94 Chapter 5 Both tolerance and persistence have been reported in low-level ciprofloxacinresistant E. coli, allowing to survive exposure to therapeutic concentrations of ciprofloxacin [24]. In tolerance, bacterial cells survive using a “hibernation mode,” in which the cell cycle and metabolism are temporarily stopped, preventing killing by antibiotics. In persistence, a bacterial subpopulation is able to survive antibiotic exposure [25]. Cross-tolerance to multi-drugs has been reported, but does not necessarily occur in all tolerant isolates and is dependent on antibiotic regimen and duration of exposure [26]. To the best of our knowledge, no studies have reported cross-tolerance in low-level ciprofloxacin-resistant S. aureus isolates to the antibiotic regimens in MRSA eradication used in this study. Therefore, the explanation for the association found in our study remains uncertain. Potentially, healthcare-associated MRSAs are more prone to failure of eradication treatment, and ciprofloxacin resistance may be a biomarker for these difficult-to-treat lineages. The recent finding of association between chp and carriage duration was not found in our study [8]. Compared to the Danish study, our patient population had more healthcare-associated MRSA. Also, there is large heterogeneity in the Danish and Dutch MRSA treatment guidelines. The main difference is the more general use of two systemic antibiotics in the Netherlands, compared to sporadic systemic treatment in Denmark. Two studies, in Denmark and Sweden, reported that PVL-positive isolates had a higher eradication success rate [15, 27]. We also found a higher (non-significant) rate of PVL-positive isolates in the successful eradication group, mainly belonging to the CA-MRSA linages ST30 and ST8-t008. However, associations do not necessarily reflect an etiologic cause, but can also reflect markers or confounders. We postulate that PVL is a marker of certain non-healthcare-associated MRSA lineages that are easier to eradicate, rather than a direct positive effect of the PVL toxin to eradication outcomes. There are multiple factors of potential influence on MRSA eradication outcome. Carriers can reacquire MRSA isolates from contamination in their environment, or by positive household members. The eradication treatment of patients in this study was performed in a specialized outpatient clinic setting, following the Dutch eradication protocol [16]. Several measures are taken to prevent reacquisition, such as simultaneous treatment of positive household members and hygienic instructions. Isolate characteristics may also play a role in the risk of spread and reacquisition of MRSA. Hetem et al. showed that in a hospital setting, the transmission of livestockassociated MRSA was 4.4 times lower compared to non-livestock-associated MRSA isolates [12]. In general, MRSA isolates can be able to survive antibiotic exposure, despite having a MIC indicating susceptibility to the antibiotic agent. Our study showed that the antibiotic treatment failure is not explained by the common
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