JAC Advance Access originally published online on June 29, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):665-668; doi:10.1093/jac/dkm235
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Macrolide-resistant Staphylococcus aureus colonization in cystic fibrosis patients: is there transmission to household contacts?
1 Department of Paediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Centre Utrecht, The Netherlands 2 Department of Medical Microbiology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, The Netherlands 3 Department of Paediatric Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, The Netherlands
* Corresponding author. Tel: +31-30-2504757; Fax: +31-30-2504747; E-mail: g.tramper{at}umcutrecht.nl
Received 28 February 2007; returned 11 April 2007; revised 21 May 2007; accepted 6 June 2007
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Abstract |
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Objectives: Patients with cystic fibrosis (CF) are frequently colonized by macrolide-resistant Staphylococcus aureus, a result of maintenance macrolide therapy. As transmission of S. aureus between household contacts is common, we examined the prevalence of macrolide-resistant S. aureus colonization in CF patients on maintenance azithromycin therapy and their household contacts and compared this with the S. aureus macrolide resistance prevalence in the community.
Patients and methods: Sixty-five CF patients on maintenance macrolide therapy and 194 household contacts were screened for S. aureus colonization by culturing sputa, cough swabs and nasal swabs. Resistance to macrolide, lincosamide and methicillin was determined by disc diffusion tests. The prevalence of macrolide-resistant S. aureus colonization in both groups was compared with figures from a nationwide study into S. aureus carriership and resistance. To assess possible transmission, genotyping of S. aureus was performed using the spa-typing method.
Results: Macrolide resistance among CF patients with S. aureus colonization was 69.6%; 75% of these isolates displayed lincosamide resistance too. Among household contacts, macrolide resistance prevalence did not differ significantly from resistance prevalence in the community (9.6% versus 6.3%; P = 0.358). No methicillin resistance was observed. No identical (macrolide-resistant and -susceptible) S. aureus genotypes were observed between CF patients and their household contacts except for one household, suggesting a probable transmission.
Conclusions: No significant increase in macrolide-resistant S. aureus colonization was observed among household contacts of CF patients on long-term azithromycin therapy. Transmission of macrolide-resistant S. aureus could not be proved by genotyping in the majority of households.
Keywords: macrolide resistance , S. aureus , staphylococcal transmission
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Introduction |
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Macrolide resistance of frequently colonizing pathogens is clearly associated with prescription of macrolide antibiotics.1,2 A subgroup of patients who frequently use macrolides are cystic fibrosis (CF) patients. These antibiotics are mainly prescribed for CF patients because of their anti-inflammatory properties. Additionally, macrolides reduce Pseudomonas aeruginosa biofilm formation and inhibit Pseudomonas quorum sensing in vitro.3 Placebo-controlled trials showed benefit with relation to frequency of exacerbations and pulmonary function after 6–9 months of macrolide treatment.4 Nevertheless, little attention is paid to long-term effects of macrolide use. Our and other groups previously reported a very high rate of macrolide-resistant Staphylococcus aureus colonization in CF patients on long-term azithromycin therapy.5,6
The resistance induced by macrolide use appears to be rapidly emerging and long-lasting, even after a short-course therapy.7,8 Macrolide resistance in S. aureus is characterized by drug efflux and prevention of drug binding on the ribosomal target site, induced by mef and erm genes, respectively. Cross-resistance to clindamycin and streptograminB is observed with the latter mechanism.
S. aureus often colonizes the respiratory tract of CF patients, but also 
30% of the healthy population are nasal S. aureus carries.2 Transmission of S. aureus is frequent among household contacts, including in families with CF patients.9 S. aureus colonization may have significant impact, because nasal S. aureus colonization is known to be a strongly associated risk factor for subsequent S. aureus infection.10,11
We hypothesized that if S. aureus transmission is frequent among household contacts, macrolide-resistant S. aureus from CF patients can spread into the community via household contacts. The same phenomenon has been observed for methicillin-resistant S. aureus colonization.12 The prevalence and transmission of macrolide-resistant S. aureus colonization might have consequences for the empirical treatment of S. aureus infections, especially in the light of cross-resistance to clindamycin.
To assess transmission of macrolide-resistant S. aureus, we examined household contacts of CF patients on maintenance macrolide therapy for nasal S. aureus carriage and subsequent macrolide resistance and compared these figures with nationwide surveillance data of S. aureus nasal carriage and resistance rates.
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Patients and methods |
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Participants and material collection
CF patients are routinely seen at the outpatient clinic of the Wilhelmina Children's Hospital, where they regularly provide sputa or cough swabs. All paediatric CF patients on maintenance azithromycin therapy (5–10 mg/kg/day) and their household contacts were asked to participate. The study was approved by the hospital ethical review board. Sixty-five CF patients with 193 household contacts (adults and children) provided informed consent. Participants were screened for nasal S. aureus colonization by culturing nasal swabs. They were instructed to firmly rotate swabs in both the anterior nares; half of the participants repeated this three times with intervals of 2 h.
Nasal swabs from the community were obtained from 2641 patients visiting their general practitioner for a non-infectious complaint. The general practitioners participated in the NIVEL sentinel station project and were located all over the Netherlands.13
A questionnaire about antibiotic use in the previous 2.5 years was obtained from household contacts.
Nasal swabs were cultured onto 5% sheep blood agar (household contacts) or mannitol salt agar (CF patients). After 24 h, all morphologically different colonies with features of S. aureus were purified on blood agar plates and identification was performed with catalase, tube coagulase and DNase testing. Resistance to macrolides, lincosamides and methicillin was determined by disc diffusion tests on Mueller–Hinton agar, inoculated with a bacterial suspension adjusted to an optical density equivalent to that of a 0.5 McFarland standard. Neo-Sensitabs (Rosco, Taastrup, Denmark) containing erythromycin, clindamycin and oxacillin were placed on the Mueller–Hinton agar with the inoculum. CLSI (formerly NCCLS) guidelines for resistance cut-off levels were used to classify the isolates. A study subject was considered colonized with macrolide-resistant S. aureus if one or more of the colonies were macrolide resistant.
To assess possible transmission between household contacts, genotyping was performed with the staphylococcal protein A (spa)-typing method, as described previously.14 Only isolates from CF patients carrying macrolide-resistant S. aureus having household contacts with S. aureus colonization (macrolide resistant and non-resistant) were typed. A dendrogram was created and patterns were assigned identical when there was 100% concordance in sequence type.
Prevalence of S. aureus colonization among household contacts and macrolide resistance was compared with figures from the nationwide study into S. aureus nasal colonization and resistance. Differences in prevalence were estimated with the 
2 test or Fisher's exact test and calculated with SPSS version 12.0 (IL, USA).
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Results |
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The prevalence of S. aureus colonization among CF patients was 35.4% (Table 1). Nasal prevalence was lower than sputa prevalence. Of CF staphylococcal carriers, 31% carried S. aureus in both nose and sputum/cough swab, 17% only had a positive nose swab and 52% had a single positive sputum/cough swab without concomitant positive nose swab. Prevalence of nasal colonization among 193 household contacts was 26.9%. There was no difference in S. aureus detection percentages after taking one nasal swab versus three nasal swabs with 2 h intervals (25.5% versus 28.4%; P = 0.649).
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Macrolide resistance among CF S. aureus was 69.6%; 75% of these isolates were inducible or constitutive clindamycin resistant. Prevalence of macrolide-resistant S. aureus among household contacts was not significantly higher than in the control population (9.6% versus 6.3%; P = 0.358). No methicillin-resistant S. aureus was detected among CF patients and household contacts.
Macrolide use among household contacts with macrolide-resistant S. aureus in the previous 2.5 years was 40%; use among household contacts with macrolide-susceptible S. aureus was 8% [Fisher's exact test P = 0.087; OR 8.2 (0.966–69.9)]. All five household contacts colonized with macrolide-resistant S. aureus shared the household with a CF patient colonized by macrolide-resistant S. aureus either continuously or intermittently during last year.
spa-genotyping (Figure 1) demonstrated sharing of isolates between non-CF household contacts (non-CF siblings and parents, no.s 6, 11, 34). No sharing of isolates within one household between CF patients and non-CF contacts was revealed except for one household (no. 46), probably indicating transmission of macrolide-resistant S. aureus between CF patient and household contact.
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Discussion |
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We did not observe an increased prevalence of macrolide-resistant S. aureus colonization among a large group of household contacts of CF patients with maintenance macrolide use and regular hospital visits. On the basis of the risk factor data from methicillin-resistant S. aureus prevalence studies,12 we expected an increased prevalence of macrolide-resistant S. aureus in household contacts of CF patients regularly.
These findings suggest that transmission of macrolide-resistant S. aureus or mobile genetic elements carrying resistance genes from CF patients to household contacts is limited. spa genotyping demonstrated no concordance between CF and household isolates in all households except one. Accordingly, we did not observe identical resistant and non-resistant isolates within one household. The latter might occur when resistance is lost after transmission and antibiotic pressure has disappeared in the household contact. However, we did not expect this because expression of macrolide resistance genes in staphylococci is able to last for a prolonged time in the absence of continuous antibiotic pressure,7,8 and continuous contact occurs between CF patients and household contacts. In contrast, transmission from CF patients to household contacts may likewise occur, as was proved in case 46 (Figure 1). Yet in the majority of household contacts, bacterial competition with susceptible S. aureus isolates might protect for colonization with resistant isolates, as was described for methicillin-resistant S. aureus.15
We did not investigate transfer of mobile genetic elements as the prevalence among household contacts was not significantly higher than in the control population. In addition, colonization with macrolide-resistant S. aureus was associated with macrolide use in the previous 2.5 years in household contacts.
Some small contrasts exist between the study and control groups. The prevalence of macrolide-resistant S. aureus colonization in the nationwide study was somewhat lower, however not significant. This control group mainly consisted of adult participants, whereas in the present study, the majority of household contacts were children. Staphylococcal colonization rates are higher in young children;10 additionally, young children more frequently experience respiratory infections, thus having a higher a priori chance of previous macrolide antibiotic therapy. Clinical S. aureus isolates from our hospital are macrolide resistant in 9% to 10%, corresponding to the prevalence in our study group.
The prevalence of nasal S. aureus in CF patients was lower than among household contacts and another CF group previously described. Goerke et al.9 estimated nasal colonization in 29% of CF patients with antibiotic use in the previous 4 weeks; 66% of patients without antibiotic use were colonized. Probable reasons for the lower prevalence in our study group are long-term exposure to antibiotic treatment and presence of chronic respiratory P. aeruginosa colonization, competing with S. aureus colonization.
The present outcome of macrolide-resistant S. aureus prevalence in household contacts differs from the prevalence in other parts of the world. In two studies from the USA, a prevalence of 26% in a student community and 32% in a more open population was observed.2,10 The contrasts can be attributed to a very low frequency of methicillin resistance and a limited antibiotic usage. Both are the result of effective control of nosocomial infections and strict antibiotic policy in the Netherlands.
In conclusion, no increased colonization with macrolide-resistant S. aureus could be established among household contacts of CF patients on maintenance azithromycin therapy. From these data, it seems that antibiotic use is a higher risk factor for macrolide-resistant S. aureus colonization than transmission from a macrolide-resistant S. aureus carrier.
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None to declare.
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Acknowledgements |
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We want to thank Dr R. Willems and M. Asbroek for their assistance with spa-typing and Dr E. E. Stobberingh for kindly providing national data on S. aureus carriership and resistance.
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References |
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3
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14
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