. aureus infections (3).
59
Several eradication strategies for MRSA carriers have been proposed (4). However, the
60
optimal treatment schedule has not yet been defined. Topical intranasal treatment with
61
mupirocin has been investigated in several studies and seems to be effective on nasal
62
decolonization (4). In studies of oral antibiotics, the use of rifampicin has been associated
63
with a higher frequency of eradication from extra-nasal sites (4). Rifampicin alone as
64
monotherapy should not be used due to high risk of development of resistance under
65
rifampicin monotherapy.
66
During the last years, it has been shown that the oropharynx is an important site for MRSA
67
colonization (5,6). Exclusive throat carriage is common (7). Also, colonization of the throat is
68
associated with long-term carriage compared to other locations such as the nares (5).
69
Eradication studies specifically designed for throat carriers are lacking, however, there are
70
indications that the oropharynx is more difficult to decolonize (8).
71
In Sweden, various non-evidence-based treatment strategies combining topical treatment with
72
systemic antibiotics are used for certain groups of MRSA throat carriers, such as patients with
73
regular healthcare contacts, patients having recurrent MRSA infections or healthcare staff.
74
Most of these contain rifampicin as one part of the treatment. Based on retrospective data (8),
75
an eradication strategy was developed and evaluated in the presented prospective study.
Page 4 of 15
76
Methods
77
Study population and setting
78
This was an open randomized study conducted in six centers in Sweden. Patients were
79
enrolled as outpatients between 2011-2015 in four University Hospitals located in Malmö,
80
Lund, Örebro and Stockholm, and in two Community Hospitals in Helsingborg and
81
Kristianstad. Sweden has a low prevalence of MRSA and all cases are reported to the
82
Regional Centre for Communicable Disease Control. Follow up is conducted at designated
83
Clinics for Infectious Diseases. Thus, all eligible patients in the regions covered by the study
84
centers could be offered to participate in the study.
85
Patients were considered eligible for inclusion if they were >4 years old and colonized with
86
MRSA in the throat, with or without colonization in other locations. Colonization was defined
87
as having at least two positive cultures during at least three months. The MRSA isolate had to
88
be sensitive to rifampicin, and also to either clindamycin or trimethoprim-sulfamethoxazole.
89
Exclusion criteria were allergy to any of the study drugs, treatment with immunosuppressive
90
drugs or pregnancy. Patients who had an ongoing infection with MRSA or treatment for skin
91
lesions or eczema were also excluded. All MRSA positive household contacts were treated at
92
the same time, either within the study or, if not meeting the inclusion criteria, according to
93
local guidelines.
94
The study was approved by the Regional Ethical Review Board in Lund (2010/353), and the
95
Swedish Medical Products Agency. A written informed consent was obtained before study
96
start.
97 98
Study design
99
The patients were divided into two groups by a randomization system (SAS PROC PLAN). If
100
two or more patients in the same household were included they were randomized into the
Page 5 of 15
101
same treatment group. Group I received nasal application with 2% mupirocin ointment
102
applied to the anterior nares three times daily for five days, and oral rifampicin (10 mg/kg
103
once daily) in combination with oral clindamycin (300 mg for adults and 5 mg/kg for
104
children, three times daily) for seven days. In case of resistance or contraindication to
105
clindamycin, this was replaced by trimethoprim-sulfamethoxazole (800mg/160 mg for adults
106
and 400mg/80mg for children, twice daily). Group II only received nasal mupirocin. All
107
patients did full-body washings with 4% chlorhexidine gluconate solution twice a week and
108
followed a hygiene protocol with instructions such as changing linens and towels. The
109
primary outcome was defined as having negative cultures two weeks, two months and six
110
months after end of treatment.
111 112
Cultures and laboratory methods
113
Cultures were taken from the nares, throat, perineum and skin lesions (if present) before the
114
start of treatment, and then again at two weeks, two months and six months after completed
115
treatment. All household members were cultured before treatment and six months after the
116
end of treatment.
117
Colonies on blood agar plates were presumptively identified as S. aureus by colony
118
morphology and/or on selective plates by giving a coloured reaction (9). Coagulase-positive
119
colonies were tested for isoxacillin susceptibility by the disk diffusion (www.eucast.org).
120
Polymerase chain reaction (PCR) for the detection of nuc/SA442 and mecA genes were used
121
for verification of MRSA (10). Spa-typing were performed as described elsewhere (10).
122 123
Statistical analysis
Page 6 of 15
124
For comparison between the two groups Fisher exact test was used. A p-value <0.05 was
125
considered significant. Comparisons of groups were performed on both individual and
126
household levels. Calculations were performed using IBM-SPSS Statistics, version 22.0.
127
Page 7 of 15
128
Results
129
69 eligible patients in 55 different households were included during the study period.
130
Seventeen patients were excluded from the analysis due to various reasons (Fig. 1). Thus 52
131
patients in 42 households were evaluated. Group I, who received systemic antibiotics together
132
with topical treatment, contained 28 patients in 22 different households. Of these, 21 patients
133
in 15 households received rifampicin and clindamycin, and 7 patients in 7 households
134
received rifampicin and trimethoprim-sulfamethoxazole. 24 patients in 20 households were
135
evaluated in Group II and received topical treatment without systemic treatment.
136
Baseline demographic and clinical characteristics were similar between groups (table 1). A
137
majority of the patients had been MRSA carriers for more than one year. 65% of the patients
138
were MRSA-carriers in the oropharynx only, and 33% were positive in both throat and nasal
139
cultures. 31% of the patients had previous attempts to eradicate MRSA. At the end of study
140
all persons in the households were cultured. Approximately one third of the study subjects had
141
culture-positive household contacts.
142
At six months following treatment, 17 (61%) of the patients who received combined systemic
143
and topical treatment (Group I) were negative for MRSA, compared with three (12%) in the
144
topical treatment-only group (Group II). Eleven (50%) of the households in Group I were
145
negative six months after treatment, compared to 2 (10%) households in Group II. The
146
difference in outcome between the groups was 40% (95 % CI 15%-65%, p=0.007).
147
Cultures taken at two weeks and two months post-treatment showed that eradication initially
148
had been successful in four additional patients in Group I. Two of these relapsed two months
149
and two six months after treatment was completed. In group II three additional patients were
150
negative two weeks after treatment and relapsed after two months. Susceptibility testing of
151
strains from relapses showed no development of resistance, neither to the oral antibiotics nor
Page 8 of 15
152
to mupirocin. The patients that relapsed were recolonized with the same strain as the initial
153
one.
154
The MRSA isolates belonged to 28 different spa-types. 6 strains belonged to the subtype t006
155
and 4 to t002. No other subtype were isolated in more than two patients.
156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176
Page 9 of 15
177 178 179
Discussion
180
The present study shows that one week of a rifampicin-containing antibiotic combination
181
decolonized 61% of the MRSA throat carriers for at least 6 months. Screening for MRSA
182
colonization is restricted to the nares in most institutions. However, during the last decade it
183
has become evident that exclusive throat carriage is common. In Sweden, which is a low-
184
prevalence country for MRSA, 17% of a screened population positive for MRSA were
185
exclusive throat carriers (9). In endemic settings figures have been even higher (5, 6).
186
Notably, accumulated data on MRSA decolonization suggests that throat carriage is more
187
difficult to eradicate (8, 11, 12). Decolonization protocols often prescribes mupirocin
188
treatment only, along with chlorhexidine washings. A previous randomized trial of
189
hospitalized patients studied rifampicin and doxycycline combined with nasal mupirocin and
190
chlorhexidine washings. The results showed that MRSA was successfully eradicated in 74 %
191
of the patients after three months (13). Pharyngeal carriage was not studied in this trial. Later,
192
observational studies have supported the effect of using two antimicrobial agents, of which
193
one was rifampicin (8, 12, 14). No specific protocol was aimed specifically at throat carriers
194
in these studies, at least not in the first round of eradication attempts.
195
In this context, the advantage of the presented study is the investigation of an important subset
196
of MRSA carriers. In addition, it is a randomized study in a low-prevalence area for MRSA.
197
Exogenous recolonization should thus be less likely. Taken together, these should make the
198
results more reliable and easier to interpret. The limitation of the study is its small sample
199
size. This makes it impossible to make any subanalyses of the reasons for relapses or the
200
differences between the two antibiotic alternatives.
Page 10 of 15
201
In conclusion, MRSA colonization in the throat is possible to eradicate. The results of this
202
study shows that topical treatment is not sufficient to decolonize throat carriers and that
203
addition of systemic treatment substantially increases the success rate.
204 205
Acknowledgements
206
The authors wish to thank all the participating patients. We thank physicians and nurses at the
207
Departments of Infectious diseases and Clinical Microbiology in Helsingborg, Kristianstad,
208
Lund, Malmö, Örebro and Stockholm for excellent work.
209 210
Declarations
211
Funding: This study was supported financially by the Gorthon Fund.
212
Competing Interests: The authors declare that they have no conflict of interest.
213
Ethical Approval: The study was approved by the Regional Ethical Review Board in Lund
214
(2010/353),
215
RCT: 2010-019727-55
216 217 218 219
Page 11 of 15
220
References
221
1.
222 223
Shorr AF. Epidemiology and economic impact of meticillin-resistant Staphylococcus aureus: review and analysis of the literature. PharmacoEconomics. 2007;25(9):751-68.
2.
Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, et al.
224
The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005
225
Dec;5(12):751-62.
226
3.
Wertheim HFL, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JAJW, et al. Risk and
227
outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-
228
carriers. The Lancet. 2004;364(9435):703-5.
229
4.
Ammerlaan HS, Kluytmans JA, Wertheim HF, Nouwen JL, Bonten MJ. Eradication of
230
methicillin-resistant Staphylococcus aureus carriage: a systematic review. Clin Infect Dis.
231
2009 Apr 1;48(7):922-30.
232
5.
Marshal C, Spelman D. Is Throat Screening Necessary To Detect Methicillin-Resistant
233
Staphylococcus aureus Colonization in Patients upon Admission to an Intensive Care Unit? J
234
Clin Microbiol. 2007; 45:3855-3855.
235
6.
Hamdan-Partida A, Sainz-Espuñes T, Bustos-Martínez J. Characterization and persistence of
236
Staphylococcus aureus strains isolated from the anterior nares and throats of healthy carriers in
237
a Mexican community. J Clin. Microbiol. 2010;48:1701-1705.
238
7.
239 240
Nurjadi D, Lependu J, Kremsner PG, Zanger P. Staphylococcus aureus throat carriage is associated with ABO-/secretor status. Journal of Infection. 2012 10;65(4):310-7.
8.
Ammerlaan HS, Kluytmans JA, Berkhout H, Buiting A, de Brauwer EI, van den Broek PJ, et
241
al. Eradication of carriage with methicillin-resistant Staphylococcus aureus: determinants of
242
treatment failure. J Antimicrob Chemother. 2011 Oct;66(10):2418-24.
243
9
244 245 246
Ringberg H, Cathrine Petersson A, Walder M, Hugo Johansson PJ. The throat: an important site for MRSA colonization. Scand J Infect Dis. 2006;38(10):888-93.
10.
Petersson AC, Olsson-Liljequist B, Miorner H, Haeggman S. Evaluating the usefulness of spa typing, in comparison with pulsed-field gel electrophoresis, for epidemiological typing of
Page 12 of 15
247
methicillin-resistant Staphylococcus aureus in a low-prevalence region in Sweden 2000-2004.
248
Clin Microbiol Infect. 2010 May;16(5):456-62.
249
11.
Gilpin DF, Small S, Bakkshi S, Kearney MP, Cardwell C, Tunney MM. Efficacy of a standard
250
methicillin-resistant Staphylococcus aureus decolonisation protocol in routine clinical
251
practice. J Hosp Infect. 2010;75:93-98.
252
12.
Buehlmann M, Frei R, Fenner L, Dangel M, Fluckiger U, Widmer AF. Highly effective
253
regimen for decolonization of methicillin-resistant Staphylococcus aureus carriers. Infect
254
Control Hosp Epidemiol. 2008 Jun;29(6):510-6.
255
13.
Simor AE, Phillips E, McGeer A, Konvalinka A, Loeb M, Devlin HR, et al. Randomized
256
controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and
257
doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus
258
aureus colonization. Clin Infect Dis. 2007 Jan 15;44(2):178-85.
259
14.
Dow G, Field D, Mancuso M, Allard J. Decolonization of methicillin-resistant Staphylococcus
260
aureus during routine hospital care: efficacy and long-term follow-up. Can J Infect Dis Med
261
Microbiol. 2010; 21:38-44.
262
Page 13 of 15
263 264
Figure 1. Flow chart of study patients and MRSA culture results.
265 266
Page 14 of 15
267
Table 1. Patient characteristics Group I
Group II
Median age,years Female gender, n (%)
40 15 (54)
36 18 (75)
Foreign-born, n (%)
10 (36)
13 (54)
Chronic diseases, n (%)* Household contacts with MRSA at the end of study, n (%)
5 (18)
6 (25)
7 (25)
9 (37)
Carriage time before inclusion, median years (range)
1,2 (0.3-11)
1,2 (0.2-5)
Throat carriage solely (%)
18 (64)
16 (67)
Carriage in both throat and nares (%)
5 (18)
4 (17)
Carriage in both throat and the perineum (%)
0
1 (4)
Carriage in throat, nose and the perineum (%)
5 (18)
3 (12)
Patients who had eradication treatments prior to the study, n (%)
8 (29)
8 (33)
(Systemic +topical n=28)
268
(Topical n=24)
*diabetes mellitus, cardiovascular disease, asthma, breastcancer, sarcoidosis, COPD, eczema
269 270
Page 15 of 15
S0924-8579(17)30313-8 http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.08.021 ANTAGE 5245
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
28-3-2017 15-8-2017
Please cite this article as: Anna-Karin Lindgren, Anna C. Nilsson, Per Åkesson, Eva Gustafsson, Eva Melander, Eradication of MRSA throat carriage - a randomized trial comparing topical treatment with rifampicin-based systemic therapy, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.08.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Version 2017-05-29
2
Eradication of MRSA throat carriage - a randomized trial comparing
3
topical treatment with rifampicin-based systemic therapy
4 5
Anna-Karin Lindgren1,2, Anna C. Nilsson2, Per Åkesson3, Eva Gustafsson4, and Eva
6
Melander2,4
7 8
1. Department of Infectious Diseases, Helsingborg Hospital, Helsingborg, Sweden
9
2. Infectious Disease Research Unit, Department of Translational Medicine, Lund University,
10
Malmö, Sweden
11
3. Department of Clinical Sciences, Division of Infection Medicine, Skåne University
12
Hospital, Lund, Sweden
13
4. Regional Centre for Communicable Disease Control, Skåne County Malmö, Sweden
14
Word count: 1560, Abstract: 217 Keywords: MRSA, eradication 15
Abbreviations: Methicillin-resistant Staphylococcus aureus (MRSA)
16
Running title: Eradication of MRSA
17
Corresponding author: Anna-Karin Lindgren: Department of Infectious Diseases,
18
Helsingborg Hospital, Södra Vallgatan 5, SE-25187 Helsingborg, Sweden.
19
Mail: anna-karin.a,[email protected], phone: +46-424062950, fax: +46-424062362
20
Alternative corresponding author: Eva Melander: Department of Communicable Diseases,
21
Skåne University Hospital, SE-20501 Malmö, Sweden. Mail: [email protected],
22
phone: +46-40337181, fax +46-40337188
Page 1 of 15
23
Highlights
24
The major findings were:
25
1) Rifampicin-based systemic antibiotics in addition to topical treatment decolonized 61% of the
26
study subjects. The follow-up time was six months. For eradication of an extra-nasal site, this
27
success rate is considered high.
28
2) Study subjects that only received topical mupirocin were not decolonized. Only 12% were
29
negative at the 6-month follow-up. Based on previous studies this might reflect spontaneous
30
decolonization. This indicates that throat carriers should not receive mupirocin treatment,
31
which is the standard protocol in many institutions.
32 33
Abstract
34
Objectives: Eradication of MRSA colonization may prevent transmission of strains between
35
patients and reduces the risk of clinical infection. Colonization of the throat is associated with
36
prolonged carriage and is more difficult to eradicate.
37
Methods: An open randomized study was conducted to evaluate two eradication protocols.
38
Patients with pharyngeal carriage of MRSA were enrolled at six Swedish centers during four
39
years. One treatment group received oral rifampicin and clindamycin or trimethoprim-
40
sulfamethoxazole for seven days, in combination with nasal mupirocin. Patients in the other
41
group were treated with nasal mupirocin, only. Patients in the same household were
42
randomized together. Both groups followed a hygiene protocol including chlorhexidine
43
washings. Cultures from the nares, perineum and throat were taken at baseline, and then two
44
weeks, two months and six months after the end of treatment.
45
Results: A total of 28 patients received rifampicin-based systemic antibiotics. The mupirocin
46
only group contained 24 subjects. At follow-up six months after the end of treatment, 61% of
47
the patients and 50% of the households in the systemic antibiotics group had culture results
48
negative for MRSA. Significantly less patients (12%) and households (10%) became
49
decolonized in the group receiving topical treatment only.
Page 2 of 15
50
Conclusions:
51
sulfamethoxazole was more effective in eliminating pharyngeal MRSA carriage compared to
52
topical treatment with mupirocin.
A
combination
of
rifampicin
and
clindamycin
or
trimethoprim-
Page 3 of 15
53
Introduction
54
In many countries, methicillin-resistant Staphylococcus aureus (MRSA) has become endemic
55
and a major challenge to the treatment of S. aureus infections. Preventing transmission of
56
MRSA is important. Infections with this pathogen are associated with considerable mortality
57
and excess hospital costs (1). Most of the patients with MRSA infections are colonized prior
58
to infection (2) and carriage of S. aureus is a risk factor of acquiring S. aureus infections (3).
59
Several eradication strategies for MRSA carriers have been proposed (4). However, the
60
optimal treatment schedule has not yet been defined. Topical intranasal treatment with
61
mupirocin has been investigated in several studies and seems to be effective on nasal
62
decolonization (4). In studies of oral antibiotics, the use of rifampicin has been associated
63
with a higher frequency of eradication from extra-nasal sites (4). Rifampicin alone as
64
monotherapy should not be used due to high risk of development of resistance under
65
rifampicin monotherapy.
66
During the last years, it has been shown that the oropharynx is an important site for MRSA
67
colonization (5,6). Exclusive throat carriage is common (7). Also, colonization of the throat is
68
associated with long-term carriage compared to other locations such as the nares (5).
69
Eradication studies specifically designed for throat carriers are lacking, however, there are
70
indications that the oropharynx is more difficult to decolonize (8).
71
In Sweden, various non-evidence-based treatment strategies combining topical treatment with
72
systemic antibiotics are used for certain groups of MRSA throat carriers, such as patients with
73
regular healthcare contacts, patients having recurrent MRSA infections or healthcare staff.
74
Most of these contain rifampicin as one part of the treatment. Based on retrospective data (8),
75
an eradication strategy was developed and evaluated in the presented prospective study.
Page 4 of 15
76
Methods
77
Study population and setting
78
This was an open randomized study conducted in six centers in Sweden. Patients were
79
enrolled as outpatients between 2011-2015 in four University Hospitals located in Malmö,
80
Lund, Örebro and Stockholm, and in two Community Hospitals in Helsingborg and
81
Kristianstad. Sweden has a low prevalence of MRSA and all cases are reported to the
82
Regional Centre for Communicable Disease Control. Follow up is conducted at designated
83
Clinics for Infectious Diseases. Thus, all eligible patients in the regions covered by the study
84
centers could be offered to participate in the study.
85
Patients were considered eligible for inclusion if they were >4 years old and colonized with
86
MRSA in the throat, with or without colonization in other locations. Colonization was defined
87
as having at least two positive cultures during at least three months. The MRSA isolate had to
88
be sensitive to rifampicin, and also to either clindamycin or trimethoprim-sulfamethoxazole.
89
Exclusion criteria were allergy to any of the study drugs, treatment with immunosuppressive
90
drugs or pregnancy. Patients who had an ongoing infection with MRSA or treatment for skin
91
lesions or eczema were also excluded. All MRSA positive household contacts were treated at
92
the same time, either within the study or, if not meeting the inclusion criteria, according to
93
local guidelines.
94
The study was approved by the Regional Ethical Review Board in Lund (2010/353), and the
95
Swedish Medical Products Agency. A written informed consent was obtained before study
96
start.
97 98
Study design
99
The patients were divided into two groups by a randomization system (SAS PROC PLAN). If
100
two or more patients in the same household were included they were randomized into the
Page 5 of 15
101
same treatment group. Group I received nasal application with 2% mupirocin ointment
102
applied to the anterior nares three times daily for five days, and oral rifampicin (10 mg/kg
103
once daily) in combination with oral clindamycin (300 mg for adults and 5 mg/kg for
104
children, three times daily) for seven days. In case of resistance or contraindication to
105
clindamycin, this was replaced by trimethoprim-sulfamethoxazole (800mg/160 mg for adults
106
and 400mg/80mg for children, twice daily). Group II only received nasal mupirocin. All
107
patients did full-body washings with 4% chlorhexidine gluconate solution twice a week and
108
followed a hygiene protocol with instructions such as changing linens and towels. The
109
primary outcome was defined as having negative cultures two weeks, two months and six
110
months after end of treatment.
111 112
Cultures and laboratory methods
113
Cultures were taken from the nares, throat, perineum and skin lesions (if present) before the
114
start of treatment, and then again at two weeks, two months and six months after completed
115
treatment. All household members were cultured before treatment and six months after the
116
end of treatment.
117
Colonies on blood agar plates were presumptively identified as S. aureus by colony
118
morphology and/or on selective plates by giving a coloured reaction (9). Coagulase-positive
119
colonies were tested for isoxacillin susceptibility by the disk diffusion (www.eucast.org).
120
Polymerase chain reaction (PCR) for the detection of nuc/SA442 and mecA genes were used
121
for verification of MRSA (10). Spa-typing were performed as described elsewhere (10).
122 123
Statistical analysis
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124
For comparison between the two groups Fisher exact test was used. A p-value <0.05 was
125
considered significant. Comparisons of groups were performed on both individual and
126
household levels. Calculations were performed using IBM-SPSS Statistics, version 22.0.
127
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128
Results
129
69 eligible patients in 55 different households were included during the study period.
130
Seventeen patients were excluded from the analysis due to various reasons (Fig. 1). Thus 52
131
patients in 42 households were evaluated. Group I, who received systemic antibiotics together
132
with topical treatment, contained 28 patients in 22 different households. Of these, 21 patients
133
in 15 households received rifampicin and clindamycin, and 7 patients in 7 households
134
received rifampicin and trimethoprim-sulfamethoxazole. 24 patients in 20 households were
135
evaluated in Group II and received topical treatment without systemic treatment.
136
Baseline demographic and clinical characteristics were similar between groups (table 1). A
137
majority of the patients had been MRSA carriers for more than one year. 65% of the patients
138
were MRSA-carriers in the oropharynx only, and 33% were positive in both throat and nasal
139
cultures. 31% of the patients had previous attempts to eradicate MRSA. At the end of study
140
all persons in the households were cultured. Approximately one third of the study subjects had
141
culture-positive household contacts.
142
At six months following treatment, 17 (61%) of the patients who received combined systemic
143
and topical treatment (Group I) were negative for MRSA, compared with three (12%) in the
144
topical treatment-only group (Group II). Eleven (50%) of the households in Group I were
145
negative six months after treatment, compared to 2 (10%) households in Group II. The
146
difference in outcome between the groups was 40% (95 % CI 15%-65%, p=0.007).
147
Cultures taken at two weeks and two months post-treatment showed that eradication initially
148
had been successful in four additional patients in Group I. Two of these relapsed two months
149
and two six months after treatment was completed. In group II three additional patients were
150
negative two weeks after treatment and relapsed after two months. Susceptibility testing of
151
strains from relapses showed no development of resistance, neither to the oral antibiotics nor
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152
to mupirocin. The patients that relapsed were recolonized with the same strain as the initial
153
one.
154
The MRSA isolates belonged to 28 different spa-types. 6 strains belonged to the subtype t006
155
and 4 to t002. No other subtype were isolated in more than two patients.
156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176
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177 178 179
Discussion
180
The present study shows that one week of a rifampicin-containing antibiotic combination
181
decolonized 61% of the MRSA throat carriers for at least 6 months. Screening for MRSA
182
colonization is restricted to the nares in most institutions. However, during the last decade it
183
has become evident that exclusive throat carriage is common. In Sweden, which is a low-
184
prevalence country for MRSA, 17% of a screened population positive for MRSA were
185
exclusive throat carriers (9). In endemic settings figures have been even higher (5, 6).
186
Notably, accumulated data on MRSA decolonization suggests that throat carriage is more
187
difficult to eradicate (8, 11, 12). Decolonization protocols often prescribes mupirocin
188
treatment only, along with chlorhexidine washings. A previous randomized trial of
189
hospitalized patients studied rifampicin and doxycycline combined with nasal mupirocin and
190
chlorhexidine washings. The results showed that MRSA was successfully eradicated in 74 %
191
of the patients after three months (13). Pharyngeal carriage was not studied in this trial. Later,
192
observational studies have supported the effect of using two antimicrobial agents, of which
193
one was rifampicin (8, 12, 14). No specific protocol was aimed specifically at throat carriers
194
in these studies, at least not in the first round of eradication attempts.
195
In this context, the advantage of the presented study is the investigation of an important subset
196
of MRSA carriers. In addition, it is a randomized study in a low-prevalence area for MRSA.
197
Exogenous recolonization should thus be less likely. Taken together, these should make the
198
results more reliable and easier to interpret. The limitation of the study is its small sample
199
size. This makes it impossible to make any subanalyses of the reasons for relapses or the
200
differences between the two antibiotic alternatives.
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201
In conclusion, MRSA colonization in the throat is possible to eradicate. The results of this
202
study shows that topical treatment is not sufficient to decolonize throat carriers and that
203
addition of systemic treatment substantially increases the success rate.
204 205
Acknowledgements
206
The authors wish to thank all the participating patients. We thank physicians and nurses at the
207
Departments of Infectious diseases and Clinical Microbiology in Helsingborg, Kristianstad,
208
Lund, Malmö, Örebro and Stockholm for excellent work.
209 210
Declarations
211
Funding: This study was supported financially by the Gorthon Fund.
212
Competing Interests: The authors declare that they have no conflict of interest.
213
Ethical Approval: The study was approved by the Regional Ethical Review Board in Lund
214
(2010/353),
215
RCT: 2010-019727-55
216 217 218 219
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220
References
221
1.
222 223
Shorr AF. Epidemiology and economic impact of meticillin-resistant Staphylococcus aureus: review and analysis of the literature. PharmacoEconomics. 2007;25(9):751-68.
2.
Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, et al.
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The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005
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Dec;5(12):751-62.
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Wertheim HFL, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JAJW, et al. Risk and
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outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-
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carriers. The Lancet. 2004;364(9435):703-5.
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Ammerlaan HS, Kluytmans JA, Wertheim HF, Nouwen JL, Bonten MJ. Eradication of
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methicillin-resistant Staphylococcus aureus carriage: a systematic review. Clin Infect Dis.
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2009 Apr 1;48(7):922-30.
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5.
Marshal C, Spelman D. Is Throat Screening Necessary To Detect Methicillin-Resistant
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Staphylococcus aureus Colonization in Patients upon Admission to an Intensive Care Unit? J
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Clin Microbiol. 2007; 45:3855-3855.
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6.
Hamdan-Partida A, Sainz-Espuñes T, Bustos-Martínez J. Characterization and persistence of
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Staphylococcus aureus strains isolated from the anterior nares and throats of healthy carriers in
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a Mexican community. J Clin. Microbiol. 2010;48:1701-1705.
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Nurjadi D, Lependu J, Kremsner PG, Zanger P. Staphylococcus aureus throat carriage is associated with ABO-/secretor status. Journal of Infection. 2012 10;65(4):310-7.
8.
Ammerlaan HS, Kluytmans JA, Berkhout H, Buiting A, de Brauwer EI, van den Broek PJ, et
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al. Eradication of carriage with methicillin-resistant Staphylococcus aureus: determinants of
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treatment failure. J Antimicrob Chemother. 2011 Oct;66(10):2418-24.
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Ringberg H, Cathrine Petersson A, Walder M, Hugo Johansson PJ. The throat: an important site for MRSA colonization. Scand J Infect Dis. 2006;38(10):888-93.
10.
Petersson AC, Olsson-Liljequist B, Miorner H, Haeggman S. Evaluating the usefulness of spa typing, in comparison with pulsed-field gel electrophoresis, for epidemiological typing of
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methicillin-resistant Staphylococcus aureus in a low-prevalence region in Sweden 2000-2004.
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Clin Microbiol Infect. 2010 May;16(5):456-62.
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11.
Gilpin DF, Small S, Bakkshi S, Kearney MP, Cardwell C, Tunney MM. Efficacy of a standard
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methicillin-resistant Staphylococcus aureus decolonisation protocol in routine clinical
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practice. J Hosp Infect. 2010;75:93-98.
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12.
Buehlmann M, Frei R, Fenner L, Dangel M, Fluckiger U, Widmer AF. Highly effective
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regimen for decolonization of methicillin-resistant Staphylococcus aureus carriers. Infect
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Control Hosp Epidemiol. 2008 Jun;29(6):510-6.
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Simor AE, Phillips E, McGeer A, Konvalinka A, Loeb M, Devlin HR, et al. Randomized
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controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and
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doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus
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aureus colonization. Clin Infect Dis. 2007 Jan 15;44(2):178-85.
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14.
Dow G, Field D, Mancuso M, Allard J. Decolonization of methicillin-resistant Staphylococcus
260
aureus during routine hospital care: efficacy and long-term follow-up. Can J Infect Dis Med
261
Microbiol. 2010; 21:38-44.
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Figure 1. Flow chart of study patients and MRSA culture results.
265 266
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267
Table 1. Patient characteristics Group I
Group II
Median age,years Female gender, n (%)
40 15 (54)
36 18 (75)
Foreign-born, n (%)
10 (36)
13 (54)
Chronic diseases, n (%)* Household contacts with MRSA at the end of study, n (%)
5 (18)
6 (25)
7 (25)
9 (37)
Carriage time before inclusion, median years (range)
1,2 (0.3-11)
1,2 (0.2-5)
Throat carriage solely (%)
18 (64)
16 (67)
Carriage in both throat and nares (%)
5 (18)
4 (17)
Carriage in both throat and the perineum (%)
0
1 (4)
Carriage in throat, nose and the perineum (%)
5 (18)
3 (12)
Patients who had eradication treatments prior to the study, n (%)
8 (29)
8 (33)
(Systemic +topical n=28)
268
(Topical n=24)
*diabetes mellitus, cardiovascular disease, asthma, breastcancer, sarcoidosis, COPD, eczema
269 270
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