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Metformin may aid weight loss in overweight teenage girls
Once-daily amoxicillin eradicates group a betahemolytic strep as well as penicillin twice a day Lennon DR, Farrell E, Martin DR, Stewart JM. Once-daily amoxicillin versus twice-daily penicillin V in group A betahaemolytic streptococcal pharyngitis. Arch Dis Child 2008;93: 474-8. Question Among children with group A -hemolytic streptococcal (GABHS) pharyngitis and a high risk for rheumatic fever, how does once-daily oral amoxicillin compare with the recommended twice-daily (BID) oral penicillin V with respect to eradicating GABHS?
Randomized, non-inferiority (ⱕ10% difference in eradication rates) trial. Design
Setting
School-based clinic in New Zealand.
Participants 353 children who had throat swabs positive for
GABHS. Intervention Amoxicillin 1500 mg once daily (or 750 mg if
bodyweight was ⱕ30 kg) orally or penicillin V 500 mg twice daily (or 250 mg if bodyweight was ⱕ20 kg) orally, each treatment for 10 days.
Eradication of GABHS, determined with follow-up throat cultures on days 3-6, 12-16, and 26-36. GABHS isolates were serotyped to distinguish bacteriologic treatment failures (and relapses) from new acquisitions.
Outcomes
The upper 95% confidence limit for the differences in positive cultures between the antibiotics was 4.9% at days 3-6, 6.5% at days 12-16, and 8.5% at days 26-36. Treatment failures (including relapses) occurred at each visit in 5.8%, 12.7% and 10.7% of amoxicillin recipients and 6.2%, 11.9% and 11.3% of penicillin V recipients, respectively. No significant differences in resolution of symptoms were noted between treatment groups. One case of unsubstantiated acute rheumatic fever occurred after 7 days of amoxicillin.
Main Results
In this adequately powered study, once-daily oral amoxicillin is not inferior to twice-daily penicillin V for the treatment and eradication of GABHS in children with pharyngitis.
Conclusions
One of the problems facing care for populations at high risk of acute rheumatic fever is that of adherence to antibiotics—which we know have to be given for a relatively long period (roughly twice as long as most antibiotic courses) to be effective at reducing this important secondary nonsuppurative complication by two-thirds. Use of amoxicillin—although broader spectrum than oral penicillin— has the advantage of its longer half-life, rendering once-daily treatment possible, and lack of absorption problems with food, which probably therefore increases adherence. This study made the comparison in a randomized trial among a group of children, who were ⬎80% Pacific Island/Maori and at high risk of acute rheumatic fever, designed to test equivalence. Unfortunately it was not blinded (which would have required a placebo second dose for the amoxicillin group), and the outcome measure Commentary
Clinical Research Abstracts for Pediatricians
was the proxy of the bacteriologic profile (checking for persistence of the original Group A beta-hemolytic Streptococcus strain) rather than acute rheumatic fever itself. But the risk of bias remains low (it is hard to see how the lack of blinding could have affected the bacteriology much). It adds to the literature suggesting that amoxicillin is equivalent to oral penicillin for this purpose—and much easier to use. Chris Del Mar, MD, FRACGP Health Sciences and Medicine, Bond University Gold Coast, Australia
Metformin may aid weight loss in overweight teenage girls Love-Osborne K, Sheeder J, Zeitler P. Addition of metformin to a lifestyle modification program in adolescents with insulin resistance. J Pediatr 2008;152:817-22. Question Among obese adolescents, does metformin, when added to a program of personal goal setting, improve weight loss and clinical status compared with placebo? Design Randomized, double-blind, placebo controlled trial. Setting
Children’s Hospital, Denver, CO.
Eighty-five adolescents (mean age 15.7 years, mean body mass index (BMI) of 39.7 kg/m2) with insulin resistance. A total of 58% of the children were Hispanic, and 34% were African-American. Participants
Participants were randomized to receive metformin (70%) or placebo (30%), along with monthly goal setting for diet and exercise modification.
Intervention
Anthropometric measures, fasting blood analysis, and glucose tolerance tests at 6 months.
Outcomes
Main Results A total of 76% of participants completed the study. There were no group differences between metformin and placebo in weight loss or measures of glucose metabolism. However, among females taking metformin, there was a significant decrease in BMI not seen in the placebo group (loss of 0.40 kg/m2 ⫾ 1.60 with metformin compared with a gain of 1.04 kg/m2 ⫾ 1.19). Furthermore, metformin adherence, when accompanied by lifestyle change, was a predictor of BMI decrease of 5% or more: 6 of 10 subjects who adhered to metformin and decreased portion size decreased BMI by ⬎5%. Goal setting alone did not result in significant weight loss. Conclusions In this group of predominately minority adolescents, monthly goal setting alone did not lead to weight loss. Although the addition of metformin had no effect on weight loss overall, the agent did significantly increase weight loss among females, and weight loss was predicted by degree of metformin adherence. However, weight loss was only found in those participants also reporting lifestyle change, particularly a decrease in portion sizes. These results suggest that metformin may be a useful agent to promote short-term weight loss among girls making modest lifestyle changes.
725
“Metformin is not a weight-loss drug,” is the caveat I have heard myself say many times as I prescribe it to my obese adolescent females with polycystic ovarian syndrome. For that population, sometimes weight loss is a welcome side effect. This new study directly evaluates the role of metformin, in combination with lifestyle modification, as a tool for weight loss in obese teens. This well-designed RCT included those at highest risk for comorbidities: Hispanics and African-Americans. The rate of completion (76%) was similar to another RCT examining effect of sibutramine for overweight adults (78.6%),1 and slightly lower than a study evaluating effect of sibutramine in overweight adolescents (90.2%).2 This occurred despite a 2:1 randomization protocol, done presumably to see positive changes in a higher proportion, and encourage study completion. In absolute terms, metformin did not statistically affect change in BMI or in metabolic parameters over the 6 month time frame. However, metformin-treated subjects had significantly higher chances of decreasing BMI by at least 5%. Also, there was a linear correlation between metformin adherence and weight loss, suggesting the biologic plausibility of a weight loss effect of this medication. Use of the extended-release preparation, rapidly titrated to a higher dose, may have led to more significant results for 2 reasons: (1) better adherence and (2) increased early success, encouraging better adherence to the goal-setting part of the study. Making these changes, as well as prolonging the study, have the potential to show significant impact of a medication that has a good benefit-to-risk ratio. Guidelines for treatment of obesity in children at this time remain focused on lifestyle changes,3 but this study represents an important step toward adding tools for those at highest risk. Commentary
Julia Warren-Ulanch, MD Carolina Endocrine Raleigh, North Carolina
REFERENCES 1. Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353:2111-20. 2. Berkowitz RI, Wadden TA, Tershakovec AM, Cronquist JL. Behavior therapy and sibutramine for the treatment of adolescent obesity: A randomized controlled trial. JAMA 2003;289:1805-12. 3. Dietz WH, Robinson TN. Overweight children and adolescents. N Engl J Med 2005;352:2100-9.
No increase in cardiorespiratory events seen after diphtheria-tetanus-acellular pertussis immunization Carbone T, McEntire B, Kissin D, Kelly D, Steinschneider A, Violaris K, et al. Absence of an increase in cardiorespiratory events after diphtheria-tetanus-acellular pertussis immunization in preterm infants: a randomized, multicenter study. Pediatrics 2008;121:e1085-90. Question Among preterm infants (⬍37 weeks gestational age), does the administration of diphtheria-tetanus-acellular pertussis (DTaP) vaccine result in an increased number of cardiorespiratory events?
726
Design Setting
Randomized controlled trial. Ten neonatal intensive care units in the United
States. Participants A total of 191 preterm infants who were 56 to 60 days chronologic age at the time of enrollment. Intervention The intervention group received DTaP vaccine, and the control group had their vaccination delayed by 4 days. Outcomes The presence and number of prolonged apnea and prolonged bradycardia episodes, as detected by a 48-hour recording after immunization. Main Results In the DTaP group, 16.1% experienced at least
1 episode of prolonged apnea compared with 20.4% of control infants (P ⬎ .05). One or more prolonged bradycardia events occurred in 58.1% of immunized infants and 56.1% of the control infants (P ⬎ .05). The immunization group and the control group each had an average of 0.5 episodes of prolonged apnea. The mean number of prolonged bradycardia episodes was 2.6 in the immunization group and 2.7 in the control group. Preterm infants who received DTaP at 2 months after birth were no more likely to experience prolonged apnea and bradycardia than were control infants. This study supports the American Academy of Pediatrics recommendation regarding DTaP immunization at 2 months of age for preterm infants.
Conclusions
Commentary This study is important because it is the first randomized trial to look at a possible relationship between the administration of DTaP in a population of preterm infants and the occurrence of prolonged episodes of apnea or bradycardia. Previous case reports and retrospective studies had shown an increase in these events, leading primary care physicians to delay vaccination of preterm infants, a practice which has conflicted with guidelines from the American Academy of Pediatrics. Notably, the authors found no difference in the overall rates of these events, either the total number or the number of more severe events. There are a couple of important caveats to these findings. First, these infants were all in neonatal intensive care units, so the results cannot be generalized to all preterm infants. Second, the study was not powered a priori. Post-hoc power calculations show that they were able to detect only rather large differences between the groups (at least an 89% increase in prolonged apnea and at least a 35% increase in prolonged bradycardia). It would be more reassuring to have a study with the power to detect even smaller differences. Third, there was a high dropout rate (18%), but the authors did a good job of accounting for all of the patients at the conclusion of the trial. This study is somewhat reassuring, but we need a larger trial, and one that also includes preterm infants who are home at 2 months.
John G. Frohna, MD, MPH University of Wisconsin American Family Children’s Hospital Madison, Wisconsin
The Journal of Pediatrics • November 2008
Randomized, non-inferiority (ⱕ10% difference in eradication rates) trial. Design
Setting
School-based clinic in New Zealand.
Participants 353 children who had throat swabs positive for
GABHS. Intervention Amoxicillin 1500 mg once daily (or 750 mg if
bodyweight was ⱕ30 kg) orally or penicillin V 500 mg twice daily (or 250 mg if bodyweight was ⱕ20 kg) orally, each treatment for 10 days.
Eradication of GABHS, determined with follow-up throat cultures on days 3-6, 12-16, and 26-36. GABHS isolates were serotyped to distinguish bacteriologic treatment failures (and relapses) from new acquisitions.
Outcomes
The upper 95% confidence limit for the differences in positive cultures between the antibiotics was 4.9% at days 3-6, 6.5% at days 12-16, and 8.5% at days 26-36. Treatment failures (including relapses) occurred at each visit in 5.8%, 12.7% and 10.7% of amoxicillin recipients and 6.2%, 11.9% and 11.3% of penicillin V recipients, respectively. No significant differences in resolution of symptoms were noted between treatment groups. One case of unsubstantiated acute rheumatic fever occurred after 7 days of amoxicillin.
Main Results
In this adequately powered study, once-daily oral amoxicillin is not inferior to twice-daily penicillin V for the treatment and eradication of GABHS in children with pharyngitis.
Conclusions
One of the problems facing care for populations at high risk of acute rheumatic fever is that of adherence to antibiotics—which we know have to be given for a relatively long period (roughly twice as long as most antibiotic courses) to be effective at reducing this important secondary nonsuppurative complication by two-thirds. Use of amoxicillin—although broader spectrum than oral penicillin— has the advantage of its longer half-life, rendering once-daily treatment possible, and lack of absorption problems with food, which probably therefore increases adherence. This study made the comparison in a randomized trial among a group of children, who were ⬎80% Pacific Island/Maori and at high risk of acute rheumatic fever, designed to test equivalence. Unfortunately it was not blinded (which would have required a placebo second dose for the amoxicillin group), and the outcome measure Commentary
Clinical Research Abstracts for Pediatricians
was the proxy of the bacteriologic profile (checking for persistence of the original Group A beta-hemolytic Streptococcus strain) rather than acute rheumatic fever itself. But the risk of bias remains low (it is hard to see how the lack of blinding could have affected the bacteriology much). It adds to the literature suggesting that amoxicillin is equivalent to oral penicillin for this purpose—and much easier to use. Chris Del Mar, MD, FRACGP Health Sciences and Medicine, Bond University Gold Coast, Australia
Metformin may aid weight loss in overweight teenage girls Love-Osborne K, Sheeder J, Zeitler P. Addition of metformin to a lifestyle modification program in adolescents with insulin resistance. J Pediatr 2008;152:817-22. Question Among obese adolescents, does metformin, when added to a program of personal goal setting, improve weight loss and clinical status compared with placebo? Design Randomized, double-blind, placebo controlled trial. Setting
Children’s Hospital, Denver, CO.
Eighty-five adolescents (mean age 15.7 years, mean body mass index (BMI) of 39.7 kg/m2) with insulin resistance. A total of 58% of the children were Hispanic, and 34% were African-American. Participants
Participants were randomized to receive metformin (70%) or placebo (30%), along with monthly goal setting for diet and exercise modification.
Intervention
Anthropometric measures, fasting blood analysis, and glucose tolerance tests at 6 months.
Outcomes
Main Results A total of 76% of participants completed the study. There were no group differences between metformin and placebo in weight loss or measures of glucose metabolism. However, among females taking metformin, there was a significant decrease in BMI not seen in the placebo group (loss of 0.40 kg/m2 ⫾ 1.60 with metformin compared with a gain of 1.04 kg/m2 ⫾ 1.19). Furthermore, metformin adherence, when accompanied by lifestyle change, was a predictor of BMI decrease of 5% or more: 6 of 10 subjects who adhered to metformin and decreased portion size decreased BMI by ⬎5%. Goal setting alone did not result in significant weight loss. Conclusions In this group of predominately minority adolescents, monthly goal setting alone did not lead to weight loss. Although the addition of metformin had no effect on weight loss overall, the agent did significantly increase weight loss among females, and weight loss was predicted by degree of metformin adherence. However, weight loss was only found in those participants also reporting lifestyle change, particularly a decrease in portion sizes. These results suggest that metformin may be a useful agent to promote short-term weight loss among girls making modest lifestyle changes.
725
“Metformin is not a weight-loss drug,” is the caveat I have heard myself say many times as I prescribe it to my obese adolescent females with polycystic ovarian syndrome. For that population, sometimes weight loss is a welcome side effect. This new study directly evaluates the role of metformin, in combination with lifestyle modification, as a tool for weight loss in obese teens. This well-designed RCT included those at highest risk for comorbidities: Hispanics and African-Americans. The rate of completion (76%) was similar to another RCT examining effect of sibutramine for overweight adults (78.6%),1 and slightly lower than a study evaluating effect of sibutramine in overweight adolescents (90.2%).2 This occurred despite a 2:1 randomization protocol, done presumably to see positive changes in a higher proportion, and encourage study completion. In absolute terms, metformin did not statistically affect change in BMI or in metabolic parameters over the 6 month time frame. However, metformin-treated subjects had significantly higher chances of decreasing BMI by at least 5%. Also, there was a linear correlation between metformin adherence and weight loss, suggesting the biologic plausibility of a weight loss effect of this medication. Use of the extended-release preparation, rapidly titrated to a higher dose, may have led to more significant results for 2 reasons: (1) better adherence and (2) increased early success, encouraging better adherence to the goal-setting part of the study. Making these changes, as well as prolonging the study, have the potential to show significant impact of a medication that has a good benefit-to-risk ratio. Guidelines for treatment of obesity in children at this time remain focused on lifestyle changes,3 but this study represents an important step toward adding tools for those at highest risk. Commentary
Julia Warren-Ulanch, MD Carolina Endocrine Raleigh, North Carolina
REFERENCES 1. Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353:2111-20. 2. Berkowitz RI, Wadden TA, Tershakovec AM, Cronquist JL. Behavior therapy and sibutramine for the treatment of adolescent obesity: A randomized controlled trial. JAMA 2003;289:1805-12. 3. Dietz WH, Robinson TN. Overweight children and adolescents. N Engl J Med 2005;352:2100-9.
No increase in cardiorespiratory events seen after diphtheria-tetanus-acellular pertussis immunization Carbone T, McEntire B, Kissin D, Kelly D, Steinschneider A, Violaris K, et al. Absence of an increase in cardiorespiratory events after diphtheria-tetanus-acellular pertussis immunization in preterm infants: a randomized, multicenter study. Pediatrics 2008;121:e1085-90. Question Among preterm infants (⬍37 weeks gestational age), does the administration of diphtheria-tetanus-acellular pertussis (DTaP) vaccine result in an increased number of cardiorespiratory events?
726
Design Setting
Randomized controlled trial. Ten neonatal intensive care units in the United
States. Participants A total of 191 preterm infants who were 56 to 60 days chronologic age at the time of enrollment. Intervention The intervention group received DTaP vaccine, and the control group had their vaccination delayed by 4 days. Outcomes The presence and number of prolonged apnea and prolonged bradycardia episodes, as detected by a 48-hour recording after immunization. Main Results In the DTaP group, 16.1% experienced at least
1 episode of prolonged apnea compared with 20.4% of control infants (P ⬎ .05). One or more prolonged bradycardia events occurred in 58.1% of immunized infants and 56.1% of the control infants (P ⬎ .05). The immunization group and the control group each had an average of 0.5 episodes of prolonged apnea. The mean number of prolonged bradycardia episodes was 2.6 in the immunization group and 2.7 in the control group. Preterm infants who received DTaP at 2 months after birth were no more likely to experience prolonged apnea and bradycardia than were control infants. This study supports the American Academy of Pediatrics recommendation regarding DTaP immunization at 2 months of age for preterm infants.
Conclusions
Commentary This study is important because it is the first randomized trial to look at a possible relationship between the administration of DTaP in a population of preterm infants and the occurrence of prolonged episodes of apnea or bradycardia. Previous case reports and retrospective studies had shown an increase in these events, leading primary care physicians to delay vaccination of preterm infants, a practice which has conflicted with guidelines from the American Academy of Pediatrics. Notably, the authors found no difference in the overall rates of these events, either the total number or the number of more severe events. There are a couple of important caveats to these findings. First, these infants were all in neonatal intensive care units, so the results cannot be generalized to all preterm infants. Second, the study was not powered a priori. Post-hoc power calculations show that they were able to detect only rather large differences between the groups (at least an 89% increase in prolonged apnea and at least a 35% increase in prolonged bradycardia). It would be more reassuring to have a study with the power to detect even smaller differences. Third, there was a high dropout rate (18%), but the authors did a good job of accounting for all of the patients at the conclusion of the trial. This study is somewhat reassuring, but we need a larger trial, and one that also includes preterm infants who are home at 2 months.
John G. Frohna, MD, MPH University of Wisconsin American Family Children’s Hospital Madison, Wisconsin
The Journal of Pediatrics • November 2008