Bacterial Infections in Patients With T1DM: Follow-up Study
The study cohort comprised of 12 954 NDCs and 4748 patients with type 1 diabetes (Table 1). Between 1996 and 2009, the total number of follow-up years was 177 268 in the NDC group and 64 194 in patients with type 1 diabetes. The total number of follow-up years in each nephropathy group was as follows: normal AER (19 804 years), microalbuminuria (4958 years), macroalbuminuria (5821 years), dialysis (856 years), and kidney transplant (2250 years). As expected, the median duration of diabetes increased along with increasing severity of nephropathy. Hypertension, asthma, and mental disorders were the most common comorbidities in patients with diabetes and in NDCs. CVD and atherosclerosis were much more frequent in patients with diabetes (17.2% and 8.1%) compared with NDCs (3.9% and 0.3%) as they are well-known macrovascular complications of diabetes. Over 10% of patients with diabetes died during follow-up as compared to 4.4% of NDCs.
Data on infections leading to hospitalization were obtained from the Finnish Hospital Discharge Register (Table 1). The patients with diabetes had a total of 3980 hospitalization events due to infections, of which 3229 (81.1%) were due to bacterial infection. The corresponding number of events in the NDCs was 2882, where 2102 (72.9%) infections had a bacterial etiology (online supplementary table S1 http://drc.bmj.com/content/3/1/e000067/suppl/DC1). The hospitalization rate was higher in patients with diabetes compared with NDCs, RR=2.30 (95% CI 2.11 to 2.51) in an adjusted model. Patients with diabetes displayed an increasing trend of hospitalizations between 1996 and 2009 with a 4% annual increase. In contrast, NDCs showed a slightly decreasing trend with a 3% annual reduction in hospitalizations (Table 2). Increasing age had a decreasing effect on hospitalization risk in patients with diabetes and NDCs. Men and women were equally hospitalized in the diabetes group. In contrast, women in the NDC group had a 44% lower hospitalization rate (RR=0.56, 95% CI 0.50 to 0.62, Table 2) compared with men. In both groups, all comorbidities increased the risk of hospitalization except rheumatoid arthritis in the diabetes group. Among comorbidities, atherosclerosis had the largest effect in both groups and it increased the risk of hospitalizations threefold: RR=3.16 (95% CI 3.11 to 5.45) for patients with diabetes; RR=3.09 (95% CI 1.87 to 3.29) for NDCs (Table 2).
Time trends for annual hospitalization rates in different nephropathy classes are shown in online supplementary figure S1 http://drc.bmj.com/content/3/1/e000067/suppl/DC1. The hospitalization rate increased with the severity of diabetic nephropathy: the mean hospitalization rate per 1000 person-years in patients with normal AER was 24.5 (95% CI 22.4 to 26.8), in patients with microalbuminuria 46.6 (95% CI 40.8 to 53.0), and in those with macroalbuminuria 78.3 (95% CI 70.0 to 84.4; Table 1). In patients with ESRD, those on dialysis had a higher hospitalization rate compared with patients with a kidney transplant; 632 (95% CI 580 to 688) versus 303 (95% CI 281 to 327) per 1000 person-years. The RRs when compared with the normoalbuminuria group were 1.23 (95% CI 0.94 to 1.60), 1.97 (95% CI 1.49 to 2.61), 11.2 (95% CI 8.1 to 15.5), and 6.72 (95% CI 4.92 to 9.18) for the microalbuminuria, macroalbuminuria, dialysis, and kidney transplantation groups, respectively. Hospitalizations were also inversely related to eGFR (online supplementary figure S3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1). The risk was the lowest and rather stable when eGFR was higher than 80 mL/min/1.73 m, but started to increase rapidly when eGFR showed reduced kidney function.
Online supplementary table S3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1 shows the hospitalization RRs obtained from multivariate ZIP modeling according to nephropathy status. Hyperglycemia was strongly associated with hospitalizations in all other groups except those on dialysis. Even in patients with normal AER, each unit increase in HbA1c increased hospitalizations by 26%.
Data on antibiotic purchases were obtained from the Finnish National Drug Prescription Register (Table 1). Patients with diabetes purchased more antibiotics annually compared with NDCs; 1.00 (95% CI 1.00 to 1.01) vs 0.47 (95% CI 0.46 to 0.47) (RR=1.71 (95% CI 1.65 to 1.77)). Antibiotic purchases increased during the study period in patients with diabetes (2% annually) and in NDCs (1% annually; Table 2). Similarly, as for hospitalizations, increasing age had a decreasing effect on antibiotic purchases in patients with diabetes and NDCs. In both groups, female patients purchased around 50% more antibiotics; RR=1.54 (95% CI 1.46 to 1.63) for patients with diabetes, 1.49 (95% CI 1.44 to 1.55) for NDCs. Atherosclerosis had the most conspicuous comorbidity effect in patients with diabetes (RR=2.94 (95% CI 2.66 to 3.25)), while respiratory diseases did the same in the NDCs (RR=1.97 (95% CI 1.89 to 2.05); Table 2).
Patients with diabetes, who had retained a normal AER during the whole follow-up period, had more antibiotic purchases than NDCs, RR=1.56 (95% CI 1.49 to 1.64). The risk ratio was only slightly decreased when further controlled for comorbidities (RR=1.48 (95% CI 1.41 to 1.55)). Time trends for annual antibiotic purchases in different nephropathy classes are shown in online supplementary figure 2 http://drc.bmj.com/content/3/1/e000067/suppl/DC1. The annual number of purchases per person was 0.65 (95% CI 0.64 to 0.66) in patients with normal AER, 0.94 (95% CI 0.91 to 0.96) in patients with microalbuminuria, 1.18 (95% CI 1.15 to 1.21) in patients with macroalbuminuria, 3.23 (95% CI 3.11 to 3.35) in patients on dialysis, and 3.03 (95% CI 2.95 to 3.10) in patients with a kidney transplant (Table 1). The RRs obtained from the fully adjusted model were 1.18 (95% CI 1.07 to 1.30) for microalbuminuria, 1.29 (95% CI 1.15 to 1.44) for macroalbuminuria, 2.43 (95% CI 2.08 to 2.84) for dialysis, and 2.74 (95% CI 2.35 to 3.17) for the kidney transplantation group compared to patients with normal AER. Similarly, as for the hospitalizations, a reduced eGFR was associated with increased antibiotic purchases (online supplementary figure 3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1). There was a modest increase in purchases with decreasing eGFR until 90 mL/min/1.73 m, and this increase was accelerated when eGFR decreased below 90 mL/min/1.73 m.
Online supplementary table S3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1 shows the antibiotic purchase RRs obtained from multivariate ZIP modeling according to nephropathy status. High HbA1c increased purchases with a range of 6–10% per unit increase in HbA1c across the nephropathy groups except in the patients with ESRD. The impact of glycemic control on antibiotic purchases was studied separately in (1) patients with normal AER and (2) patients with microalbuminuria or macroalbuminuria. Among patients with microalbuminuria and macroalbuminuria, patients with poor glycemic control (HbA1c ≥9%) had 1.25 (95% CI 1.08 to 1.45) times more antibiotic purchases than those with good glycemic control (HbA1c <7%). In contrast, the number of antibiotic purchases in patients with normal AER was higher already when HbA1c was ≥7% (RR=1.22 (95% CI 1.14 to 1.31)). In patients with normal AER, the number of antibiotic purchases leveled off when HbA1c was ≥8% and in patients with microalbuminuria or macroalbuminuria when HbA1c was ≥9% (figure 1).
(Enlarge Image)
Figure 1.
Association between antibiotic purchases and glycated hemoglobin (HbA1c) values in patients with and without diabetic nephropathy. Patients with normal albumin excretion rate and microalbuminuria/macroalbuminuria are shown as open and closed squares, respectively. p Values (p<0.05; *p<0.001).
We also wanted to assess whether the frequent use of antibiotics could be associated with the progression of nephropathy. As seen in figure 2, the mean number of antibiotic purchases was higher in the group that developed microalbuminuria compared with the reference group with normal AER. In patients with incident microalbuminuria, the number of antibiotic purchases was higher at the time of nephropathy diagnosis (year 0) compared with 4 years before the progression (year −4; p=0.04 for time effect). In contrast, no significant differences were observed in the number of antibiotic purchases in patients with normal AER during the follow-up (p=0.52 for time effect).
(Enlarge Image)
Figure 2.
Relationships between annual antibiotic purchase rates and progression of microalbuminuria in patients with type 1 diabetes. Annual number of antibiotic purchases in patients with type 1 diabetes and incident microalbuminuria (progressors, n=219; closed squares), and their age, sex, and diabetes duration (±2 years) matched controls with type 1 diabetes that have retained a normal albumin excretion rate during the whole follow-up period (non-progressors, n=874; open squares). The first year of incident microalbuminuria is shown as year 0. Controls were matched for sex, age, and diabetes duration (±2 years). Values are expressed as means with 95% CIs, and were adjusted for sex, HbA1c, and diabetes duration. A dashed horizontal line indicates the level of significance between years −4 and 0 in the incident microalbuminuria group. p Values (p<0.05; *p<0.01;**p<0.001) apply to the differences in annual antibiotic purchase rates between progressors and non-progressors.
Results
The study cohort comprised of 12 954 NDCs and 4748 patients with type 1 diabetes (Table 1). Between 1996 and 2009, the total number of follow-up years was 177 268 in the NDC group and 64 194 in patients with type 1 diabetes. The total number of follow-up years in each nephropathy group was as follows: normal AER (19 804 years), microalbuminuria (4958 years), macroalbuminuria (5821 years), dialysis (856 years), and kidney transplant (2250 years). As expected, the median duration of diabetes increased along with increasing severity of nephropathy. Hypertension, asthma, and mental disorders were the most common comorbidities in patients with diabetes and in NDCs. CVD and atherosclerosis were much more frequent in patients with diabetes (17.2% and 8.1%) compared with NDCs (3.9% and 0.3%) as they are well-known macrovascular complications of diabetes. Over 10% of patients with diabetes died during follow-up as compared to 4.4% of NDCs.
Hospitalization Due to Infections
Data on infections leading to hospitalization were obtained from the Finnish Hospital Discharge Register (Table 1). The patients with diabetes had a total of 3980 hospitalization events due to infections, of which 3229 (81.1%) were due to bacterial infection. The corresponding number of events in the NDCs was 2882, where 2102 (72.9%) infections had a bacterial etiology (online supplementary table S1 http://drc.bmj.com/content/3/1/e000067/suppl/DC1). The hospitalization rate was higher in patients with diabetes compared with NDCs, RR=2.30 (95% CI 2.11 to 2.51) in an adjusted model. Patients with diabetes displayed an increasing trend of hospitalizations between 1996 and 2009 with a 4% annual increase. In contrast, NDCs showed a slightly decreasing trend with a 3% annual reduction in hospitalizations (Table 2). Increasing age had a decreasing effect on hospitalization risk in patients with diabetes and NDCs. Men and women were equally hospitalized in the diabetes group. In contrast, women in the NDC group had a 44% lower hospitalization rate (RR=0.56, 95% CI 0.50 to 0.62, Table 2) compared with men. In both groups, all comorbidities increased the risk of hospitalization except rheumatoid arthritis in the diabetes group. Among comorbidities, atherosclerosis had the largest effect in both groups and it increased the risk of hospitalizations threefold: RR=3.16 (95% CI 3.11 to 5.45) for patients with diabetes; RR=3.09 (95% CI 1.87 to 3.29) for NDCs (Table 2).
Time trends for annual hospitalization rates in different nephropathy classes are shown in online supplementary figure S1 http://drc.bmj.com/content/3/1/e000067/suppl/DC1. The hospitalization rate increased with the severity of diabetic nephropathy: the mean hospitalization rate per 1000 person-years in patients with normal AER was 24.5 (95% CI 22.4 to 26.8), in patients with microalbuminuria 46.6 (95% CI 40.8 to 53.0), and in those with macroalbuminuria 78.3 (95% CI 70.0 to 84.4; Table 1). In patients with ESRD, those on dialysis had a higher hospitalization rate compared with patients with a kidney transplant; 632 (95% CI 580 to 688) versus 303 (95% CI 281 to 327) per 1000 person-years. The RRs when compared with the normoalbuminuria group were 1.23 (95% CI 0.94 to 1.60), 1.97 (95% CI 1.49 to 2.61), 11.2 (95% CI 8.1 to 15.5), and 6.72 (95% CI 4.92 to 9.18) for the microalbuminuria, macroalbuminuria, dialysis, and kidney transplantation groups, respectively. Hospitalizations were also inversely related to eGFR (online supplementary figure S3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1). The risk was the lowest and rather stable when eGFR was higher than 80 mL/min/1.73 m, but started to increase rapidly when eGFR showed reduced kidney function.
Online supplementary table S3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1 shows the hospitalization RRs obtained from multivariate ZIP modeling according to nephropathy status. Hyperglycemia was strongly associated with hospitalizations in all other groups except those on dialysis. Even in patients with normal AER, each unit increase in HbA1c increased hospitalizations by 26%.
Outpatient Purchases of Antibiotics
Data on antibiotic purchases were obtained from the Finnish National Drug Prescription Register (Table 1). Patients with diabetes purchased more antibiotics annually compared with NDCs; 1.00 (95% CI 1.00 to 1.01) vs 0.47 (95% CI 0.46 to 0.47) (RR=1.71 (95% CI 1.65 to 1.77)). Antibiotic purchases increased during the study period in patients with diabetes (2% annually) and in NDCs (1% annually; Table 2). Similarly, as for hospitalizations, increasing age had a decreasing effect on antibiotic purchases in patients with diabetes and NDCs. In both groups, female patients purchased around 50% more antibiotics; RR=1.54 (95% CI 1.46 to 1.63) for patients with diabetes, 1.49 (95% CI 1.44 to 1.55) for NDCs. Atherosclerosis had the most conspicuous comorbidity effect in patients with diabetes (RR=2.94 (95% CI 2.66 to 3.25)), while respiratory diseases did the same in the NDCs (RR=1.97 (95% CI 1.89 to 2.05); Table 2).
Patients with diabetes, who had retained a normal AER during the whole follow-up period, had more antibiotic purchases than NDCs, RR=1.56 (95% CI 1.49 to 1.64). The risk ratio was only slightly decreased when further controlled for comorbidities (RR=1.48 (95% CI 1.41 to 1.55)). Time trends for annual antibiotic purchases in different nephropathy classes are shown in online supplementary figure 2 http://drc.bmj.com/content/3/1/e000067/suppl/DC1. The annual number of purchases per person was 0.65 (95% CI 0.64 to 0.66) in patients with normal AER, 0.94 (95% CI 0.91 to 0.96) in patients with microalbuminuria, 1.18 (95% CI 1.15 to 1.21) in patients with macroalbuminuria, 3.23 (95% CI 3.11 to 3.35) in patients on dialysis, and 3.03 (95% CI 2.95 to 3.10) in patients with a kidney transplant (Table 1). The RRs obtained from the fully adjusted model were 1.18 (95% CI 1.07 to 1.30) for microalbuminuria, 1.29 (95% CI 1.15 to 1.44) for macroalbuminuria, 2.43 (95% CI 2.08 to 2.84) for dialysis, and 2.74 (95% CI 2.35 to 3.17) for the kidney transplantation group compared to patients with normal AER. Similarly, as for the hospitalizations, a reduced eGFR was associated with increased antibiotic purchases (online supplementary figure 3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1). There was a modest increase in purchases with decreasing eGFR until 90 mL/min/1.73 m, and this increase was accelerated when eGFR decreased below 90 mL/min/1.73 m.
Online supplementary table S3 http://drc.bmj.com/content/3/1/e000067/suppl/DC1 shows the antibiotic purchase RRs obtained from multivariate ZIP modeling according to nephropathy status. High HbA1c increased purchases with a range of 6–10% per unit increase in HbA1c across the nephropathy groups except in the patients with ESRD. The impact of glycemic control on antibiotic purchases was studied separately in (1) patients with normal AER and (2) patients with microalbuminuria or macroalbuminuria. Among patients with microalbuminuria and macroalbuminuria, patients with poor glycemic control (HbA1c ≥9%) had 1.25 (95% CI 1.08 to 1.45) times more antibiotic purchases than those with good glycemic control (HbA1c <7%). In contrast, the number of antibiotic purchases in patients with normal AER was higher already when HbA1c was ≥7% (RR=1.22 (95% CI 1.14 to 1.31)). In patients with normal AER, the number of antibiotic purchases leveled off when HbA1c was ≥8% and in patients with microalbuminuria or macroalbuminuria when HbA1c was ≥9% (figure 1).
(Enlarge Image)
Figure 1.
Association between antibiotic purchases and glycated hemoglobin (HbA1c) values in patients with and without diabetic nephropathy. Patients with normal albumin excretion rate and microalbuminuria/macroalbuminuria are shown as open and closed squares, respectively. p Values (p<0.05; *p<0.001).
We also wanted to assess whether the frequent use of antibiotics could be associated with the progression of nephropathy. As seen in figure 2, the mean number of antibiotic purchases was higher in the group that developed microalbuminuria compared with the reference group with normal AER. In patients with incident microalbuminuria, the number of antibiotic purchases was higher at the time of nephropathy diagnosis (year 0) compared with 4 years before the progression (year −4; p=0.04 for time effect). In contrast, no significant differences were observed in the number of antibiotic purchases in patients with normal AER during the follow-up (p=0.52 for time effect).
(Enlarge Image)
Figure 2.
Relationships between annual antibiotic purchase rates and progression of microalbuminuria in patients with type 1 diabetes. Annual number of antibiotic purchases in patients with type 1 diabetes and incident microalbuminuria (progressors, n=219; closed squares), and their age, sex, and diabetes duration (±2 years) matched controls with type 1 diabetes that have retained a normal albumin excretion rate during the whole follow-up period (non-progressors, n=874; open squares). The first year of incident microalbuminuria is shown as year 0. Controls were matched for sex, age, and diabetes duration (±2 years). Values are expressed as means with 95% CIs, and were adjusted for sex, HbA1c, and diabetes duration. A dashed horizontal line indicates the level of significance between years −4 and 0 in the incident microalbuminuria group. p Values (p<0.05; *p<0.01;**p<0.001) apply to the differences in annual antibiotic purchase rates between progressors and non-progressors.
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