Staphylococcus aureus infections in pediatric patients with diabetes mellitus

Journal of Infection (2012) 65, 135e141

www.elsevierhealth.com/journals/jinf

Staphylococcus aureus infections in pediatric patients with diabetes mellitus* Erin N. Menne a, Rona Yoffe Sonabend a, Edward O. Mason a, Linda B. Lamberth a, Wendy A. Hammerman a, Charles G. Minard b, Sheldon L. Kaplan a, Kristina G. Hulten a,* a b

Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States

Accepted 2 April 2012 Available online 7 April 2012

KEYWORDS Diabetes; Staphylococcus aureus; MRSA; Infection; Glycemic index

Summary Objectives: To describe Staphylococcus aureus infections in children with diabetes mellitus (DM). Methods: Children with DM (cases) and S. aureus infections (2/02-6/10) were identified from a surveillance database. Patient charts were reviewed, and S. aureus isolates were characterized by molecular methods. Cases were compared to age-matched controls without DM but with CA-S. aureus skin and soft tissue infections (SSTI) using conditional logistic regression. Results: Forty-seven cases were identified; 41 were matched with 123 controls. Four cases had osteomyelitis and 43 had SSTI. Mean age was 14.2 years and 63% of cases had hemoglobin (Hb) A1c levels above 10%. Cases and controls differed by gender (85% vs. 45% female, P < 0.001), BMI% (median 87% vs. 72%, P Z 0.04), methicillin-resistant S. aureus (MRSA) infection (49% vs. 68%, P Z 0.04), and recurrent infections (22% vs. 4%, P Z 0.001). Among cases, 88% of recurrences were caused by MRSA. Conclusions: The majority of cases had poor glycemic control, more recurrences, fewer primary MRSA infections and were more likely to be female compared to a control group. Improved glycemic control may reduce the risk for infection, and decrease hospitalizations due to S. aureus infections. ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction Diabetes mellitus is increasing among children worldwide. It is estimated that about 65,000 children under 15 years of

age develop type 1 diabetes mellitus each year1 and recent studies have shown an increase in the number of children with type 2 diabetes mellitus.2,3 Type 2 diabetes accounted for 2e4% of new cases of diabetes in children and adolescents before 1992, but may now account for up to 45% of

*

This study was, in part funded by a grant from Pfizer. * Corresponding author. 1102 Bates Ave., Ste 1150, Houston, TX 77030. Tel.: þ1 832 824 4330; fax: þ1 832 825 4347. E-mail address: [email protected] (K.G. Hulten).

0163-4453/$36 ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2012.04.001

136 new-onset cases among adolescents.3 The increasing prevalence of type 2 diabetes in children and adolescents has paralleled increasing rates of overweight and obese children and adolescents.2 Among adults, diabetic patients are more susceptible to infections compared to healthy individuals.4,5 Common sites of infection in diabetic patients include the respiratory tract, urinary tract, and skin and soft tissues.6 The increased prevalence of infection may involve impairment of phagocytic activity of polymorphonuclear leukocytes which is depressed in diabetic patients due to a high serum concentration of glucose.7,8 In one study, a direct correlation was found between the overall prevalence of infection in adult patients with diabetes and their mean plasma glucose levels,5 and it has been suggested that a tight control of blood sugar levels in diabetic patients may prevent the risks and complications of infections. There are no data investigating the impact of glycemic control on infectious complications in the pediatric population. Staphyloccocus aureus is known to cause pediatric infections ranging from skin and soft tissue infections to invasive infections such as osteomyelitis, septic arthritis, bacteremia and pneumonia. In the United States, communityacquired methicillin-resistant S. aureus (CA-MRSA) has emerged as a major cause of S. aureus infections in addition to methicillin susceptible S. aureus (MSSA).9 The increase in CA-MRSA infections among both children and adults has been mainly attributed to one particular clone, USA300, which causes the majority of CA-MRSA infections at Texas Children’s Hospital (TCH), Houston, TX, and in many other regions of the United States. USA300 has also been described among MSSA isolates,10,11 and has been associated with skin and soft tissue infections (SSTI)12,13 as well as severe invasive disease.14e16 Features associated with USA300 include the PantoneValentine leukocidin, a poreforming toxin, a SCCmec cassette type IV conferring the oxacillin resistance, and an arginine catabolic mobile element (ACME).17,18 While the role of MRSA in adult diabetic foot infections has been well described,19 general studies on S. aureus infections in patients with diabetes mellitus are lacking, especially in the pediatric population. Large studies on MRSA infections frequently identify diabetes as a risk factor, and a recent publication compiling results from three randomized controlled treatment trials for MRSA SSTIs found that patients with diabetes did not respond as well to treatment as did those without diabetes.20 No studies have described in detail the S. aureus infections seen in children and adolescents with diabetes mellitus. We hypothesized that S. aureus infections in children with diabetes mellitus would differ from those of normal children with respect to clinical course, e.g., the infections would be more difficult to treat and there would be more complications. Based on previous studies we expected these differences to be related to the level of glycemic control. The first objective of this study was to identify the clinical characteristics of pediatric diabetes patients with S. aureus infections at our institution. We compared patients with type 1 vs. type 2 diabetes mellitus and patients grouped according to their level of glycemic control

E.N. Menne et al. (hemoglobin A1c levels greater or less than 10%). We also characterized the corresponding S. aureus isolates. Second, we compared the patient characteristics from the study population to a group of age-matched controls, which consisted of previously healthy children with a S. aureus SSTI who sought care at TCH within the study period.

Materials and methods Study design and patients Patients with S. aureus infections have been prospectively identified and their isolates collected at TCH, Houston, TX, since August 1, 2001.21 The study was approved by the Baylor College of Medicine Institutional Review Board and was exempt from obtaining informed consent. From the surveillance database, pediatric patients with diabetes, who presented with S. aureus infections to TCH between February 2002 and June 2010, were identified. Patients were excluded if they had cystic fibrosis related diabetes mellitus, steroid induced hyperglycemia or a medical condition associated with compromised immunity such as cancer or adrenal insufficiency. Patients with minor medical conditions such as thyroid disorder, hypertension, or lipid abnormality were not excluded. Demographic and clinical information were obtained from the hospital electronic medical records. Data on the type and location of infection, antibiotic therapy, duration of hospitalization, and history of recurrent infection were extracted. Assessment of blood glucose control was based on hemoglobin A1c levels at the time of infection or as close to the time of infection as possible, within three months before or after the date of the hospital visit. A hemoglobin A1c value <7.5% was considered to be good glycemic control; >10% suggested poorly controlled diabetes with an associated risk for diabetic ketoacidosis.22 S. aureus infections in the diabetic population were first analyzed focusing on type 1 vs. type 2 diabetes mellitus and glycemic control. We compared the findings for the diabetes group to a control group without risk factors consisting of patients with community-acquired S. aureus SSTI infections. Three age-matched controls per case were randomly selected from the surveillance database. The medical charts were reviewed for gender, race, BMI percentile, site of infection and diagnosis, inpatient or outpatient treatment, number of hospital days, white blood cell count, isolate antibiotic susceptibilities, and number of recurrent infections. Only recurrent infections that were medically attended at TCH were captured. Recurrent infection was any repeat infection that occurred >2 weeks after the previous infection. The caseecontrol study was performed excluding four cases with diagnoses other than skin and soft tissue infections (SSTI) and two cases with new-onset diabetes mellitus.

Laboratory methods The clinical microbiology laboratory of TCH initially isolated S. aureus strains and determined antibiotic susceptibilities by disk diffusion with the use of Clinical

S. aureus infections in pediatric diabetes patients

137

and Laboratory Standards Institute (CLSI) methods and interpretation guidelines.23 Inducible macrolideelincosamideestreptogramin B (MLSB) resistance was routinely tested by double disk diffusion.23 Isolates were stored in horse blood at 80  C in the infectious disease laboratory until further use. The strains were grown on tryptic soy agar plates containing 5% sheep blood. Isolates were typed and analyzed by pulsed field gel electrophoresis (PFGE) as previously described.21 Bacterial DNA was isolated with the QIA cube (Qiagen, Valencia, CA) using Qiagen’s DNeasy blood and tissue kit

Table 1

according to the manufacturer’s protocol for gram-positive bacteria. Presence of the PantoneValentine leukocidin (PVL) genes was determined by polymerase chain reaction (PCR) and multiplex PCR was used to determine the staphylococcal cassette chromosome (SCC) mec type for all MRSA strains.21

Statistical analysis Categorical variables were compared across groups using Fisher’s exact test and continuous variables were compared using the nonparametric KolmogoroveSmirnov test. Odds

Comparison of patients with S. aureus infections and Type 1 vs. Type 2 diabetes.

Gender, n (%) Female Race, n (%) Caucasian Black Hispanic Age, years Mean  SD Median (range) BMI percentile Mean  SD Median (range) Weight, n (%) Normal Overweight Obese Incision & Drainage, n (%) Age at onset of diabetes, years Mean  SD Median (range) Duration of diabetes at date of encounter, years Mean  SD Median (range) Hemoglobin A1c level, n (%)b n <10% 10% Intensive Insulin Management, n (%) Pump Therapy, n (%) Inpatient care, n (%) Hospital days Mean  SD Median (range) S. aureus, n (%) MRSA MSSA Patients with recurrent infections, n (%)

Pa

Type 1 diabetes (n Z 36)

Type 2 diabetes (n Z 11)

28 (77.8)

11 (100)

0.170

13 (36.1) 17 (47.2) 6 (16.7)

0 (0) 6 (54.6) 5 (45.5)

0.018

13.9  4.1 15.0 (2.1e18.6)

15.4  2.0 14.9 (11.7e18.8)

0.333

77.7  17.9 81.7 (34.6e99.0)

96.1  6.4 99.0 (77.8e99.7)

0.002

19 (52.8) 10 (27.8) 7 (19.4) 26 (72.2)

1 2 8 6

0.003

7.5  3.8 8.0 (0.8e16.0)

12.7  2.2 13.0 (8.0e15.0)

5.4  3.7 4.0 (0e16.0)

1.9  1.7 2.0 (0e5.0)

0.107

33 11 (36.4) 22 (63.6) 11 (30.6) 4 (11.1) 26 (72.2)

8 4 4 0 0 7

0.434

5.1  8.5 3.0 (0e44)

6.2  7.0 4.0 (0e20)

0.656

19 (52.8) 17 (47.2) 9 (25.0)

4 (36.4) 7 (63.6) 0 (0)

0.494

(9.1) (18.2) (72.7) (54.6)

(55.6) (44.4) (0) (0) (63.6)

0.292 <0.001

0.046 0.560 0.710

0.092

a Categorical variables were compared using Fisher’s exact test and continuous variables were compared using the nonparametric KolmogoroveSmirnov test. b Six patients had no hemoglobin A1c level within the specified time frame (3 months before or after the date of the hospital visit).

138 ratios comparing cases to controls were estimated using conditional logistic regression. Statistically significant risk factors were further considered in a multivariable logistic regression model. Stata (College Station, TX) and SAS (Cary, NC) were used to perform all analyses assuming a 0.05 level of significance.

Results Cases Forty-seven patients with diabetes who had a S. aureus infection from between February 2002 and June 2010 were identified. Nine patients had a total of 16 recurrent infections. Only the first incident of infection was included in the main analysis; recurrences were compared separately. Thirty-nine (83.0%) patients were female. The mean age at time of infection was 14.2 years (SD Z 3.7). The mean BMI percentile was 82.0% (SD Z 17.7), 12 (25.5%) patients were classified as overweight and 15 (31.9%) as obese using the Centers for Disease Control and Prevention definitions.24 Thirty-six (76.6%) patients had type 1 diabetes and 11 (23.4%) had type 2 diabetes (Table 1). Primary S. aureus infections consisted of skin and soft tissue infections (36 abscesses, 2 infected wounds, 2 pustules and one each of an infected insect bite, folliculitis, and otitis externa) and four invasive infections (four osteomyelitis with bacteremia). Thirty-three (70.2%) of the primary infection episodes required inpatient treatment. Hemoglobin A1c levels was available within the specified time period for 41 of the 47 cases. The mean hemoglobin A1c was 10.9% (SD Z 2.6). Only 3 (7.3%) patients had a hemoglobin A1c < 7.5%. The cases were compared according to whether they had type 1 or type 2 diabetes (Table 1). Race (P Z 0.02), BMI percentile (P Z 0.002), weight group (P Z 0.003), age at onset of diabetes (P < 0.001) and intensive insulin management (P Z 0.05) were significantly different between groups. None of the Type 2 diabetes patients were on intensive insulin management and none experienced recurrent infections compared with 30.6% and 25% of the Type 1 diabetes patients, respectively. Although not statistically significant, Type 2 diabetes patients had a shorter time between onset of diabetes and the infection incident compared with Type 1 diabetes patients (median 2 years vs. 4, P Z 0.11). After adjusting for age at onset in a logistic regression model, only BMI percentile maintained statistical significance (P Z 0.02). Race, weight group, and intensive insulin management were no longer significant (P  0.06).

E.N. Menne et al.

Recurrences Nine cases had a total of 16 recurrent infections. Patients experienced between one and three recurrences after the initial infection during the study period. Eight patients had recurrent abscesses and one patient had a primary pustulosis infection followed by an episode of diffuse impetigo. For 8 of the 16 recurrences, the patient was hospitalized. Patients without recurrent infections were compared to those with recurrent infections. All cases with recurrences had type 1 diabetes. Recurrences occurred between two weeks to two and a half years after the initial infection. Fourteen (81.3%) of 16 recurrent isolates were MRSA. The antibiotic susceptibilities of the primary infection isolates were compared to the recurrent infection isolates. Nine of the 47 (19.2%) primary isolates were non-susceptible to clindamycin vs. 8 of the 16 (50%) recurrent isolates (P < 0.02). Twenty-three of the 47 (48.9%) primary isolates were MRSA vs. 14/16 (87.5%) recurrent isolates (P Z 0.008). Seven of 9 (77.8%) patients who had recurrences had an

S. aureus isolate molecular analysis Sixty primary and recurrent isolates from 44 cases were available for the molecular studies (3 primary infection isolates from 3 patients were not available). Thirty-six (60.0%) were MRSA and 24 (40.0%) were MSSA. Overall, 42 (70.0%) isolates were USA300. All of the MRSA isolates were USA300, SCCmec type IV, and PVL genes positive. Six (25.0%) of the 24 MSSA isolates were USA300 and 14 (58.0%) were PVL genes positive.

Figure 1 Pulsed-field gel electrophoresis (PFGE) and GelCompar II analysis of initial and recurrent S. aureus isolates from nine type 1 diabetes patients. Isolates are presented per patient with the initial isolate presented on top, followed by recurrent isolates below, in chronological order. The time intervals since the previous S. aureus infection are specified. S-MSSA, R-MRSA.

S. aureus infections in pediatric diabetes patients initial MRSA infection vs. 16 of 39 (42.1%) patients with no recurrences (P Z 0.054). Fourteen (87.5%) of 16 recurrent isolates were USA300. In all but one patient, the recurrent isolate was identical to the initial/previous infecting isolate. One patient with an initial MSSA infection had a recurrent infection with an unrelated MSSA isolate. This re-infection occurred almost 2 years after the first infection (Fig. 1). Seven of 9 patients were treated with clindamycin for their primary infections, one patient with a clindamycin resistant isolate received trimethoprim-sulfamethoxazole and one patient with an MSSA pustulosis infection received cephalexin. Three of 8 patients with primary clindamycin susceptible isolates had subsequent recurrences with clindamycin resistant isolates.

Caseecontrol comparisons The age-matched control group consisted of 123 patients with community-acquired S. aureus skin and soft tissue

Table 2

139 infections. BMI percentile was available for only 25 of the controls. (Table 2). Cases were more likely to be female (P < 0.001), black (P < 0.008), have a greater BMI percentile (P Z 0.04), and have an MSSA infection (P Z 0.04). After adjusting for gender in a multivariable logistic regression model, none of the other variables maintained statistical significance (P  0.12). Recurrent infections were about 6.3 times (95% CI: 1.9, 20.7) more likely to occur among cases compared with controls. There was also a trend for cases to spend more days in the hospital (P Z 0.07).

Discussion In recent years, CA-MRSA infections have become increasingly prevalent among pediatric patients and diabetes has been described as a risk factor for S. aureus infection among both adults and children.25,26 While no recent studies have investigated S. aureus infections in children and adolescents with type 1 and type 2 diabetes, several studies describe S. aureus nasal colonization, which may

Age matched caseecontrol analysis for patients with skin and soft tissue infections.

Gender, n (%) Male Female Race, n (%) Caucasian African American Hispanic Other/Unknown BMI percentile n Mean  SD Median (range) Weight Group, n (%) Normal Overweight Obese Location of care, n (%) Inpatient Hospital days n Mean  SD Median (range) S. aureus, n (%) MRSA MSSA WBC count n Mean  SD (cells 103/mm3) Median (range) Patients with recurrent infections, n (%)

Pa

Cases (n Z 41)

Controls (n Z 123)

Odds ratio (95% CI)

6 (14.6) 35 (85.4)

68 (55.3) 55 (44.7)

6.4 (2.6, 15.8)

12 (29.3) 22 (53.7) 7 (17.1) 0 (0)

40 34 39 10

1.0 2.2 0.6 0.2

41 83.0  16.5 87.4 (42.7e99.7)

25 61.4  37.1 71.7 (1.2e99.4)

1.0 (1.0, 1.1)

17 (41.5) 10 (24.4) 14 (34.2)

14 (56.0) 4 (16.0) 7 (28.0)

1.0 (ref) 2.0 (0.4, 11.2) 1.7 (0.4, 8.0)

0.515

27 (65.9)

66 (53.7)

1.5 (0.8e3.1)

0.205

41 3.0  3.0 2.0 (0e11)

123 1.8  2.1 2.0 (0e10)

1.2 (1.0e1.3)

20 (48.8) 21 (51.2)

84 (68.3) 39 (31.7)

2.1 (1.1e4.3)

15 12.7  4.6

33 11.7  3.5

12.3 (6.0e22.4) 9 (22.0)

11.8 (4.4e18.1) 5 (4.1)

(32.5) (27.6) (31.7) (8.1)

<0.001

(ref) (0.9, 5.9)b (0.2, 1.9)b (0, 1.3)b

0.008

0.037

0.066

0.039

0.928

1.4 (0.9e2.4) 6.3 (1.9e20.7)

0.001

a Categorical variables were compared using Fisher’s exact test and continuous variables were compared using the nonparametric KolmogoroveSmirnov test. b Odds ratios were estimated using exact, conditional logistic regression.

140 predispose to infection.27 The studies differ widely in the percentage of adult and pediatric diabetes patients that are S. aureus carriers, with rates ranging from 11 to 76%.28,29 Furthermore, S. aureus nasal colonization rates tended to be greater for patients with a higher (>9%) hemoglobin A1c.28 In the present study, pediatric diabetes patients presenting with S. aureus infections between 2002 and 2010 were evaluated. The mean age at the time of infection was 14.2 years old, which is much older than what was previously found among community-acquired S. aureus infections at the same institution.9 The diabetic patients in this study presented with S. aureus infections during adolescence, a time that frequently involves poor glycemic control for both type 1 and type 2 diabetes patients.30,31 The worsening of glycemic control during adolescence appears to be caused by physiological changes of puberty, such as increased insulin resistance, and psychological factors that affect adherence to treatment regimens.32 A study by Morris et al. demonstrated that patients aged 10e20 years had a higher hemoglobin A1c and a lower adherence index when compared to patients younger than 10 years or older than 20 years.33 Failure to take insulin occurred in at least 28% of patients and was directly associated with poor glycemic control and acute complications related to diabetes.33 The female gender has been shown to be at greatest risk for poor metabolic control during adolescence.31 The majority of diabetic patients with S. aureus infections in this study were female. Dabadghao et al. found that worsening of glycemic control in adolescence is associated with an increase in BMI, particularly in females.31 Studies demonstrate that self-concept is an important predictor of metabolic control in adolescent girls.34 Therefore, close surveillance of adolescents to maintain good glycemic control may be necessary to reduce the risk of S. aureus infections. In our study, the mean hemoglobin A1c value of patients around the time of infection was 10.9%. Current ADA recommendations state the desired hemoglobin A1c value during adolescence is 7.5%, with a goal of 7.0% being reasonable if it can be achieved without excessive hypoglycemia.22 We report only three (7.3%) patients with a hemoglobin A1c <7.5% around the time of their primary S. aureus infection. Thus, the majority of patients in this study were poorly controlled. This finding is in line with previous reports on the increased susceptibility to infections for patients with diabetes, especially those with poor glycemic control.5e7,35 We found that only type 1 diabetes patients had recurrent S. aureus infections. Furthermore, type 1 diabetes patients appeared to have a longer duration of their diabetes prior to the S. aureus infection, although this finding did not reach statistical significance. There was no difference in hemoglobin A1c values of type 1 and type 2 diabetes patients, therefore the greater number of recurrences in type 1 diabetes patients may be intrinsic to the disease or may possibly be related to the longer duration of the patients’ diabetes at the time of infection. Limitations of this study included the retrospective study design and the number of cases. The lack of a control group of diabetes patients who did not have a S. aureus

E.N. Menne et al. infection was also a limitation, since risk for infection in relation to glycemic control and differences between patients with type 1 and type 2 diabetes could have been better defined. Further studies comparing glycemic control of diabetes patients with and without S. aureus infections are required to better establish the relationship between glycemic control and risk for infection. In addition to S. aureus infections, investigating a broader range of infections in diabetic children and adolescents would be beneficial. In conclusion, our study showed that S. aureus infections were associated with females and poorly controlled diabetes, and the patients with diabetes were more prone to recurrences compared to children with no underlying risk factors.

Acknowledgment The study was presented, in part, as a poster at the Pediatric Academic Society Annual Meeting, Denver, Colorado, April 30eMay 3, 2011, Paper #535. This study was supported, in part, by an investigator initiated grant from Pfizer (Kaplan). The funding source had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr. Kaplan is the local PI for a study initiated by Cubist.

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