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Deep blue: macrolide-naive resistant, green: clarithromycin-containing eradication-naive but other macrolide treatment exposed resistant, light blue: resistant with a history of Helicobacter pylori eradication with a clarithromycin-containing treatment regimen.
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Full size image Primary and secondary resistance defined by prior Cla eradication According to the common definition of primary Cla-res in gastroenterology, the proportion of resistant patients with no prior history of clarithromycin-containing eradication treatment was Resistance mutations were found in Table 2 Clarithromycin resistance rates of H.
Full size table Primary and secondary resistance defined by any prior macrolide use Compared to the above approach, a definition of primary Cla-res that excluded any prior macrolide consumption found a significantly reduced percentage, as only 5.
However, Analysis of primary and secondary resistance rates A significant sex difference was found in eradication-naive resistant cases: In contrast, no significant difference was found between macrolide-naive females and males when primary Cla-res rates were assessed by considering all prior macrolide consumption Table 2.
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However, in the macrolide-exposed group, women showed a significantly higher prevalence of Cla-res than men Table 2with higher average numbers of macrolide-dispensing occasions and boxes dispensed per person 3. A significant difference was observed between rates of eradication-induced and other macrolide-treatment-related secondary resistance Table 2. Regarding the latter, clarithromycin therapy for purposes other than H.
The difference between secondary resistance rates observed after eradication and non-eradication use of clarithromycin was statistically significant Mathematical modeling of the transmission dynamics of H.
Assuming that a heteroresistant infected individual exposes the infectee to both resistant and susceptible H. By applying the results of the model to the 5.
Table 3 Parameters and results outputs of the mathematical model. Full size table Fig. The results of the retrospective cohort analysis are framed in light blue.
The conclusions of the constructed epidemiological model are framed in light red. The sources of primary resistance cases were inferred from the epidemiological model.
Colors of the pie charts: Cla-resistant — light red, Cla-susceptible — light blue, No previous eradication therapy — dark cyan, Previous Cla eradication therapy — light brown, Macrolide-naive primary resistant — lavender, Non-eradication-purpose macrolide-exposed - dark blue, Spontaneous mutation — green, Transmission of resistant bacteria — light red.
Colors of the pie chart: Cla-susceptible bacteria — light blue, Cla-resistant bacteria — light red. Colors of the pie charts: Previous Cla eradication attempt — light brown, Infection with resistant type — light red, Spontaneous mutation — green, Other macrolide use — dark blue.
Full size image We have also modeled the effect of discontinuing macrolide use for indications other than H. With the current rate of macrolide consumption, we predict an increase of approximately 0.
The model shows a noticeably slower long-term growth rate of Cla-res prevalence among infected individuals with the discontinuation of non-eradication-purpose macrolide use green line than with the current situation with a constant level of macrolide consumptionin which the model predicts a more rapidly increasing rate of Cla-res infections red line.
Full size image Discussion We conducted one of the largest studies on Cla-res H. We established a mathematical model to characterize the transmission dynamics of Cla-res H. Primary Cla-res of H. However, this approach has several limitations. Clarithromycin is used to treat various other bacterial infective diseases, which may lead to Cla-res of H. This bystander selection unintended selection of resistant H. Nevertheless, most of the previously published studies on the epidemiology of Cla-res have used jacquemet eric svájc anti aging definition of primary resistance because the prior antibiotic consumption of the patients for non-eradication purposes is frequently unknown.
Some authors have assessed macrolide consumption at the population level by using antibiotic sales data 1619which is not appropriate for revealing acquired Cla-res in individual cases. Others asked patients to list prior antibiotic treatments or reviewed their medical records where available from treating hospitals, outpatient clinics, and family doctors 1625 However, human memory is prone to substantial gaps and errors Moreover, antibiotic treatment data from individual treatment sites do not necessarily cover all possible sources of antibiotics; therefore, these inaccurate approaches commonly ignore the use of macrolides for non-eradication purposes.
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We found an overall H. Based on the common definition best anti aging cream 2021 uk prior eradication attempt with a clarithromycin-containing regimenthe primary Cla-res rate reached The prevalence of Cla-res was significantly lower 5.
A possible role of macrolide exposure from macrolide remnants in food and water was excluded, as no macrolide traces over the threshold were detected in alimentary products in the study period personal communication with Dr.
Moreover, food processing, especially heat treatment, mostly inactivates these antibiotics Therefore, we considered these macrolide-naive but Cla-res patients to be the real primary resistance cases. However, the question arises as to how this primary resistance develops.
Some patients may acquire a Cla-res H. On the other hand, H. Previous in vitro and experimental studies have determined the frequency of spontaneous mutation to Cla-res in H. On this basis, we calculated that Cla-res bacteria continuously appear in chronic H. However, we found no published data on the prevalence of this spontaneous-mutation-induced primary resistance in the human population.
Thus, we established a mathematical model describing the population dynamics of Cla-res H. Among the macrolide-naive Cla-res patients, this model predicts the ratio of transmitted to mutation-originated resistant infections by considering several factors, e. By modeling the population dynamics of Cla-res H.
This strongly supports the idea that it is very rare for Cla-res H. Although the relative transmission fitness of Cla-res bacteria is predicted to be 0.
In another aspect, Thus, spontaneous mutation seems to have only marginal significance in the origin of primary Cla-res cases compared to the spread of resistant strains. This underscores the importance of controlling the population level of clarithromycin resistance.
We have also modeled the effect of discontinuing the use of macrolides for indications other than H. In the model, this approach noticeably slows the long-term growth rate of Cla-res prevalence compared to the current practice, whereas if the current strategy is continued with a constant level of macrolide consumptionthe model predicts a faster increase in the prevalence of clarithromycin resistance.
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In order to explain the predicted outcome of the first strategy, it is important to note that H. Moreover, the cumulative effect of transmission of the Cla-res H. Consequently, the overall result of the effects discussed above is a slower but still increasing trajectory of the prevalence of clarithromycin resistance.
This is in close agreement with the experiences in Taiwan, where a reimbursement regulation restricted the use of antibiotics from 1 February in patients with upper respiratory infection Previous studies demonstrated a strong correlation between phenotypic and FISH-detected genotypic Cla-res 34 A further advantage is that resistance status is diagnosed from morphologically identified, viable H.
Our results showed that nearly half of the resistant cases were heteroresistant.
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However, given the high prevalence of this type of resistance, further studies should clarify optimal therapeutic strategies for heteroresistant cases, in line with our recently best anti aging cream 2021 uk concept of heteroresistance In accordance with the literature 3738we found significantly higher Cla-res prevalence in females To put this into context, women in our cohort were observed to have higher macrolide consumption than men, in accordance with the literature 39 Therefore, based on our results, susceptibility testing is suggested prior to the use of clarithromycin for eradication in women under 70 years of age and men between 30 and 39 years of age in the studied population.
Conversely, considering the need for cost-effectiveness, testing is not necessarily required in adult males except those aged 30—39 years or in women older than 70 if there is no history of prior macrolide use.
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As clarithromycin-based conventional triple therapy is still the safest eradication treatment, especially with regard to side effects causing long-term changes in the gut microbiota, this therapy is worth keeping in use The prevalence of secondary resistance the Cla-res rate of the macrolide-exposed group was found to be A significant difference was found between the rates of resistance caused by eradication This was confirmed by further analyses showing that both non-eradication use of clarithromycin and treatment with other macrolides led to Cla-res less frequently Accordingly, the greatest risk factor for acquiring Cla-res is an unsuccessful eradication attempt, which underscores the need to find more effective therapeutic approaches for H.
Moreover, by minimizing the use of clarithromycin for other indications, a reduced secondary resistance rate would be achieved As other macrolides were found to cause significantly less Cla-res, replacement of clarithromycin with other macrolides or nonmacrolide antibiotics is recommended for indications other than H.
As with the majority of studies, our study also has some limitations. Our test is unable to diagnose rare Cla-res mutations or resistance caused by uncommon genetic mechanisms, which is a limitation of this study.
However, this seems to have very limited relevance, as further point mutations of the peptidyl transferase region of 23S rRNA are very rare or associated with little or no phenotypic resistance 43 Regarding the prediction of the spontaneous mutation versus transmission origins of the primary macrolide-naive resistance cases 1.
Moreover, a long time period might be necessary for the spread of resistance from one mutated bacterium in the whole bacterial population in the absence of selection pressure from macrolides.
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Thus, the sampling error no resistant bacteria in the biopsy specimen might lead to underestimation of the presence of mutated resistant bacteria and consequently the prevalence of these spontaneous-mutation-originated cases.
Our epidemiological model accounts for the most important state transitions due to infection, medication use, and emergence of resistance.
To keep the equations tractable, we made several simplifications. We assumed that infections with different Cla-res statuses share certain parameters. We ignored the best anti aging cream 2021 uk of unintended H. We assumed that spontaneous mutation and macrolide use in a host infected with wild-type Cla-susceptible H. The model also has the usual limitations of compartmental models: it assumes a homogeneous, well-mixed population and mass-action incidence.
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In conclusion, we have demonstrated an age-dependent preponderance of females in secondary acquired Cla-res of H. This resistance may be caused not only by unsuccessful eradication attempts anti aging bőr toll also by prior consumption of any other macrolide.
Conversely, the prevalence of real primary Cla-res is significantly lower among H. This type of resistance originates predominantly from transmitted Cla-res strains but occasionally from spontaneous mutations as well. In light of all this, it is highly important to identify any prior macrolide use by patients, as this increases the chance of secondary resistance to clarithromycin-containing eradication therapy.