All patients provided written informed consent for TIPSS implantation.

This study was performed in accordance with the Declaration of Helsinki and it has been approved by the local ethics committee of the University Hospital of Freiburg (no. EK 37/12).


The present study was an observational study.

Patients were analysed retrospectively from the day of TIPSS implantation.

All patients were followed-up until death or last contact.

The primary endpoint was overall sur- vival calculated from the day of TIPSS implantation.

The cut-off point for survival data was 15th of June 2013.

Furthermore, primary endpoints were efficacy and safety of TIPSS implantation in HCC patients.

In patients receiving HCC therapy, treatment response was defined as the secondary endpoint.


Continuous variables are expressed as median with range (minimum-maximum), whereas categorial vari- ables are reported as frequencies and percentages.


For continuous variables differences were determined using Wilcoxon-Mann-Whitney and Kruskal-Wallis tests, whereas v 2 tests or Fisher's Exact tests were used for categorial variables.

Differences in laboratory parame- ters before, 1 and 3 months after TIPSS procedure were 128 Aliment Pharmacol Ther 2015; 41: 126-136 ª 2014 John Wiley & Sons Ltd D. Bettinger et al. 13652036, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/apt.12994 by Mcgill University, Wiley Online Library on [18/05/2024].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License assessed using Friedman tests.

For sub-analyses of statistically significant Kruskal-Wallis or Friedman test, the Bonferroni correction was applied.

P values <0.05 were considered being significant.


OS was calculated using Kaplan-Meier analyses with death being recorded as event.

Differences in OS were calculated using log-rank tests.

Statistical analyses were performed with SPSS (Version 20.0; IBM, New York, NY, USA) and GraphPad Prism (Version 5; GraphPad Soft- ware, San Diego, CA, USA).


Table 1 summarises the demographical and clinical char- acteristics of the 40 enrolled patients at time of TIPSS implantation.

The leading aetiology of liver disease was chronic alcohol abuse (62.5%) followed by chronic hepa- titis C virus (HCV) infection (27.5%) and NAFLD (5.0%).


TIPSS implantation was performed due to ascites in 23 of 40 patients (57.5%).

In 14 of 40 patients (35.0%), TIPSS was indicated after oesophageal variceal haemor- rhage.

In four of these patients, an emergency TIPSS implantation for an acute bleeding episode was per- formed.

In all of these patients, HCC was known before emergency TIPSS implantation.

Three patients (7.5%) had treatment refractory ascites and experienced former variceal bleeding leading to TIPSS implantation.


In 13 of 40 patients (32.5%), portal hypertension was aggravated by PVT.

In 11/13 patients (84.6%) PVT was diagnosed concomitantly with HCC and tumour invasion was confirmed by computed tomography (CT) and therefore being classified as malignant PVT.

In two patients, PVT without tumour invasion of portal vein was diagnosed more than 6 months before diagnosis of HCC, so that these PVTs were described as nonneoplas- tic.

Among the patients with PVT 11/13 patients pre- sented with refractory ascites.


Sixteen patients (40.0%) were within the Milan criteria while 24/40 patients (60.0%) were outside.

Mean size of the largest HCC nodules each was 3.7 AE 1.8 cm.

In 15 of 40 patients (37.5%), HCC was located centrally.

Table 2 presents the tumour characteristics including location of HCC, the size of the largest HCC nodule and the extent of PVT in all 40 patients who were allocated to TIPSS implantation.


The shunt was successfully placed in all 40 patients.

After TIPSS implantation, portal vein pressure (PVP) decreased from median 26.5 (15-38) mmHg to 21 (10- 27) mmHg.

Portosytemic gradient (PSG) decreased from median 20.0 (13.0-33.0) mmHg to 8.0 (2-16) mmHg (P < 0.001).

After TIPSS implantation in patients with variceal haemorrhage no further bleeding episodes appeared.

Response to TIPSS was observed in 20 of 27 patients treated for ascites (74.1%, Figure S1; including the patients both with ascites and variceal bleeding).


During TIPSS implantation, no severe complications were observed, especially no tumour rupture or severe haemorrhage.

In four of 17 patients (23.5%) with oesophageal varices, TIPSS implantation was performed to control acute bleeding.

One of these patients was in a haemorrhagic shock and multi-organ failure and death occurred.

In another patient, acute renal failure developed which was rescued by conservative treatment.


Laboratory tests with regard to liver function revealed no significant impairment in liver function (Figure S2).

Indeed, INR and albumin remained stable (data not shown) whereas an increase in bilirubin levels was observed after TIPSS implantation (1.7 mg/dL vs. 2.4 mg/dL vs. 2.9 mg/dL, P = 0.018).

AST and ALT lev- els did not increase significantly.

Overall, MELD score did not change significantly after TIPSS implantation.


TIPSS insufficiency was suspected when clinical symp- toms of portal hypertension reappeared and/or when reduction in blood flow within TIPSS was diagnosed in CDUS.

Eight of 40 patients (20.0%) were diagnosed with shunt insufficiency during follow-up CDUS examination.

TIPSS thrombosis occurred in three of 40 patients (7.5%) within 30 days after TIPSS implantation.

All patients with shunt thrombosis had bare metal stents (BMS).

Only in one patient shunt dysfunction was due to tumour invasion of the TIPSS as confirmed by CT.


During follow-up, only one patient developed lung metastasis 7 years after diagnosis of HCC and 6 years after TIPSS implantation.

This patient had no invasion of portal vein and HCC was not located in central seg- ments excluding tumour cell seeding by TIPSS implanta- tion.


During the follow-up period, 36 of 40 (90.0%) patients with TIPSS implantation died.

Median OS after TIPSS implantation was 180 days (0-443.4).

30-day and 90-day survival rates were 97.5% and 75.0%, respectively.

One-year and 5-year survival rates were 42.5% and 7.5%, respectively (Figure 1).


In 34 of 36 patients (94.4%) the cause of death was progression of tumour disease.

Two patients died due to multi-organ failure after TIPSS implantation.


Patients with PVT had a median OS of 5.2 months (4.3-6.0), while OS in patients without PVT was 17 months (3.2-18.7).

This difference in survival did not reach statistical significance (P = 0.890, Figure 2).


In patients with PVT, there were no life-limiting technical complications.


After successful TIPSS implantation, 11 of 40 patients (27.5%) were treated with selective segmental or subseg- mental transarterial approaches.

These patients had preserved liver function and had sufficient portal vein flow.

Nine patients were treated with transarterial chemoembolisation (TACE), while two patients did not receive embolisation after transarterial chemoperfusion (TAC).

Treatment response was evaluated in eight of 11 patients according to the modified RECIST (mRECIST) criteria (Figure S3).

One patient showed complete remis- sion (CR), five patients had stable disease (SD) and in two patients follow-up imaging confirmed progressive disease (PD).

Overall, four patients had complications after transarterial treatment of HCC.

Two patients presented with HE and one patient each developed


Portal hypertension and HCC are common complica- tions in patients with advanced liver cirrhosis.

Portal hypertension may result in life-threatening complications such as acute variceal bleeding or hepatorenal syndrome and is therefore an important cause of morbidity and mortality in these patients.

As HCC also represents a late-stage complication of liver cirrhosis, several patients present with portal hypertension and HCC.

To date, however, no guidelines for the treatment of portal hyper- tension in HCC patients are established.


In patients without HCC TIPSS has been shown to be a minimally invasive method to treat portal hypertension and its associated complications.

15, 16, 19 However, pri- mary hepatic malignancy is considered a relative contra- indication for TIPSS implantation although relevant information does not exist to support this recommenda- tion.

To date, only few studies with small cohorts have focused on the efficacy and safety of TIPSS implantation in patients with hepatic malignancies including HCC and hepatic metastases (Table 3).

Therefore, we set out to analyse HCC patients with portal hypertension due to PVT and advanced liver cirrhosis receiving TIPSS implantation at our institution with regard to efficacy and safety of TIPSS insertion as well as OS.


First, we focused on feasibility and safety of TIPSS implantation.

Importantly, apart from SPH as a result of liver cirrhosis, we also included 13 patients (32.5%) with PVT.

These patients are of special interest as TIPSS implantation may be associated with higher rates of tech- nical failure and complications.

39, 40 In patients with liver cirrhosis and PVT, TIPSS implantation is feasible, effective and safe in selected patients.

41 However, TIPSS implantation in malignant PVT is discussed controver- sially.

In our cohort, all procedures were performed suc- cessfully and we observed no severe procedure-related complications such as tumour rupture or severe proce- dure-related complications neither in patients with PVT nor in our other patients.

These results show that severe procedure-related complications are rare in patients with HCC as long as these patients are strictly selected (pre-interventional CDUS for exclusion of portal and


One reason for the restriction to perform TIPSS pro- cedure in HCC patients is the risk of tumour seeding as TIPSS may traverse malignant tumour tissue, especially in centrally located tumours.

A hypothetical risk is the development of pulmonary metastases spreading via the portal venous system.

However, in our study, only one patient developed pulmonary metastasis 6 years after TIPSS implantation and, therefore, we did not associate this metastasis with TIPSS.

Wallace et al. examined nine patients with intra- and extrahepatic malignancies receiv- ing TIPSS due to portal hypertension.

They observed development of pulmonary metastases in two of nine patients 10 and 5 months after TIPSS implantation.

44 Liu et al. detected seven of 58 patients with metastases during follow-up after TIPSS implantation.

42 In our cohort, none of the patients with centrally located HCC developed metastases, but interpretation of these data is difficult as follow-up of our patients may have been too short (211 days) and 1- and 5-year survival rates were 42.5% and 7.5%, respectively.


Second, we evaluated efficacy of TIPSS in patients with HCC.

TIPSS was highly effective in both patients with ascites as well as bleeding and PSG decreased sig- nificantly.

Ascites has been shown to be an important negative prognostic factor in patients with HCC within the Milan criteria undergoing nontransplant therapies.

45 Therefore, it is important to control ascites in these patients and in this setting TIPSS implantation may con- tribute to improved survival.


In 20.0% of our patients shunt insufficiency occurred.

TIPSS thrombosis occurred in three patients (7.5%) within the first months after TIPSS implantation.

Wallace et al. reported a similar rate (8%) of shunt occlusion within the first 30 days.

27 More- over, Saxon et al. even observed a shunt occlusion rate of 17% within 30 days after TIPSS implantation in their cohort of 116 patients with liver cirrhosis, but without HCC.

46 Several mechanisms have been discussed that may explain this early shunt occlusion in patients with and without HCC.


Trauma of malignant and also of not-malignant liver tissue may stimulate coagulation leading to shunt occlusion and especially tumour patients may be at higher risk due to a procoagulant imbalance.

Furthermore, it is also possible that tumour may invade the shunt.

However, as no autopsies have been performed in our study cohort we cannot prove this hypothesis.

Interestingly, Saxon et al. provided evi- dence that bile duct damage during TIPSS implantation is a major cause for early shunt occlusion.

47 In summary, further prospective studies are warranted to determine the role of shunt occlusion in these patients and to eval- uate anticoagulation strategies as a preventive measure.


Third, we set out to determine the incidence of post-TIPSS HE.

In several studies, rates of HE range from 13 up to 47%.

In the cohort by Liu et al., HE occurred in 25.9% of the patients.

28 Wallace et al. even reported a rate of 44%.

27 We also observed a similar rate of post-TIPSS HE with 40.0%.

One of these patients developed severe grade IV HE and died of multiorgan failure.


Fourth, we analysed OS in our HCC patients receiv- ing TIPSS implantation.

Median OS was 180 days after TIPSS procedure.

Two patients died shortly after TIPSS procedure due to multi-organ failure.

One of these patients had TIPSS implantation to control acute vari- ceal haemorrhage, but bleeding could not be controlled sufficiently.

The other patient developed severe grade IV HE and also died of multi-organ failure.

Our median OS was significantly higher compared to the study by Liu et al. who reported a median OS of 77 days after TIPSS implantation.

28 Their 30-day survival rate was 49%.

Notably, in comparison to our study their patients had advanced tumour disease as all patients had PVT and in our cohort tumour size was significantly smaller, which contributes to our good survival.

Wallace et al. reported a 30-day survival rate of 84%.

27 Our data even showed a rate of 97.5%.

This high 30-day survival rate can be explained by strict selection for TIPSS implanta- tion in our patient cohort.

Furthermore, OS in patients with PVT was lower than in patients without PVT reflecting the more advanced tumour stage in these patients.

But, importantly, there were no technical com- plications after TIPSS implantation in patients with PVT leading to in-hospital death and in these patients prognosis was especially limited by progression of tumour disease.

Fifth, we analysed the efficacy and safety of HCC treatment after TIPSS implantation.

27.5% of patients with TIPSS were treated with transarterial therapies.

In nine patients, TACE was performed whereas the remain- ing two patients were treated with transarterial chemop- erfusion (TAC) without embolisation.

TACE takes the advantage of the hepatic dual blood supply resulting in embolisation of the tumour feeding hepatic arteries while portal venous flow to normal hepatocytes is preserved.

In a patent TIPSS, the hepatic portal venous perfusion is altered as portal venous flow is decompressed in the sys- temic circulation.

Therefore, TACE in TIPSS patients has been considered a relative contraindication as the result of hepatic ischaemia might be increased.

Although HCC derives his blood primarily from hepatic arteries, portal venous contribution is observed in some HCCs.

48, 49 This important change in the blood supply may aggra- vate tumour necrosis and therefore, TACE in TIPSS patients may be associated with increased hepatotoxicity.


In our cohort, no patients developed severe hepatotoxic- ity.

Severe complications were an episode of acute HE in two patients and the development of hydropic decom- pensation and spontaneous bacterial peritonitis, but these complications were manageable by conservative treat- ment.

These findings are in accordance with the morbid- ity and mortality rates in other studies.

50, 51 Moreover, we evaluated efficacy of transarterial treatment in our HCC patients with TIPSS.

Most of our patients had stable disease and only one patient had complete remission.

In accordance with our findings, Kuo et al. showed that the rate of complete remission after TACE is significantly higher in patients without TIPSS compared to TIPSS patients.

51 This may be due to arterioportal shunting which is common after TIPSS implantation.

52 This may have a negative effect on TACE efficacy, especially as it may divert a portion of the chemoembolic agent away from the tumour.

Overall, it is important to state that using selective transarterial approaches, TACE in TIPSS patients maybe safe and can lead to stable tumour disease.


In conclusion, we were able to show that TIPSS implantation in patients with HCC is an effective and safe procedure and selective HCC treatment after TIPSS implantation is possible and safe.

Considering the limita- tions of our study namely the retrospective design with a missing control group, the long observation period from 1995 to 2012, the small sample size and also the individ- ual decision for TIPSS implantation in HCC patients, further well-designed prospective studies comparing HCC patients with portal hypertension treated with TIPSS or standard medical treatment are needed to ana- lyse the effect of TIPSS implantation on OS in these patients cohort.


Guarantor of the article: Michael Schultheiß, MD.


Author contribution: Dominik Bettinger: study concept and design, analysis and interpretation of the data, drafting of the manuscript and statistical analysis.

Eva Kn€ uppel: acquisition of the data.

Wulf Euringer: performed the TIPSS implantation.

Hans Christian Span- genberg: study concept and design and study supervi- sion.

Martin R€ ossle: performed the TIPSS implantation and critical revision of the manuscript.

Robert Thimme: interpretation of the data, supervision of the study and critical revision of the manuscript.

Michael Schultheiß: supervision of the study, drafting and critical revision of the manuscript.

All authors approved the final version of the manuscript.


Hepatocellular carcinoma (HCC) complicating cirrhosis occurs more frequently as cirrhosis becomes advanced and therefore HCC often co-exists with significant liver dysfunction and portal hypertension.


In the widely accepted Barcelona-Clinic Liver Cancer (BCLC) staging system patients with very advanced liver disease (i.e. Child–Pugh stage C) have the worst outlook [1].


Indeed, in the early natural history studies in HCC, a significant proportion of deaths were due to complications of portal hypertension [2].


The presence of HCC, and in particular a central lesion, is considered a relative contra-indication to TIPSS though there is little evidence to indicate poor outcomes in this patient group [3].


To explore this issue further, Bettinger et al. report their experience of TIPSS in 40 patients with HCC and symptomatic portal hypertension [4].


This report, from a centre with extensive experience of TIPSS, highlights several issues with regard to indications, patient selection, and outcomes for patients with HCC.


First, patient selection was strict: only 15% of patients with HCC and symptomatic portal hypertension were selected for TIPSS.


The indications for TIPSS were frequently refractory ascites and varices though only 10% were for acute, uncontrolled variceal haemorrhage.


Although the broad criteria for selection were specified, factors considered to be absolute contraindications were not reported and perhaps surprisingly some patients with malignant portal venous involvement were treated with TIPSS.


Second, the clinical outcomes after TIPSS were acceptable, with technical success and complications similar to published data, despite most patients having bare metal TIPSS and the presence of portal vein thrombosis.


However, without stratification by BCLC stage it is difficult to determine how these patients have survived in comparison to their peers.


TIPSS may therefore have a role in the management of patients with HCC and symptomatic portal hypertension in selected cases and in experienced centres.


The use of TIPSS here appears to have been largely palliative, successfully providing control of portal hypertension and symptoms, and on occasion allowing the use of selective chemoembolization.


Any benefit in terms of survival, however, could only be inferred from further comparative studies.


With great interest, we read the editorial by Rowe and Tripathi and thank the authors for their comments concerning our paper published in the current issue of AP&T [1], [2].

Patients with end-stage liver disease are often affected by portal hypertension and hepatocellular carcinoma (HCC).

Symptomatic portal hypertension (SPH) is associated with impaired survival in HCC patients.

In our retrospective study investigating TIPSS implantation in HCC patients, we were able to show a good clinical control of SPH in HCC patients, especially in those with small HCC [2].


As the authors state correctly, our patients were highly selected and the decision to perform TIPSS implantation was made on an individual basis.

Due to the retrospective design of our study, it was not entirely possible to evaluate the absolute contraindications in patients with HCC and SPH who were not allocated to TIPSS implantation.

However, main contraindications included uncontrolled tumour growth and poor performance status of a given patient, but absolute and relative contraindications need to be clearly defined in further studies.

Indeed, another important issue to be investigated will be the role of TIPSS implantation in patients with malignant portal vein thrombosis in HCC patients.


Furthermore, Rowe and Tripathi point out that it will be important to stratify these patients according to the BCLC classification to determine overall survival.

We fully agree with this comment and indeed further studies are needed that include a control group of HCC patients with SPH, who are therefore treated with medical or endoscopic treatment.

In our opinion, it will be important to focus on patients with BCLC A suffering from SPH and are therefore not allocated to curative surgical resection.

TIPSS may resolve SPH and thus, these patients may be allocated to surgery.

Further prospective studies including a control group should focus on this important issue.


In summary, our retrospective observation study highlights several important points and clinical relevant aspects, which can be evaluated in further well-designed prospective studies.


The introduction of continuous glucose monitoring (CGM) represents one of the most important advancements within diabetes treatment and self-management over the last decades.

CGM provides easy access to current glucose levels, glucose trends, and the retrospective analysis of glucose excursions, thus facilitating easier and better diabetes management for both people living with diabetes (PLWD) and health care professionals.

As a result, PLWD using CGM technology show improvement in HbA1c, glucose variability, hypoglycemia prevalence, overall well-being, and treatment satisfaction and have less fear of hypoglycemia compared to SMBG [1-3].


One critical issue with this technology remains the quality of the accuracy of glucose measurements, even though vast improvements in this regard have become evident over the last years [4-7].

Nevertheless, most current CGM have already reached accuracy levels of SMBG and are, therefore, labeled for nonadjunctive use by regulators, meaning that CGM can be utilized for treatment decisions without the subsequent SMBG confirmation [8-11].

Furthermore, as CGM enables easy assessment of the time spent in target range (TIR), which has been shown to be a valid marker of glycemic control alongside HbA1c, there has been an evolution of individual treatment guidelines for CGM use with a focus on TIR [12].

However, further improvement in CGM accuracy, particularly in the hypoglycemic range, is crucial for the development of reliable diabetes technology, especially for automated insulin delivery systems, as well as for reducing the burden of diabetes management for PLWD.


Another key aspect of CGM technology that is crucial to adherence is comfort in both wearing and inserting the sensor.

Registry data show that wearing discomfort is the Biosensors 2022, 12, 106.

https://doi.org/10.3390/bios12020106 https://www.mdpi.com/journal/biosensors prevailing factor for CGM discontinuation [13].

Therefore, new developments in diabetes technology aim to reduce discomfort in diabetes management and, thus, facilitate better quality of life with diabetes.


As CGM technology is made available to a growing number of PLWD, the negative impact on the environment and natural resources increases due to the use of disposable products and accumulation of plastic and medical waste, including hazardous parts such as insertion needles.

This problem is increasingly being addressed not only by environmental organizations but also by users of diabetes technology and patient organizations.

There- fore, the Diabetes Technology Society started its Green Diabetes Initiative to promote the development of medical devices in terms of sustainability and reduce the environmental impact associated with advancements in diabetes technology [14].


In the present analysis, we aimed to assess the accuracy and usability of a novel CGM system that is the first to feature predominately reusable components with needle- free insertion.


In this monocentric, open-label, non-randomized, single-arm clinical study, eight in dividuals with type 1 diabetes were equipped with two sensors of the GlucoMen ® Da CGM system (Waveform Cascade, A. Menarini Diagnostics, Florence, Italy; Figure 1) t wear at home.

This novel CGM features a needle-free insertion system containing a single use, disposable sensor, the reusable transmitter to be recharged after 14 days of use (fo up to 5 years), the reusable sensor insertion tool (for up to 5 years), the transmitter charg ing unit with a USB port, and the GlucoMen ® Day App supported by Android and iO devices allowing for viewing glucose levels and trends, for calibrating the system, and fo setting alarms.


The sensors were simultaneously inserted into the subcutaneous adipose tissue o the opposite sides of the lower abdomen and worn for 14 days.

Additionally, participant were requested to calibrate the CGM devices once daily and perform 8-9 finger-prick glu cose tests per day (GlucoMen Day METER, A. Menarini Diagnostics, Florence, Italy).


The primary objective was to assess the device's accuracy compared to a laborator reference instrument (YSI 2300, Yellow Springs, OH, USA).

The secondary objectives in cluded comparing CGM to SMBG and a precision assessment by evaluating the agreemen between the two sensors worn in parallel.

Additionally, a usability assessment includin a 10-item questionnaire with an ordinal rating scale asking about insertion pain, adhesiv adherence, problems with calibration, reliability of readings, usability of and satisfactio with the mobile application, device wearability, and overall experience was performed.


On days 4 and 10 of the study, a 5-h meal and insulin challenge was performed at the research center.

Each participant consumed a standardized meal containing 100 g of carbohydrates and received an increased insulin bolus (the regular bolus insulin dose plus 20%) subcutaneously.

Venous plasma and capillary blood samples were collected simultaneously every 20 min.

Plasma glucose was measured on site with YSI, while SMBG was performed using the study-specific BG meter.


CGM accuracy was assessed by calculating MARD, MAD (mean absolute difference), Median ARD, Median AD, and CEG for both CGM/YSI and CGM/SMBG matched pairs.

Following a frequently used approach in glucose monitoring system accuracy evaluations, MARD (and median ARD), as a percentage error, was calculated for glucose above the 100 mg/dL threshold only (i.e., values in the 100- to 400-mg/dL range), while, for the lower glucose values (ranging from 40-99 mg/dL), it calculated the absolute error as MAD (and median AD) [15,16].

The lag time between CGM and blood glucose data was determined for each sensor and applied prior to calculating MARD and MAD.

The lag time was calculated as the shift in time that provided the best CGM/reference correlation, using the Poincarè method (time shift giving the best R 2 vs. references), and was adjusted for SMBG and YSI data and for YSI data individually for each sensor.

The average lag time was calculated as the weighted average (based on the respective N of data) of the lag time of all the sensors.

All statistical analyses were performed following the intention-to-treat principle.


Eight adult participants (3 females (37.5%), age 41.6 ± 13.3 years, BMI 28.0 ± 6.1 kg/m 2 , HbA1c 55.6 ± 12.2 mmol/mol, diabetes duration 13.9 ± 6.5 years) completed the study.

During the study period, on average, 94.4% of the theoretically possible data was collected and used for analysis after applying the exclusion criteria for data recording (estimated CGM signal).


Overall, the 450 CGM/YSI matched pairs available for analysis were generated from glucose data collected within the range of 40-400 mg/dL. This resulted in a MARD of 9.7 (±9.4)% and a MAD of 20.5 (±18.7) mg/dL, as summarized in Table 1.

By analyzing specific glucose ranges, it was observed that sensor accuracy as assessed by MARD was better in the 201-400-mg/dL range compared to the 100-200-mg/dL range (6.1% vs. 10.7%), while MAD was lower in the 40-70-mg/dL range compared to the 71-99-mg/dL range (19.5 vs. 20.9 mg/dL).

Furthermore, both MARD and MAD were lower on day 4 compared to day 10 (7.4% vs. 11.4% and 17.7 vs. 27.3 mg/dL).

CEG analysis showed that 84.9% of CGM/YSI data pairs was in the clinically acceptable zone A, while the combined percentage for zone A and B was 97.8.

CEG is displayed in Figure 2a.


During sensor use at the research center and at home, a total of 1957 CGM/SMBG matched data pairs were collected in the range of 40-400 mg/dL. The overall MARD was 13.1 (±12.8)% for values between 100-400 mg/dL, while the MAD for glucose values between 40-99 mg/dL was 16.6 (±16.8) mg/dL, as summarized in Table 1.

Similar to what was observed for YSI, the MARD and MAD were lower in the higher glucose range (13.4% for 100-200 mg/dL vs. 12.2% for 201-400 mg/dL and 20.2 mg/dL for 40-70 mg/dL vs. 15.2 mg/dL for 71-99 mg/dL), while the CEG analysis showed a combined percentage of 98.2 for zones A and B (Figure 2b).


Glucose values recorded by the two sensors worn in parallel were evaluated using mean ± SD and coefficient of variation (CV) for each participant.

An average SD of 11.1 mg/dL and an average CV of 9.7% were observed, demonstrating acceptable agreement between the two sensors.


The participants were requested to complete a questionnaire containing 10 questions with an ordinal five-scale answer rating.

When asked about pain perception at insertion, 50% stated that the procedure was painless and 25% claimed it to be less painful than finger pricking.

The remaining 25% found the insertion as painful as routinely used SMBG (12.5%) or more painful than finger pricking (12.5%).

There was also predominant satisfaction with sensor adhesive, wearability, calibration procedure, and user-friendliness of the dedicated mobile application.

The results of the usability assessment can be found in the supplementary appendix (Figure S1).


High CGM accuracy is crucial for good diabetes management, especially when CGM readings are used for insulin dosing both alone or in combination with open/closed-loop systems.

Accurate readings are also essential for precise calculations of time in range (TIR), a parameter that has become increasingly popular for treatment decisions and the overall assessment of glycemic control.

By modeling the 7-point glucose profiles collected in the DCCT (Diabetes Control and Complications Trial), it was shown that TIR was strongly associated with development of microalbuminuria and retinopathy progression, suggesting that it represents a valid surrogate indicator of microvascular complications [17].


So far, MARD has been commonly used to assess overall CGM accuracy, while MAD is used to assess accuracy in the low glycemic range.

Good CGM performance is generally assumed in systems with an overall MARD < 10%, although analytical performance cannot be fully assessed by a single parameter [18].

In the present analysis, the GlucoMen ® Day CGM achieved a MARD of 9.7% compared to YSI during meal/insulin challenges (with one daily calibration), while compared to SMBG, a MARD of 13.1% was obtained over the 14-day wear period.

The higher MARD calculated for SMBG may result from lower accuracy associated with glucose meters compared to laboratory reference.

This finding is often seen during assessment of CGM devices at home [19-21].

The results of the present analysis are comparable to those obtained for other CGM systems such as the real-time (rt) CGM G6 (Dexcom, San Diego, CA, USA) with a MARD of 9.9% or the intermittently scanned (is) CGM systems Freestyle Libre 1 and 2 (Abbott, Chicago, IL, USA) with respective MARDs of 12.0% and 9.2% in adults compared to YSI [22-24].


Furthermore, similar to earlier findings in CGM systems, there was an increase in MARD/MAD in the low glycemic range while accuracy was higher in hyperglycemic ranges [25-27].

Since this effect was more pronounced during the meal challenges in our analysis, it can be assumed that the assessed CGM system is more accurate following post- prandial glucose excursions.

Interestingly, MAD was slightly lower in the 40-70-mg/dL range compared to the 71-99-mg/dL range, suggesting an increased or at least stable accuracy in relevant hypoglycemia, whereas other CGM systems show an impaired ac- curacy when BG levels drop below 70 mg/dL [22,25,27].

Given the fact that most CGM systems are prescribed due to impaired hypoglycemia awareness, CGM accuracy in hypo- glycemia is essential for giving a timely warning and taking adequate countermeasures to avoid hypoglycemia.


In addition to MARD/MAD as measures of numerical accuracy, clinical accuracy, as expressed by CEG, should also be evaluated to support the sensor performance data and should be favored over Clarke Error Grid or Continuous Error Grid analysis [15].

In our study, the CEG analysis showed 98% of all data pairs in the clinically relevant zones A and B for both reference methods, thereby verifying the clinical accuracy of GlucoMen ® Day.

For comparison, the CEG analysis of Freestyle Libre 1 and 2 showed a respective 99.7% and 99.9% of matched pairs in zones A and B [23-25].


Advancements in diabetes technology have so far drastically decreased the burden for people with diabetes.

The reduction of painful procedures associated with diabetes management improved quality of life and facilitated good glycemic control [28-30].

The replacement of SMBG and introduction of CGM in pediatric patients with diabetes was a crucial advance in reducing finger pricking.

However, especially in young children, sensor insertions are reported to be one of several barriers of this technology regardless of the significant advances of CGM use for children and parents in diabetes management [31].

Further reduction of painful procedures may lead to increased adherence in CGM users, which is known to be age-dependent and especially poor in adolescents [32].


In the present analysis, the CGM system with needle-free insertion intended for ages 6 and above resulted in high user satisfaction in the majority of users claiming the insertion procedure to be painless or less painful than finger pricking.


An important innovative feature of GlucoMen ® Day CGM is reusability of most components, resulting in reduced environmental impact.

The wish for reducing the ecological footprint of diabetes technology is frequently expressed by users and patient organizations, especially in the face of the present climate crisis.

Common CGM insertion systems often include bulky, disposable applicators that contribute to a substantial increase in plastic and potentially hazardous medical waste accompanied by a significant amount of packaging waste.

This represents a rising problem worldwide and is fueled by the, per se, favorable, increasing availability of CGM.

Looking at data from the DPV (Diabetes Patienten Verlaufsdokumentation) and the T1D exchange registry, CGM use in type 1 diabetes increased from 6% in 2011 to 38% in 2018 [33].

In absolute numbers, CGM use is presumably even higher due to its prevalence in type 2 diabetes and is expected to grow due to increasing reimbursement by healthcare providers.

The growing ecological burden associated with diabetes technology is already acknowledged by the scientific community and is subject to ongoing discussion [14,34].


GlucoMen ® Day CGM includes a rechargeable transmitter and a reusable needle-free sensor insertion applicator, both of which can be used for up to 5 years.

Due to reduced insertion pain and reusable components, this and similar systems can help promote sustainable diabetes technology and stimulate other positive developments in this sector, such as biodegradable components.

Therefore, regulatory bodies should aim to establish rules for design and development of diabetes technology with reusable components that meet medical needs and are environmentally friendly.

Additionally, waste reduction should be accounted for in cost-effectiveness calculations and reimbursement strategies for such products.


The present analysis suggests that the GlucoMen ® Day CGM is a user- and environ- mentally friendly system that meets the current clinical requirements for state-of-the-art CGMs.

The reduced ecological impact of this needle-free system has to be emphasized and may support further advances in sustainable diabetes technology.


In their recent article entitled “Accuracy Assessment of the GlucoMen® Day CGM System in Individuals with Type 1 Diabetes: A Pilot Study” [1], Hochfellner and colleagues presented the results of an accuracy and usability evaluation of a novel continuous glucose monitoring (CGM) system.

While we appreciate the importance of assessing the accuracy of CGM systems, we would like to comment on certain aspects of the data analysis, presentation of results and conclusions.


In the section describing the data analysis (Section 2.2), it is stated that “the lag time between CGM and blood glucose data was determined for each sensor and applied prior to calculating MARD and MAD”, where MARD and MAD are common accuracy parameters representing mean absolute relative and mean absolute deviation between CGM and comparator measurements, respectively.

This correction of lag time before accuracy determination was common in microdialysis-based systems [2,3] or for prototype CGM systems [4].

However, in market-ready CGM systems intended to provide real-time glucose data such as the system examined in the article, the accuracy should be evaluated with respect to the CGM values displayed to the user.

The effect of the lag time correction on the reported accuracy parameters cannot be assessed because neither the average lag time mentioned in Section 2.2. nor MARD and MAD results before lag time correction are presented.

In general, however, a lag time correction leads to a reduction in MARD and MAD.


Regarding the MARD, it should be pointed out that for its calculation, only glucose levels ≥100 mg/dL were used (Table 1), whereas for glucose levels <100 mg/dL, MAD results were presented.

This is an important detail missing from the abstract and the discussion, where MARD results were reported.


As a consequence of choosing to correct for time lag and to use only glucose levels ≥100 mg/dL for MARD calculation, we would argue that the accuracy results reported in the article cannot be compared to the cited findings of CGM performance studies without lag time correction and MARD results determined across the full glucose range [5–7].

Another aspect of the reported study that impairs the comparability to previous results is the low sample size of eight subjects, which is not discussed.


Due to these differences in methodology between this and other studies, we therefore question the validity of the conclusion that the “analysis suggests the GlucoMen® Day CGM [ . . . ] meets the current clinical requirements for state-of-the-art CGMs”.


We thank Dr. Freckmann et al. [ 1] for the comment and for the detailed review of our data.

Referring to the first point about the correction of lag time, we agree that the chosen approach has some limitations in the interpretation of the results.

This aspect can be discussed together with the second point concerning mean absolute relative difference (MARD) data representation.

The main aim of this study was to conduct an evaluation of the GlucoMen® Day CGM system, which had recently been launched on the market by A. Menarini Diagnostics based on available data related to the CE registration study.

For this reason, we limited the number of enrolled participants to just eight, resulting in limited statistics, and the methods and metrics for analysis were chosen according to the same methods used in the system CE registration study [2].

Thus, actually, the results met the predefined accuracy criteria of the trial, but we can agree that they cannot be consistently compared with other research on CGM accuracy assessment.


In order to avoid any confusion, such results can be better clarified as follows: when comparing CGM to PG, the MARD for values ≥ 100 mg/dL was 9.7 [2.6–14.6]%.

The MARD for values ≥ 100 mg/dL for CGM vs. SMBG was 13.1 [3.5–18.6]%.

The mean absolute difference (MAD) for glucose values < 100 mg/dL was 20.5 ± 18.7 mg/dL (vs. PG) and 16.6 ± 16.8 mg/dL (vs. SMBG).

The preference of MAD for lower glycemic intervals has mainly a mathematical reason: the relative (percentage) bias between a measurement and its reference increases the lower the reference value.

Based on this principle, for example, ISO 15197:2015 for BGMs specifies to use an absolute bias for values below 100 mg/dL and % bias at values higher or equal to 100 mg/dL. Such considerations are also widely discussed in the literature [3].

Therefore, also given the small sample size of this study, MAD was considered to be more appropriate for lower glucose concentration ranges, while the chosen cut-off of 100 mg/dL was derived for comparison purposes with available data for this system and other CGM studies [2,4].


To conclude, the present analysis confirmed that the GlucoMen® Day CGM is a user- and environmentally friendly system with performance in line with previously reported accuracy criteria.

In future studies, the system will be more extensively evaluated based on current metrics to determine whether it meets the clinical requirements for state-of-the-art CGMs and user expectations.


The ecologic niche for S. aureus in humans is in the anterior nares, where S. aureus can be identified most consistently in humans [27].

One-quarter to one-third of healthy persons har- bor S. aureus in the nose at any time [27].

Although S. aureus can also be found on the skin or in the rectum or vagina, the nose appears to be the primary reservoir for replication and spread to other bodily sites.

This idea is supported by studies that have revealed that, if S. aureus nasal carriage is temporarily eliminated by use of an intranasal topical antibiotic (e.g., mu- pirocin), colonization often simultaneously disappears from other colonized body sites [28].

Nasal S. aureus isolates are often identical to strains that later cause clinical infection, as assessed by PFGE [29, 30].


The proof of principle demonstrating the importance of nasal colonization's role in the pathogenesis of S. aureus infection is that, when colonization is eradicated, the risk of clinical infec- tion is lowered [27].

This observation has spurred attempts to eradicate S. aureus from the nose to prevent infection among high-risk groups.

Unfortunately, nasal decolonization strategies have limitations.

Short-term eradication is generally successful, but patients are often later recolonized with the same strain [26, 28, 31].

This suggests that recolonization from sources exogenous to the nose can occur.

Another limitation is that recolonizing strains are sometimes resistant to the previously used intranasal topical antibiotic [32].


To illustrate, 2 outbreak investigations of CA-MRSA infec- tions in football teams revealed that the responsible CA-MRSA clone was not found in the nares of infected players, uninfected teammates/staff, or the environment [7, 33].

This suggests that the strain was acquired from a nonnasal endogenous source or an environmental source.

An investigation of community- dwelling rural Alaskans with CA-MRSA infection found that the majority of cases of S. aureus disease (185%) were caused by MRSA, but most nasal colonizations (67%) in infected per- sons, household members, and uninfected control subjects in- volved MSSA [34].

Taken together, these studies suggest that CA-MRSA infection was not "the tip of the iceberg" that rep- resented a clinical progression of massive background coloni- zation.

Instead, the findings suggested that CA-MRSA nasal colonization, while uncommon, could be associated with an uncommonly high risk of CA-MRSA infection.

Alternatively, CA-MRSA could be acquired from nonnasal body sites or con- taminated environments.


Data on CA-MRSA infection among MSM-especially HIV- infected MSM-have provided additional insight into the role of colonization in CA-MRSA infection.

CA-MRSA infection among MSM has been associated with high-risk behaviors, in- cluding use of methamphetamines and other illicit drugs, high- risk sexual behavior, use of the Internet to find sexual contacts, occurrence of skin-abrading sex, and history of sexually trans- mitted infections [10, 35-37].

CA-MRSA infection often occurs at sites in which skin-skin contact occurs during sexual activ- ities.

In one investigation, 32 (27%) of 118 MSM in San Fran- cisco, California, and 47 (39%) of 121 MSM from Boston, Massachusetts, had CA-MRSA infection involving the buttocks and/or genitoperineal sites [38].

Others have reported the oc- currence of CA-MRSA infection in the buttocks and genito- perineal sites associated with heterosexual sexual activity [39].

The high disease burden involving buttocks and/or genitoper- ineal sites caused by CA-MRSA suggests that CA-MRSA strains may be transmitted during sexual contact as a result of direct skin-skin contact and may even be considered to be an agent of sexually transmitted infection.


Another investigation has shed light on the pathogenesis of CA-MRSA in MSM.

In a point prevalence study of MRSA colonization among community-dwelling HIV-infected MSM (among whom CA-MRSA infections occurred frequently), na- sal MRSA colonization was uncommon (7 [4%] of 158 MSM); it was relatively uncommon when compared with MSSA col- onization (36 [23%] of 158 MSM) [40].

Among the 6 patients with recent, prior MRSA infection, only 1 was colonized with MRSA, suggesting that nasal colonization may have only a modest role in infection pathogenesis and that the CA-MRSA infection was acquired via other routes.


Other data support the role of nonnasal colonization in the pathogenesis of CA-MRSA.

One investigation of 65 patients with acute CA-MRSA infection found that 40% were colonized with MRSA and that the prevalences of MRSA colonization in the nares, axilla, inguinal area, and rectum were 26%, 8%, 20%, and 15%, respectively [41].

In contrast, in 35 subjects with acute CA-MSSA, HA-MRSA, or HA-MSSA infection, nonnasal S. aureus colonization was rare (3% of subjects).

This suggests that colonization patterns in CA-MRSA infection may be dis- tinct from the patterns of traditional S. aureus infection and thus play a role in, for example, the sexual transmission of CA- MRSA.


Outbreaks of CA-MRSA infection have repeatedly occurred among athletes.

In these outbreaks, players are believed to spread the infection through repeated skin-skin contact, es- pecially contact between broken skin, which occurs in games and practices [33].

In theses outbreaks, CA-MRSA infection was associated with exposures to various contaminated fomites, including whirlpools, shared razors, and shared towels [7, 33].

Other fomites implicated in outbreaks of sports team-associ- ated CA-MRSA infection include benches, body suits worn by fencers, and even a bar of soap [6, 33, 42].

In non-sports team outbreaks, sauna benches have been implicated [34].

In non- outbreak settings, close contact with a person who has a skin infection was also associated with CA-MRSA infection [43].

Because S. aureus can colonize commonly touched household objects, such as toilet handles, doorknobs, and kitchen sinks [44], it is feasible that households can serve as reservoirs for CA-MRSA strains and may play an important role in recurrent infections that can plague households [20, 21, 23].


Environmental sources of S. aureus as a cause for infection are not new or unique to CA-MRSA infection.

In hospitals, S. aureus and MRSA have been isolated from stethoscopes, pagers, bed spaces, workstations, and other places [45-47].

Aggressive control of MRSA strains in the environment has contributed to effective strategies to prevent MRSA infection.

For example, in The Netherlands, the so-called "search-and-destroy" policy has minimized HA-MRSA infections to such a degree that they have become uncommon, and the rate of HA-MRSA in The Netherlands is far below the rates in neighboring countries [48].

One key component of the search-and-destroy method is ag- gressive environmental (hospital ward) cleaning, in which wards where MRSA has been isolated are closed and extensively cleaned [49].

Although the reason behind the success of the search-and-destroy method is almost certainly multifactorial (e.g., it also involves aggressive screening and decolonization of patients and health care workers, among other measures) [49], its heavy emphasis on environmental decontamination may be a key component.

Its success compared with other MRSA control measures lends credence to the notion that en- vironmental sources are an important component of MRSA pathogenesis.


Clearly, the dynamics of community living differ markedly from the dynamics of health care settings.

On the basis of CA- MRSA outbreak data, it is possible that infection pathogenesis relies much more on acquisition from environmental sources and less on antecedent nasal colonization.

In fact, a conceptual model of CA-MRSA transmission highlights noncolonization routes of CA-MRSA acquisition.


This model, the "Five Cs of CA-MRSA Transmission" [50, 51], was developed by the Cen- ters for Disease Control and Prevention and suggests that MRSA infection results from the following constellation of risks: (1) contact (direct skin-skin contact); (2) cleanliness; (3) compromised skin integrity; (4) contaminated objects, surfaces, and items; and (5) crowded living conditions.

Some have added a 6th "C": exposure to antibiotic capsules (and tablets, liquids, etc.) on the basis of data that prior antibiotic use is a risk for CA-MRSA acquisition [33, 34, 52].


The 5 Cs model is impor- tant in that it helps explain CA-MRSA infections found in outbreak situations.

This model's role outside of outbreaks may not be as clear, because crowding living situations may not play a major role (e.g., New York City, to date, has experienced a relatively low rate of CA-MRSA infection) [53].

Taken in sum, data from outbreaks of CA-MRSA infection and from endemic infections suggest that antecedent nasal colonization may play a much less prominent role in the pathogenesis of CA-MRSA than was previously believed.


The prevalence of MRSA disease in the United States has in- creased dramatically as a result of the emergence of the CA- Downloaded from https://academic.oup.com/cid/article/46/5/752/287593 by Robert Crown Law Library user on 06 October 2025 CLINICAL PRACTICE • CID 2008:46 (1 March) • 755 MRSA clone USA300.

First isolated in 2000 [54], USA300 has been implicated in epidemiologically unassociated outbreaks in at least 38 US states (figure 1) [5-7, 10, 20, 33, 39, 42, 52, 54- 68].

Although many USA300 infections occur in the context of outbreaks, many are sporadic and do not involve any well- defined populations [69, 70].

USA300 is now also epidemic in many communities across the United States and accounts for 150% of all S. aureus infections [53, 71, 72].

Longitudinal anal- ysis of S. aureus disease at an urban medical center in the United States illustrates the epidemic character of this clone (figure 2) [73, 74].

The frequency of CA-MRSA disease increased 115- fold between 1996 and 2004, resulting in a concomitant dou- bling of overall S. aureus disease.

This epidemic could be at- tributed entirely to the rapid dissemination of a single clone of this species: from 1 case involving USA300 in 2000 to 1021 cases involving USA300 in 2004 (figure 2).


The international spread of USA300 has been recently re- ported, with outbreaks of infection in Canada and many Eu- ropean countries [75-81].

Exportation of USA300 may be fa- cilitated by a history of recent travel to the United States [75- 77].

It is of interest that USA300 first gained a foothold in Canada among persons with a history of incarceration, illicit drug use, and homelessness [82]; the same risk factors were noted among the early patients infected with the USA300 strain described in the United States [5, 54, 55, 73], suggesting that USA300 may emerge in the more marginalized populations with increased frequency of person-person contact.

However, this strain has clearly also established itself in nonmarginalized populations, such as healthy children [72].

The long history of effective MRSA control and prevention in some countries, such as The Netherlands, could be unraveled by community dissem- ination of USA300.


USA300 has become such a globally successful CA-MRSA clone in terms of causing human disease that it is reasonable to think of it as the prototypical CA-MRSA strain.

Thus, un- derstanding the pathogenesis of USA300 infection may be crit- ical to understanding the pathogenesis of CA-MRSA infection.

Its unique molecular characteristics may also be key compo- nents of the pathogenesis of CA-MRSA.


Presence of Panton-Valentine leukocidin (PVL) is epidemio- logically strongly associated with USA300 and other CA-MRSA strains.

The vast majority PVL-positive S. aureus isolates found worldwide are clustered in just 4 CA-MRSA lineages: ST1/ MW2, the US Midwest clone; ST8/USA300, the epidemic-prone American clone; ST30/USA1100, the Southwest Pacific Oceania clone; and ST80, the European clone.

The linkage of PVL to the 4 CA-MRSA genetic backgrounds may explain some of the unique epidemiological properties associated with CA-MRSA Downloaded from https://academic.oup.com/cid/article/46/5/752/287593 by Robert Crown Law Library user on 06 October 2025 756 • CID 2008:46 (1 March) • CLINICAL PRACTICE strains, although PVL's role in the spread of CA-MRSA is not clear [83].

The role of PVL in disease pathogenesis is also controversial.

Some animal studies have failed to find PVL as a major virulence factor [84], although others have found that it has a role in the pathogenesis of the pulmonary infection [85].


USA300 and other CA-MRSA strains also contain a different staphylococcal chromosomal cassette mec (SCCmec), confer- ring resistance to the entire class of b-lactam antibiotics.

In the absence of antibiotic treatment, SCCmec is thought to reduce the biological fitness of MRSA [86-88].

CA-MRSA, however, carries an allotype of SCCmec that is smaller in size than those typically found in nosocomial strains; this may impose only a slight cost to fitness, because it does not contain resistance genes other than mecA, which encodes an altered target penicillin- binding protein 2a.

CA-MRSA may also contain other genomic adaptations that allow it to overcome the presumed fitness cost of SCCmec.

Integrated next to the type IV SCCmec element is a putative pathogenicity island called type I arginine catabolic mobile element (ACME) [89].

Type I ACME is uniquely found in USA300 and not in other S. aureus strains.

The physical linkage between ACME and type IV SCCmec suggests that se- lection for enhanced fitness could coselect for increasing fre- quencies of not only b-lactam resistance but also other mul- tidrug resistant determinants, including multidrug resistance conjugative plasmids, which are carried by a subset of USA300 strains [89].


The ACME-SCCmec linkage is of great interest, because it was first discovered in the USA300 genome [89].

Horizontal acquisition of ACME from the ubiquitous skin commensal Staphylococcus epidermidis may enhance the growth and sur- vival of USA300 in the host-particularly on the human skin [89].

Deletion of ACME resulted in attenuated virulence of a clinical USA300 in a rabbit infection model [90].

Because the type I ACME found in USA300 has not been found in other CA-MRSA lineages, ACME could contribute to the epidemic character unique to this clone.

Indeed, only USA300 exhibits enhanced capacity to cause widespread epidemic disease and to displace other ACME-negative CA-MRSA clones, including ST1/MW2, ST30/USA1100, and ST80 [57, 73, 76, 91].

More- over, recent comprehensive proteomic analysis revealed that USA300 produced many virulence determinants in greater abundance than did ST1/MW2, including a-hemolysin, enter- otoxins Q and K, staphylokinase, and proteases [92].

In sum- mary, there are likely pathogen-level factors in CA-MRSA strains that enhance its pathogenicity.

Compared with other CA-MRSA strains, USA300 strains may have features that are particularly well suited to cause disease, although these features are, at this time, poorly understood.


The role of human host defenses against S. aureus is a final key factor in the pathogenesis of CA-MRSA and S. aureus in- fections.

Clearly, qualitative deficiencies in neutrophil function are associated with S. aureus infection [93].

Other host factors associated with infection risk include antimicrobial peptides [94], although our current understanding of host response to S. aureus is very limited.


Skin integrity is also key to prevention of S. aureus infection [33].

A distinct feature of CA-MRSA disease is the high disease burden among healthy community-dwelling individuals.

Many patients with CA-MRSA infection, however, have reported a breach in skin integrity that served as the portal of infection.

For example, skin infections often resulted from activities that resulted in skin trauma, such as those resulting from physical


Downloaded from https://academic.oup.com/cid/article/46/5/752/287593 by Robert Crown Law Library user on 06 October 2025 CLINICAL PRACTICE • CID 2008:46 (1 March) • 757 contact sports [7, 33, 42], injection drug use [95], and shaving of the genital area before sexual activity [39, 96].

Many children do not have recognized breeches in skin integrity before in- fection.

Whether this means there was none or that these breeches were not recognized or recalled is not clear.

The role of other host defenses in the pathogenesis of CA-MRSA, how- ever, remains poorly understood.


Data from outbreaks of infection and from endemic infections suggest that CA-MRSA behaves in a manner that is patho- genically distinct from HA-MRSA.

Although longitudinal nat- ural history studies have not been performed, epidemiologic and basic studies suggest that nasal colonization plays a less prominent role in the transmission and pathogenesis.

These studies also suggest that CA-MRSA colonization may not commonly precede infection.

Direct person-person and fo- mite-person transmission appear to be important routes of CA-MRSA infection.

It is possible that the genetically distinct CA-MRSA strains have important nonnasal niches (e.g., in- guinal regions) that act as reservoirs for transmission (e.g., via sexual behavior) or perhaps even reinfection.

Unique mo- lecular characteristics of CA-MRSA strains-especially the USA300 strain-may facilitate their pathogenicity and spread.

Host factors play an important but poorly understood role in CA-MRSA pathogenesis.


There are now compelling data suggesting that the patho- genesis of CA-MRSA is unique and distinct from that of HA- MRSA.

Rather than using the model of HA-MRSA that asserts that there is a stepwise progression from MRSA colonization to MRSA infection [26], we think that a model for CA-MRSA pathogenesis should consider the distinct epidemiological phe- nomena of CA-MRSA (figure 3).

Reliance on models of HA- MRSA transmission for prevention of CA-MRSA infection may result in the development of suboptimal prevention strategies.

For example, decolonization strategies that rely only on nasal decolonization may not be successful, because they do not ad- dress nonnasal colonization or decolonization of the patient's environs.

Prevention efforts may require total body decoloni- zation, decolonization of close or household contacts, and/or decolonization of the patient's household or workplace.

Suc- cessful efforts to prevent CA-MRSA reinfection or transmission will need to be based on a firm understanding of the unique CA-MRSA pathogenesis.

Longitudinal investigations will be key in helping us further understand CA-MRSA pathogenesis.


Background. Community-associated Staphylococcus aureus infections often affect multiple members of a household.

We compared 2 approaches to S. aureus eradication: decolonizing the entire household versus decolonizing the index case alone.


Methods.

An open-label, randomized trial enrolled 183 pediatric patients (cases) with community-onset S. aureus skin abscesses and colonization of anterior nares, axillae, or inguinal folds from 2008 to 2009 at primary and tertiary centers.

Participants were randomized to decolonization of the case alone (index group) or of all household members (household group).

The 5-day regimen included hygiene education, twice-daily intranasal mupirocin, and daily chlorhexidine body washes.

Colonization of cases and subsequent skin and soft tissue infection (SSTI) in cases and household contacts were ascertained at 1, 3, 6, and 12 months.


Results.

Among 147 cases with 1-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 50% of cases in the index group and 51% in the household group (P = 1.00).

Among 126 cases completing 12-month follow-up, S. aureus was eradicated from 54% of the index group versus 66% of the household group (P = .28).

Over 12 months, recurrent SSTI was reported in 72% of cases in the index group and 52% in the household group (P = .02).

SSTI incidence in household contacts was significantly lower in the household versus index group during the first 6 months; this trend continued at 12 months.


Conclusions.

Household decolonization was not more effective than individual decolonization in eradicating community-associated S. aureus carriage from cases.

However, household decolonization reduced the incidence of subsequent SSTI in cases and their household contacts.

Clinical Trials Registration.


The incidence of staphylococcal skin and soft tissue infection (SSTI) has risen dramatically over the past decade [1, 2].

This epidemic has been driven largely by a community-associated Staphylococcus aureus clone designated USA300, which includes methicillin-resistant and methicillin-sensitive strains [3, 4].

Recurrent S. aureus SSTIs are especially problematic; recurrence rates >20% over 3 months have been reported [5–7].

Community-associated S. aureus infections cluster within households [8–10].

We previously demonstrated that children were at a 7-fold greater risk for developing SSTI if a household member had a recent SSTI [11].

Although community-associated methicillin-resistant Staphylococcus aureus (MRSA) transmission dynamics are not well established, it is believed that household contacts may serve as reservoirs for S. aureus transmission.

Thus, patients treated for S. aureus infection may reacquire the organism from colonized household contacts, potentially placing them at risk for recurrence.


Staphylococcus aureus nasal colonization is a risk factor for SSTI development [11–13].

Decolonization measures used to prevent healthcare-associated MRSA infections (eg, mupirocin ointment and chlorhexidine antiseptic) [14–18] are often prescribed for patients in community settings in an effort to prevent recurrent SSTI [19].

However, it is unclear whether decolonization should be performed by all household members or only by affected individuals.


The primary objective of this study was to compare S. aureus eradication from index cases when decolonization measures were performed by the index case alone compared with measures performed by all household members.

Secondary objectives included comparing incidence of SSTI in index cases and household contacts between treatment groups and evaluating adherence to decolonization measures.

We hypothesized that decolonization of all household members would be twice as effective in eradicating index case S. aureus carriage compared with decolonization of the index case alone.


METHODS Study Design The Staphylococcus aureus Decolonization Study (SuDS) was an open-label, randomized controlled trial.

The Washington University Institutional Review Board approved this study.


Definitions A case was defined as a pediatric patient with community-onset S. aureus SSTI and S. aureus colonization.

A household contact was defined as an individual spending more than half of each week in the case’s household.

Decolonization was defined as use of antimicrobial agents to eliminate S. aureus carriage [20].

Eradication was defined as absence of S. aureus carriage at 3 sampled body sites.


Participants Recruitment for this study was a 2-step process.

First, patients aged 6 months to 20 years with acute community-onset SSTI requiring drainage were screened at the St Louis Children’s Hospital (SLCH) ambulatory wound center and emergency department and from 9 community pediatric practices affiliated with a practice-based research network in metropolitan St Louis (Figure 1).

Patients were excluded from screening if they had an indwelling catheter, percutaneous medical device, or postoperative wound infection; were undergoing dialysis; or resided in a long-term care facility.

At screening, verbal informed consent and demographic information were obtained.

Culture swabs (BBL Liquid Stuart; Becton Dickinson [BD], Sparks, Maryland) were collected from the anterior nares, axillae, and inguinal folds.

Wound culture results were obtained from the SLCH microbiology laboratory or the primary provider to confirm S. aureus as the infecting organism.

Second, patients with both S. aureus (MRSA or methicillin-sensitive S. aureus [MSSA]) colonization and infection were subsequently invited to return to SLCH for trial enrollment.

To assess colonization status of the cases’ household contacts, swabs (BBL Liquid Amies; BD) from the anterior nares, axillae, and inguinal folds, accompanied by directions for culture collection, were mailed to the cases’ homes (a procedure validated previously by our group and others) [21, 22].


Study Intervention and Randomization Trial enrollment was conducted in the SLCH Clinical Research Center (CRC) from July 2008 to November 2009, after the case’s acute SSTI had healed (median time from screening, 21 days; interquartile range,15–31 days; no difference between treatment groups).

At trial enrollment, written informed consent was provided for the case and each household contact.

Participant assent was obtained for minors ≥7 years of age.

Randomization was conducted with an Internet-based, computer-generated randomization schedule (Randomization.com) using permutation blocks of 6 and 8.

The designated intervention for each participant was sealed inside a sequentially numbered security envelope and opened at enrollment by a research coordinator.

All participants received a standardized hygiene curriculum advising them to avoid sharing personal hygiene items (eg, razors, brushes, and towels), to use liquid pump or pour soaps and lotions (rather than bar soaps and jars of lotion), and to launder (in hot water) bed linens at least once weekly and towels and washcloths after each use.

The 5-day decolonization regimen included twice-daily application of 2% mupirocin ointment to the anterior nares with a sterile cotton applicator and daily use of Hibiclens (4% chlorhexidine gluconate, Mölnlycke Health Care, Norcross, Georgia) in the bath or shower.

Participants were instructed to apply the Hibiclens with the hands or with a clean washcloth and wash all body parts, excluding the face, followed by a thorough rinse with water.

Participants were randomized to 1 of 2 study groups: the index group in which only the case was instructed to perform decolonization, and the household group in which the case and all household contacts (>6 months of age and not pregnant) were instructed to perform decolonization.

Oral and printed instructions were provided to study participants.

Study staff demonstrated application of mupirocin ointment to the anterior nares.

Participants were provided with all study materials needed to complete decolonization measures at home.


Data Collection at Baseline and Follow-up A standardized questionnaire was administered to each case at enrollment to collect demographic information for each case and household contact, details of the household environment, and case characteristics.

One week after enrollment, a parent or guardian of each case was telephoned to assess adherence and adverse reactions to the decolonization protocol.

Index cases were followed longitudinally with visits 1, 3, 6, and 12 months after enrollment at the SLCH CRC or the primary provider’s office.

To assess S. aureus colonization status of the case, nasal, axillary, and inguinal swabs were collected at each follow-up visit.

A survey was administered to ascertain interval development of SSTI in the case or any household contact.

Descriptions of SSTI included skin abscess or boil, cellulitis, impetigo, or spider bite (because community-associated MRSA abscesses may be mistaken for spider bites) [4].

All follow-up was completed by November 2010.

Participants remained blinded to colonization culture results until completion of their 12-month follow-up.

Over the 1-year study, 22 cases completed ≥1 follow-up visit by mail due to the distance of their home from SLCH.

For these cases, the follow-up survey was conducted by telephone, and swabs were mailed for home collection as detailed above.

For cases unable to be contacted for follow-up, SLCH medical records were examined to identify recurrent SSTI.

In addition, medical record review was performed at the primary provider’s office for cases reporting recurrent SSTI for which they sought medical care.


Study Outcomes The primary outcome measure was S. aureus eradication of the case 1 month after randomization.

Secondary outcomes were S. aureus eradication from the case at 3, 6, and 12 months; incidence of SSTI in the case or household contacts over 12 months; and adherence to decolonization measures.


Laboratory Methods Colonization culture swabs were incubated in tryptic soy broth with 6.5% sodium chloride (BBL; BD) overnight at 35°C.

The broth was plated to trypticase soy agar with 5% sheep’s blood (BBL; BD) and incubated at 35°C overnight.

Staphylococcus aureus isolates were identified, and antibiotic susceptibility testing was performed according to Clinical and Laboratory Standards Institute procedures as previously described [23, 24].

Laboratory personnel were blinded to randomization assignments.

Swabs collected at home all yielded normal flora for the appropriate body site, suggesting that samples were indeed representative of these sites.


Sample-Size Calculation and Statistical Analysis We anticipated that 50% of cases would achieve S. aureus eradication when measures were performed by the case alone ([25] and Fritz, unpublished data).

On this basis, 65 participants were needed in each group to detect 50% relative reduction in S. aureus colonization in the case at 1 month (α = .05, study power 80% by Pearson’s χ2 test).

We anticipated 25% attrition and therefore enrolled 183 households.

Statistical analyses were performed with SPSS for Windows 17.0 (IBM SPSS, Chicago, Illinois).

Baseline characteristics between treatment groups were evaluated by the Student t test (continuous data) and Pearson’s χ2 test or Fisher’s exact test (categorical data).

Outcome measures were evaluated by modified intention-to-treat analysis at each time point by Fisher’s exact test.

Specifically, participants were analyzed in the arm to which they were assigned, and the analysis for each time point included participants with evaluable data at that time point.

All tests of significance were 2-tailed.

P values ≤.05 were considered significant.

Odds ratios were considered significant if the 95% confidence interval did not include 1.

Relationships between treatment group and outcomes (index case S. aureus eradication and recurrent SSTI) were evaluated using multivariable binary logistic regression, adjusting for potential confounding characteristics that differed significantly between treatment groups at baseline; adjusted odds ratios were reported.


RESULTS Baseline Patient Characteristics One hundred eighty-three cases and their households were enrolled in the study; 91 were randomized to the household group and 92 to the index group (Figure 1).

The mean age (SD) of the cases was 6.0 (5.8) years.

Females (58%) and African Americans (58%) were predominant.

Characteristics of cases in the treatment groups were similarly distributed at baseline, except that those randomized to the household group were less likely than those in the index group to have Medicaid or no health insurance (P = .02) and more likely to be colonized with MRSA (P = .04) (Table 1).


Primary and Secondary Outcomes S. aureus Eradication at 1 Month Among 147 cases with 1-month colonization data, S. aureus was eradicated from 51% in the household group and 50% in the index group (P = 1.00) (Figure 2).


S. aureus Eradication at 3, 6, and 12 Months At 3 months, cases in the household group had a higher rate of S. aureus eradication (72%) than those in the index group (54%; P = .05); this difference was not significant when adjusting for baseline differences between treatment groups (P = .07).

Eradication rates at 6 and 12 months did not differ between groups (Figure 2).

When stratified by MRSA and MSSA baseline colonization, eradication rates between treatment groups did not differ significantly (data not shown).


Recurrent SSTI in Cases At 1 month, recurrent SSTI was self-reported for 15% of case in the household group and 26% in the index group (P = .12).

Assessment of the cumulative recurrence of self-reported SSTI revealed that cases in the household group were less likely than those in the index group to report recurrent SSTI after 3 months (28% vs 47%; P = .02), 6 months (38% vs 61%; P = .008), and 12 months (52% vs 72%; P = .02) (Figure 3A).

Recurrent SSTI rates did not differ when stratified by baseline MRSA versus MSSA infection (data not shown).

Of 175 self-reported recurrent SSTIs in 90 cases, medical care was sought for 117 (67%) SSTIs.

Of these, 56 (48%) cases reported requiring a drainage procedure, and 93 (79%) reportedly were prescribed antibiotics.

Of the 117 SSTIs for which cases reported seeking medical care, 107 (91%) were confirmed upon review of medical records.

At 1 month, recurrent SSTI was documented by a physician in 13% of cases in the household group and 19% of cases in the index group (P = .38).

Cases in the household group were less likely than those in the index group to have a physician-documented recurrent SSTI after 3 months (15% vs 34%; P = .007), 6 months (22% vs 43%; P = .008), and 12 months (36% vs 55%; P = .03) (Figure 3B).

In multivariable analyses, adjusting for baseline differences between treatment groups (insurance and MRSA colonization status) did not change the effect size of the relationship between treatment group and recurrent SSTI in cases (Figure 3A and 3B).


SSTI in Household Contacts Household contacts of cases in the household group were less likely than those in the index group to report SSTI at 1 month (2% vs 7%; P = .005), 3 months (4% vs 10%; P = .01), and 6 months (9% vs 16%; P = .04).

At 12 months, a trend remained toward decreased SSTI among household contacts in the household group (16% vs 22%, P = .10) (Figure 4).


Protocol Adherence No serious adverse events were reported.

Of 162 (88%) cases providing information, 35 (22%) reported side effects, including dry skin (23 [14%]), rash (9 [6%]), and hives (3 [2%]).

Most parents of cases (85%) found the protocol easy to implement.

Parents perceived chlorhexidine body washes to be the easiest study component, whereas washing towels after each use was perceived to be the most difficult.

Cases were considered adherent to the decolonization protocol if they used mupirocin twice daily and chlorhexidine daily for ≥5 days and followed ≥3 hygiene recommendations.

Duration of use of study medications by cases ranged from 0 to 30 (median, 5) days.

The majority (131 of 162 [81%]) of cases were adherent with the protocol (index group, 69 of 84 [82%]; household group, 62 of 78 [80%]; P = .69).

In the household group, 74% (220 of 299) of the household contacts performed decolonization measures for ≥5 days as prescribed.

Parents and siblings (77%) were more likely to be adherent than other household members (63%; P = .03).

Twenty-nine (10%) of 295 household contacts in the index group (instructed not to perform decolonization) reported using the study materials.


DISCUSSION While data are emerging regarding the effectiveness of regimens to eradicate S. aureus from patients in community settings, the optimal approach to decolonization remains unclear [20, 25–27].

Community-associated S. aureus is a disease affecting households; in the present study, we evaluated an individual versus household approach to S. aureus eradication.

We found that S. aureus eradication from cases did not differ between treatment groups over 12 months.

Interestingly, we found that a household decolonization approach resulted in fewer subsequent SSTIs in both cases and their household contacts.

The finding of reduced SSTI despite no difference in eradication rates between treatment groups is surprising given the fact that endogenous S. aureus colonization is a predictor of nosocomial infection [28–30].

However, in the community setting, other factors may contribute to S. aureus pathogenesis and SSTI development [31].

Some authors propose that skin-to-skin and skin-to-fomite contact may play a greater role in S. aureus pathogenesis than does endogenous colonization [31].

This model of transmission is supported by the observation that not all patients with S. aureus SSTI are colonized with S. aureus [31, 32].

In the present study, 20% of screened patients with confirmed S. aureus SSTI were not colonized with S. aureus in the nares, axillae, or inguinal folds.

Furthermore, while many patients with SSTI are S. aureus carriers, an endogenous colonizing strain may not be the strain causing disease.

In a study of pediatric patients with S. aureus SSTI and nasal colonization, only 59% were colonized with a strain concordant with the strain recovered from the infection site [6].

This suggests that acquisition of a new strain (via person-to-person contact or from environmental surfaces) results in symptomatic infection.

A better understanding of the molecular epidemiology of community-associated S. aureus colonization and infection is essential to developing interventions that will improve patient outcomes.


The household decolonization data presented here can inform a common clinical practice that had been previously unstudied.

In a 2006 survey of infectious diseases consultants inquiring about strategies to prevent recurrent community-associated SSTIs, approximately half the respondents reported prescribing decolonization measures for all family members, while 4% treated only colonized family members [19].

The effectiveness of decolonization measures in reducing SSTI might be similar if measures were targeted only at S. aureus carriers; such an approach would decrease the burden and cost of performing these measures.

However, culturing all household members may not be practical in a community setting.

If decolonization measures are prescribed for patients with recurrent SSTI, the findings of this study support an approach directed at all household members.


This study has several limitations.

We did not directly observe the performance of decolonization measures by participants, although 81% of cases and 74% of household contacts asked to perform the protocol reported adherence with prescribed measures.

Additionally, 10% of household contacts not assigned to the protocol used the index case’s materials.

Although we recognize the limitations of self-reporting an SSTI, our conclusions are also borne out by the analysis limited to physician-documented SSTIs.

The decolonization regimen selected for this trial (intranasal mupirocin and chlorhexidine body washes) was selected based on data from healthcare-based trials [17, 18, 33] and the popularity of this regimen among infectious disease practitioners for patients in the community [19].

Bleach and chlorhexidine-impregnated cloths are alternatives for decolonization [34–36].

Finally, because we hypothesized that the effect size would be greater earlier in the follow-up period (within the first 3 months), we modeled the outcomes individually at each time point; alternative modeling strategies (eg, generalized hierarchical linear modeling) might also have been considered.


This study has unique strengths.

Though nasal screening is frequently the sole means used to detect S. aureus colonization [37–40], other sites [38, 41–43] may represent important niches for S. aureus colonization.

We sampled 3 body sites that yielded important data on the distinct colonization patterns of community-associated S. aureus [22, 31].

Indeed, nearly one-third of colonized cases and household contacts would not have been detected had only the nares been sampled.

Also, due to the breadth of age, race, household size, and geographic distribution of our participants, these results may be generalizable to other populations affected by community-associated S. aureus.

The ongoing community-associated S. aureus epidemic is a significant public health burden that affects millions of individuals.

This entity is particularly challenging within households, where the reservoir of S. aureus may perpetuate ongoing disease.

At present, we lack effective validated methods to prevent these infections [20].

This is the first randomized trial of S. aureus decolonization strategies in the community setting to demonstrate a reduction in the burden of SSTI [25–27].

However, this study is only a first step in demonstrating that a household approach can decrease the impact of S. aureus, as >50% of cases in the household group reported recurrent SSTI over a 1-year period.

Further studies elucidating the roles of household colonization pressure and household environmental contamination in community-associated S. aureus transmission and disease are needed to guide subsequent trials of optimized strategies for interrupting staphylococcal transmission.


Community-associated Staphylococcus aureus skin and soft tissue infections (SSTIs) are a common reason healthy and immunocompromised persons seek medical attention [1, 2].

In the United States, the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA) infections has dramatically shifted SSTI epidemiology.

Visits to US physician offices, hospital outpatient departments, and emergency departments for SSTIs increased by 50% between 1997 and 2004 [3], and hospital admissions increased by 29% during 2000–2004 [4].

These increases appear to be driven by the dramatic increase in CA-MRSA infections [3, 4].

One notable aspect of CA-MRSA skin infections is their predilection to cause subsequent disease.

Recurrent SSTIs are frequently encountered in patients with community-associated S. aureus and CA-MRSA [1], and recurrence rates exceeding 50% have been described in selected populations [5].

Unfortunately, there are few data to guide clinicians and patients on optimal methods for prevention.


In this issue of Clinical Infectious Diseases, Fritz et al [6] present results of a randomized clinical trial on prevention of community-associated S. aureus SSTI infection.

The investigators randomized children with S. aureus infection plus S. aureus colonization in the nares, axilla, or inguinal folds into a 5-day decolonization regimen that targeted either the infected child alone or the entire household.

The investigators exploited the knowledge that many households’ members are also colonized with the infecting isolate [7] and thus may serve as reservoirs for pathogenic S. aureus strains.

Results of this trial are intriguing.

First, although there were no significant differences in colonization eradication of case (index) subjects between treatment allocation groups (54% vs 66%; P = .28), self-reported infection rates differed between groups (72% in the index group vs 52% in the household decolonization group; P = .02).

Second, the regimen under study was brief (5 days), and household implementation was described as easy and relatively well tolerated.


Like any important clinical trial, findings from Fritz et al [6] raise more questions than they answer.

To frame these issues, it is useful to look at the findings in the context of the clinician or patient faced with community-associated S. aureus infection, specifically: Is decolonization of S. aureus after S. aureus infection needed?

Interestingly, the study design of Fritz et al does not answer the key question: Does S. aureus decolonization prevent subsequent S. aureus infection?

At this time, there are no data from randomized clinical trials showing that decolonization reduces recurrent infections compared with no decolonization effort.

We still lack clear evidence to demonstrate the efficacy of S. aureus eradication of the index child compared with no decolonization.

Despite the lack of an untreated control group, the finding that decolonization of the household unit was more effective at preventing infections than was decolonization of just the index patient is important and supports the concept that decolonization may be an effective tool to prevent recurrent infection.


During the physician-patient dialogue on S. aureus decolonization, the prudent clinician should recommend the regimen described by Fritz et al as a safe and well-tolerated protocol.

Other decolonization regimens, for example, bleach baths [2], remain unproven.

We must remind ourselves that patients and parents in this investigation constituted a relatively motivated group that agreed to participate in a 12-month trial involving the entire family.

Not all households may be so motivated.

Offering this regimen after a single infection may be futile unless the family is highly motivated.

We must also remind ourselves and our patients that even among those randomized to household decolonization, 52% of index subjects reported recurrent disease.


Do I need to check for colonization prior to household decolonization?

The investigators found that only 80% of children with S. aureus SSTIs were colonized with S. aureus and therefore eligible for trial participation.

They also correctly note that even if colonization is found, more than one-third of subjects could be colonized with strains different from the infecting isolate.

Thus, this trial does not address whether index patients without detected S. aureus colonization would benefit from household decolonization.

Trial findings suggest that before considering decolonization, clinicians should screen the nares, axilla, and inguinal folds for S. aureus colonization.

( If the index patient had MRSA, then testing solely for MRSA would likely be sufficient.) If colonization is detected, then motivated, willing families should be offered decolonization.

If colonization is absent, clinicians must convey that decolonizing household members may result in no benefit.


What about adults with S. aureus infection?

Adults are not just big children.

Their relative independence leads them to behaviors and exposures that may result in acquisition of S. aureus infections in different manners than children.

The relatively low proportion of MRSA-colonized patients with MRSA infection in some investigations argues that adults may be acquiring pathogenic isolates from fomites or other persons [8].

Thus, it is unclear whether results of this trial would be applicable to adults.

If the regimen is offered to households of index adults, we must be honest with our patients and let them know that this regimen’s efficacy, while promising, is unproven.


Given the low risk of the decolonization regimen, is there any downside to household decolonization?

The intervention used by Fritz et al, although relatively easy to use, is far from perfect.

The investigators did not quantify whether infecting or colonizing isolates developed mupirocin or chlorhexidine resistance.

Although the likelihood of colonized patients’ S. aureus isolates developing mupirocin resistance during the therapeutic regimen described by Fritz et al is probably very low [9], increasing use of mupirocin could drive the prevalence of mupirocin-resistant S. aureus higher, which may in turn lead to treatment failures.

Therefore, we must remain judicious in our use of this agent in medical institutions and the outpatient setting.

Fortunately, chlorhexidine resistance appears to be rare [10]; however, our understanding of the mechanism and its prevalence is in its infancy.

In addition, although well tolerated, chlorhexidine—including the product used for the trial (Hibiclens)—is complicated to use optimally.

Patients need to avoid getting the product in open wounds and in mucous membranes.

The product works best when it is left on for many hours and is easily inactivated by soap, creams, and lotions [11].

Washing clothes and linens with residual chlorhexidine using bleach containing detergents will cause staining.

Thus, prescribing chlorhexidine requires considerable patient education.

Fortunately, materials on proper use are available on the Internet [12], but practitioners need to familiarize themselves with proper use of both mupirocin and chlorhexidine and provide detailed verbal and written materials on optimal use.


So is current evidence limiting us to just recommend decolonization to children with S. aureus infections known to be colonized with S. aureus and willing to have their household use this regimen? From an evidence-based medicine perspective, the answer is yes. That said, the burden of suffering from recurrent S. aureus infections is substantial. And we owe it to our patients to make the best recommendations on prevention on the basis of our contemporary understanding of the literature available to us.

If an adult suffering from recurrent S. aureus SSTI asks for help preventing subsequent infections, it would be a disservice not to counsel the patient about the pros and cons of decolonization therapy.

But we need to acknowledge that we do not know whether this regimen works and that there may be adverse effects.

Given the inordinate amount of physical and psychological suffering caused by S. aureus infections [13], the knowledge that something promising but unproven can be tried may provide some comfort.

Hopefully, in the future, more definitive trials on community-associated S. aureus infection prevention in adults and other populations will be able to provide additional key critical evidence about prevention of this very common infection.


The Global Navigation Satellite System (GNSS) receivers, which are widely distributed on the Earth's surface, are very useful for monitoring changes in the ionosphere.

The ionosphere is the largest source of error in signal propagation from GNSS satellites to single-frequency GNSS receivers.

Accurately estimating the total electron content (TEC) in the ionosphere can improve the position accuracy for the GNSS users.

GNSS TEC can be obtained easily from the geometry-free linear combination (P1-P2 or C1-P2) using data of different frequencies.

However, GNSS satellites and ground receivers have their own hardware biases, which act as large sources of error in calculating the ionospheric TEC.

These hardware-associated biases still remain in the ionospheric TEC after subtracting the measurements at two different frequencies.

These differences in hardware biases inherent in different GNSS code measurements are called differential code biases (DCBs).

Methods for estimating the DCB have been reported in many studies [1-9].


The GNSS satellite and receiver DCB (rDCB) values are different for each satellite and receiver.

In general, the DCBs of the GNSS receivers are larger than those of the GNSS satellites.

GNSS satellites have DCB values of several nanoseconds (ns), while those of GNSS receivers can reach up to a few tens of ns.

Wilson and Mannucci [10] demonstrated that global positioning system (GPS) satellite DCBs have long-term stability with a root mean square (RMS) error of approximately 0.2 ns.

Hernandez-Pajares et al. [ 11] showed that GPS satellite DCBs will remain in the range of several ns for about 10 years.

They also observed some periodic behaviors in them, and suggested that these could be related to the ionospheric TEC.


GNSS DCBs are affected by various factors, such as data quality, estimation method, receiver type, and antenna characteristics.

The diurnal variations of the rDCB can differ depending on the temperature of the hardware inside the receiver [12-15].

Mannucci et al. [ 16] suggested that the rDCB value can be more stable and more accurate when the ionospheric activity is in a somewhat quiet condition than when it is in a disturbed condition.

Furthermore, Zhang et al. [ 17] reported that geomagnetic conditions can affect the accuracy of rDCB values.

They noted that there was a difference in rDCB between disturbed and quiet geomagnetic conditions.

Recently, Choi and Lee [18] also reported that the rDCB can change significantly depending on the grounding status of the antennas at GNSS sites.


The International GNSS Service (IGS) has been providing reliable Global Ionosphere Map (GIM) products since 1998 [19,20].

There are several international associate analysis centers (IAACs) such as the Center for Orbit Determination in Europe, the Jet Propulsion Laboratory, the European Space Operations Center of the European Space Agency, the Technical University of Catalonia, and the GNSS Research Center of Wuhan University.

Typically GIM products are provided on a daily basis by each IAAC and IGS.

In addition, they contain DCBs for the GNSS satellites and the IGS stations.

DCBs and their associated RMS values are available in the daily GIM products.


The variability of DCBs related to ionospheric TEC changes has been reported by previous studies.

For example, Zhang et al. [ 21] reported that DCBs are related to ionospheric variability.

Considering the basic ionospheric approximation in the DCB estimation approach, they suggested that the day-to-day variation of GPS satellite DCBs is associated with the strength of the ionospheric day-to-day variation.

Themens et al. [ 22] investigated that the behavior of GPS rDCB in the high-latitude region shows seasonal and temperature variability.

In addition, ionospheric gradients at middle- and low-latitude regions can generate seasonal and solar-cycle variations of rDCB [23,24].

However, a few case studies of DCB variability related to ionospheric change have been conducted in low-latitude or high-latitude regions.


In this study, we focus on the relationship between the stability of rDCB and ionospheric TEC change with solar activity during a period of three years from 2014 to 2016.

This period corresponds to solar cycle 24, and has a gradual decrease in the number of sunspots.

The stability of the rDCB is analyzed in terms of rDCB RMS value, which can be obtained from the European Space Agency hourly rapid GIM (EHRG) products.

Using the EHRG GIMs, we investigate vertical total electron content (VTEC), rDCB, and rDCB RMS values for the GNSS stations in three different latitude regions.

In addition, correlation coefficients are considered to measure the linear relationships between pairs of variables (VTEC and rDCB, VTEC and rDCB RMS).


EHRG GIM products are generated on a daily basis using data from about 220 GNSS stations of the IGS.

They are modeled using the ionospheric model, based on spherical harmonic expansion up to degree and order 15, which are provided by the IGS.

GIM products can be downloaded via the Crustal Dynamic Data Information System server (ftp://cddis.gsfc.nasa.gov/).

As of 2014, EHRG GIM products provided in IONosphere EXchange (IONEX) format have the vertical TEC (VTEC) with a temporal resolution of 1 hour, and a spatial resolution with 2.5 • in latitude and 5 • in longitude, respectively. They also include the P1-P2 DCB for all GPS satellites, and rDCB for ground stations for each day.


Ionospheric TEC can be calculated from the geometry-free linear combination using dual-frequency GNSS measurements.

The electron density in the ionosphere along the line of sight from a satellite to receiver is referred to as TEC.

It can be directly calculated using Equation (1).


where STEC represents the slant TEC.

P 1 and P 2 are GNSS pseudoranges.

f 1 and f 2 are the frequencies of GNSS signals.

d s and d r are GNSS satellite DCB and receiver DCB, respectively.

To estimate the GNSS satellite and receiver DCBs, constraint condition is required to separate the satellite and receiver DCBs.

It is assumed that the sum of all available GNSS satellite DCBs is zero.


In general, GIMs use the spherical harmonic expansion method to derive the spatial distribution of ionospheric TEC.

The spherical harmonic expansion technique is shown in Equation (2) [25,26].


where, VTEC is the vertical TEC, β and s are the geocentric latitude and solar-fixed longitude of ionospheric pierce points, respectively.

N denotes the maximum degree of the spherical harmonic expansion.

P nm represents the normalized associated Legendre function with the degree n and the order m. C nm and S nm are the TEC unknown coefficients of spherical harmonics.

F is a slant factor.

STEC is converted to VTEC by a slant factor.