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What are the adverse effects of prolonged opioid use in patients with chronic pain?
CONSTIPATION, NAUSEA, AND DYSPEPSIA are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.)
Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports).
Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report).
Evidence summary
Chronic pain is usually defined as pain persisting longer than 3 months. Evidence of the efficacy of opioids for noncancer pain has led to increased opioid prescribing over the past 20 years and with it, growing concern about adverse effects from long-term use.1
Nausea, constipation, dyspepsia lead side-effects parade
A Cochrane systematic review of 26 studies (25 observational studies and 1 randomized controlled trial [RCT]) of adults who had taken opioids for noncancer pain for at least 6 months assessed the adverse effects of long-term opioid therapy.2 Although the authors couldn’t quantify the incidence of adverse effects because of inconsistent reporting and definition of effects, they stated that the most common complications were nausea, constipation, and dyspepsia. The review found that 22.9% of patients (95% confidence interval [CI], 15.3-32.8) discontinued oral opioids because of adverse effects.
A cross-sectional observational study evaluated self-reported adverse effects in 889 patients who received opioid therapy for noncancer pain lasting at least 3 months.3 Forty percent of patients reported constipation and 18% sexual dysfunction. Patients taking opioids daily experienced more constipation than patients taking the drugs intermittently (39% vs 24%; number needed to harm [NNH]=7; P<.05).
Sexual dysfunction, fatigue, depression aren’t far behind
A case-control study of 20 male cancer survivors with neuropathic pain who took 200 mg of morphine-equivalent daily for a year found that 90% of patients in the opioid group experienced hypogonadism with symptoms of sexual dysfunction, fatigue, and depression, compared with 40% of the 20 controls (NNH=2; 95% CI, 1-5).4
A case-controlled observational study of 54 men with noncancer pain who took opioids for 1 year found that 39 of 45 men who had normal erectile function before opioid therapy reported severe erectile dysfunction while taking the drugs.5 Levels of testosterone and estradiol were significantly lower (P<.0001) in the men taking opioids than the 27 opioid-free controls.
Potentially fatal arrhythmias are a risk for some patients
From 1969 to 2002, 59 cases of QT prolongation or torsades de pointes in methadone users, 5 (8.5%) of them fatal, were reported to the US Food and Drug Administration’s Medwatch Database.6 The mean daily methadone dose was 410 mg (median dose 345 mg, range 29-1680 mg). Length of therapy was not reported. In 44 (75%) of reported cases, patients had other known risks for QT prolongation or torsades de pointes, including female sex, interacting medications, potassium or magnesium abnormalities, and structural heart disease.
Buprenorphine may cause acute hepatitis
No apparent long-term hepatic adverse effects are associated with chronic opioid use. However, a 2004 case series described acute cytolytic hepatitis in 7 patients taking buprenorphine, all with hepatitis C and a history of intravenous drug abuse.7 Acute symptoms resolved quickly in all cases, and only 3 patients required a reduction in buprenorphine dosage.
Prolonged use may increase sensitivity to pain
Case reports and case series have found that prolonged use of opioids causes increased sensitivity to pain in some patients, which is difficult to differentiate from opioid tolerance.8
Recommendations
The American Pain Society (APS) recommends anticipating, identifying, and treating opioid-related adverse effects such as constipation or nausea.1 APS advises against using opioid antagonists to prevent or treat bowel dysfunction, and encourages older patients or patients with an increased risk of developing constipation to start a bowel regimen. Patients with complaints suggesting hypogonadism should be tested for hormonal deficiencies.
The Center for Substance Abuse and Treatment recommends obtaining a cardiac history and an electrocardiogram (EKG) on all patients before starting methadone and repeating the EKG at 30 days and annually thereafter to evaluate for QT prolongation.9 Prescribers should also warn patients of the risk of methadone-induced arrhythmias and be aware of interacting medications that prolong the QT interval or reduce methadone elimination.
1. Chou R, Fanciullo GJ, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009;10:113-130.
2. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.-
3. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137-146.
4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851-858.
5. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.
6. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-753.
7. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037.
8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;20:1943-1953.
9. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
CONSTIPATION, NAUSEA, AND DYSPEPSIA are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.)
Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports).
Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report).
Evidence summary
Chronic pain is usually defined as pain persisting longer than 3 months. Evidence of the efficacy of opioids for noncancer pain has led to increased opioid prescribing over the past 20 years and with it, growing concern about adverse effects from long-term use.1
Nausea, constipation, dyspepsia lead side-effects parade
A Cochrane systematic review of 26 studies (25 observational studies and 1 randomized controlled trial [RCT]) of adults who had taken opioids for noncancer pain for at least 6 months assessed the adverse effects of long-term opioid therapy.2 Although the authors couldn’t quantify the incidence of adverse effects because of inconsistent reporting and definition of effects, they stated that the most common complications were nausea, constipation, and dyspepsia. The review found that 22.9% of patients (95% confidence interval [CI], 15.3-32.8) discontinued oral opioids because of adverse effects.
A cross-sectional observational study evaluated self-reported adverse effects in 889 patients who received opioid therapy for noncancer pain lasting at least 3 months.3 Forty percent of patients reported constipation and 18% sexual dysfunction. Patients taking opioids daily experienced more constipation than patients taking the drugs intermittently (39% vs 24%; number needed to harm [NNH]=7; P<.05).
Sexual dysfunction, fatigue, depression aren’t far behind
A case-control study of 20 male cancer survivors with neuropathic pain who took 200 mg of morphine-equivalent daily for a year found that 90% of patients in the opioid group experienced hypogonadism with symptoms of sexual dysfunction, fatigue, and depression, compared with 40% of the 20 controls (NNH=2; 95% CI, 1-5).4
A case-controlled observational study of 54 men with noncancer pain who took opioids for 1 year found that 39 of 45 men who had normal erectile function before opioid therapy reported severe erectile dysfunction while taking the drugs.5 Levels of testosterone and estradiol were significantly lower (P<.0001) in the men taking opioids than the 27 opioid-free controls.
Potentially fatal arrhythmias are a risk for some patients
From 1969 to 2002, 59 cases of QT prolongation or torsades de pointes in methadone users, 5 (8.5%) of them fatal, were reported to the US Food and Drug Administration’s Medwatch Database.6 The mean daily methadone dose was 410 mg (median dose 345 mg, range 29-1680 mg). Length of therapy was not reported. In 44 (75%) of reported cases, patients had other known risks for QT prolongation or torsades de pointes, including female sex, interacting medications, potassium or magnesium abnormalities, and structural heart disease.
Buprenorphine may cause acute hepatitis
No apparent long-term hepatic adverse effects are associated with chronic opioid use. However, a 2004 case series described acute cytolytic hepatitis in 7 patients taking buprenorphine, all with hepatitis C and a history of intravenous drug abuse.7 Acute symptoms resolved quickly in all cases, and only 3 patients required a reduction in buprenorphine dosage.
Prolonged use may increase sensitivity to pain
Case reports and case series have found that prolonged use of opioids causes increased sensitivity to pain in some patients, which is difficult to differentiate from opioid tolerance.8
Recommendations
The American Pain Society (APS) recommends anticipating, identifying, and treating opioid-related adverse effects such as constipation or nausea.1 APS advises against using opioid antagonists to prevent or treat bowel dysfunction, and encourages older patients or patients with an increased risk of developing constipation to start a bowel regimen. Patients with complaints suggesting hypogonadism should be tested for hormonal deficiencies.
The Center for Substance Abuse and Treatment recommends obtaining a cardiac history and an electrocardiogram (EKG) on all patients before starting methadone and repeating the EKG at 30 days and annually thereafter to evaluate for QT prolongation.9 Prescribers should also warn patients of the risk of methadone-induced arrhythmias and be aware of interacting medications that prolong the QT interval or reduce methadone elimination.
CONSTIPATION, NAUSEA, AND DYSPEPSIA are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.)
Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports).
Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report).
Evidence summary
Chronic pain is usually defined as pain persisting longer than 3 months. Evidence of the efficacy of opioids for noncancer pain has led to increased opioid prescribing over the past 20 years and with it, growing concern about adverse effects from long-term use.1
Nausea, constipation, dyspepsia lead side-effects parade
A Cochrane systematic review of 26 studies (25 observational studies and 1 randomized controlled trial [RCT]) of adults who had taken opioids for noncancer pain for at least 6 months assessed the adverse effects of long-term opioid therapy.2 Although the authors couldn’t quantify the incidence of adverse effects because of inconsistent reporting and definition of effects, they stated that the most common complications were nausea, constipation, and dyspepsia. The review found that 22.9% of patients (95% confidence interval [CI], 15.3-32.8) discontinued oral opioids because of adverse effects.
A cross-sectional observational study evaluated self-reported adverse effects in 889 patients who received opioid therapy for noncancer pain lasting at least 3 months.3 Forty percent of patients reported constipation and 18% sexual dysfunction. Patients taking opioids daily experienced more constipation than patients taking the drugs intermittently (39% vs 24%; number needed to harm [NNH]=7; P<.05).
Sexual dysfunction, fatigue, depression aren’t far behind
A case-control study of 20 male cancer survivors with neuropathic pain who took 200 mg of morphine-equivalent daily for a year found that 90% of patients in the opioid group experienced hypogonadism with symptoms of sexual dysfunction, fatigue, and depression, compared with 40% of the 20 controls (NNH=2; 95% CI, 1-5).4
A case-controlled observational study of 54 men with noncancer pain who took opioids for 1 year found that 39 of 45 men who had normal erectile function before opioid therapy reported severe erectile dysfunction while taking the drugs.5 Levels of testosterone and estradiol were significantly lower (P<.0001) in the men taking opioids than the 27 opioid-free controls.
Potentially fatal arrhythmias are a risk for some patients
From 1969 to 2002, 59 cases of QT prolongation or torsades de pointes in methadone users, 5 (8.5%) of them fatal, were reported to the US Food and Drug Administration’s Medwatch Database.6 The mean daily methadone dose was 410 mg (median dose 345 mg, range 29-1680 mg). Length of therapy was not reported. In 44 (75%) of reported cases, patients had other known risks for QT prolongation or torsades de pointes, including female sex, interacting medications, potassium or magnesium abnormalities, and structural heart disease.
Buprenorphine may cause acute hepatitis
No apparent long-term hepatic adverse effects are associated with chronic opioid use. However, a 2004 case series described acute cytolytic hepatitis in 7 patients taking buprenorphine, all with hepatitis C and a history of intravenous drug abuse.7 Acute symptoms resolved quickly in all cases, and only 3 patients required a reduction in buprenorphine dosage.
Prolonged use may increase sensitivity to pain
Case reports and case series have found that prolonged use of opioids causes increased sensitivity to pain in some patients, which is difficult to differentiate from opioid tolerance.8
Recommendations
The American Pain Society (APS) recommends anticipating, identifying, and treating opioid-related adverse effects such as constipation or nausea.1 APS advises against using opioid antagonists to prevent or treat bowel dysfunction, and encourages older patients or patients with an increased risk of developing constipation to start a bowel regimen. Patients with complaints suggesting hypogonadism should be tested for hormonal deficiencies.
The Center for Substance Abuse and Treatment recommends obtaining a cardiac history and an electrocardiogram (EKG) on all patients before starting methadone and repeating the EKG at 30 days and annually thereafter to evaluate for QT prolongation.9 Prescribers should also warn patients of the risk of methadone-induced arrhythmias and be aware of interacting medications that prolong the QT interval or reduce methadone elimination.
1. Chou R, Fanciullo GJ, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009;10:113-130.
2. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.-
3. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137-146.
4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851-858.
5. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.
6. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-753.
7. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037.
8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;20:1943-1953.
9. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
1. Chou R, Fanciullo GJ, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009;10:113-130.
2. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.-
3. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137-146.
4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851-858.
5. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.
6. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-753.
7. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037.
8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;20:1943-1953.
9. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
Evidence-based answers from the Family Physicians Inquiries Network
Which asthma patients should get the pneumococcal vaccine?
ADULTS BETWEEN THE AGES OF 19 AND 64 YEARS who have chronic lung disease, including asthma, should get the vaccine, as should all patients 65 years and older (strength of recommendation [SOR]: C, consensus guidelines). Evidence doesn’t support routine vaccination of children with asthma or adults younger than 65 years who don’t have chronic lung disease to decrease asthma-related or pneumonia-related hospitalizations (SOR: B, 1 retrospective cohort study and 1 retrospective, case-controlled cohort study).
Evidence summary
A 5-year retrospective cohort study of 9170 patients evaluated the effect of pneumococcal vaccination on incidence and length of all-cause hospitalizations and hospitalizations related to respiratory and otorhinolaryngologic syndromes, including asthma and pneumonia.1 The vaccine was given to all patients older than 64 years (7834 patients [85%]) and any patient at risk for pneumococcal infection or complications, including patients with asthma, chronic obstructive pulmonary disease (COPD), bronchitis, chronic respiratory disease, cardiovascular disease, chronic renal failure, diabetes mellitus, immunodeficiency, and functional or anatomic asplenia (1336 patients [15%]).
The number of all-cause hospitalizations was reduced by 58% in patients who received the pneumococcal vaccine (relative risk [RR]=0.96; 95% confidence interval [CI], 0.94-0.98). In vaccinated patients with asthma (793 patients [8.7%]), asthma-related hospitalizations decreased by 78% (RR=1.82; 95% CI, 1.35-2.45; NNT=49) and average asthma-related length of hospital stay was shortened by about 2 days (P=.039). The study found no difference in pneumonia-related hospitalizations among all vaccinated patients.
Effect on younger patients is unclear
Because the investigators didn’t analyze asthma-related or pneumonia-related hospitalizations among asthmatic patients 64 years and younger, the effect of pneumococcal vaccination on this younger subgroup can’t be differentiated from the entire group of patients with asthma.1
What about pneumococcal hospitalization?
A retrospective, case-controlled cohort study examined the impact of pneumococcal vaccination on any pneumococcal-related hospitalization in patients with COPD or asthma.2 The study included 2746 adults with asthma (74.2% younger than 64 years) who were followed for about 2.1 years before and 2.6 years after vaccination.
Investigators found no significant differences in risk of pneumococcal-related hospitalization between asthma patients and controls throughout the study. They didn’t evaluate asthma-related hospital admissions.
Impact of vaccine on invasive disease in younger asthma patients?
A retrospective, nested, case-controlled study examined the relationship between asthma and invasive pneumococcal disease (IPD) in 6985 patients enrolled in Tennessee’s Medicaid program.3 Patients 2 to 49 years of age with any IPD diagnosis were identified using International Classification of Diseases (ICD-9-CM) codes and followed for 8 years.
Asthma patients without coexisting conditions that confer a high risk of IPD (such as diabetes, cardiac disease, and infection with human immunodeficiency virus) had a 14.7% risk of IPD compared with a risk of only 7.4% in age-matched controls (adjusted odds ratio=2.4; 95% CI, 1.7-3.4). The authors concluded that this Medicaid population with asthma had an increased incidence of IPD of 1 to 3 cases annually per 10,000 people. The effect of pneumococcal vaccination on the incidence of IPD in these younger asthma patients is unknown, however.3
Recommendations
The National Asthma Education and Prevention Program (NAEPP)4 and the Global Initiative for Asthma (GINA)5 make no recommendations regarding the administration of the pneumococcal vaccine.
The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all adults 65 years and older and adults 19 years and older with chronic lung disease, including asthma, or other chronic medical conditions such as cardiovascular diseases, diabetes, chronic liver diseases, chronic alcoholism, chronic renal failure, asplenia, and other immunocompromising conditions.6
The British Department of Health recommends vaccination with either the 7-valent conjugate or the 23-valent polysaccharide pneumococcal vaccine for all asthma patients taking systemic steroids longer than 1 month at a dose equivalent to prednisolone 20 mg daily and for children weighing less than 20 kg who take daily steroids at a dose of ≥1 mg/kg. Efficacy studies aren’t available to support this recommendation.7
1. Ansaldi F, Turello V, Lai P, et al. Effectiveness of a 23-valent polysaccharide vaccine in preventing pneumonia and non-invasive pneumococcal infection in elderly people: a large-scale retrospective cohort study. J Int Med Res. 2005;33:490-500.
2. Lee TA, Weaver FM, Weiss KB. Impact of pneumococcal vaccination on pneumonia rates in patients with COPD and asthma. J Gen Intern Med. 2007;22:62-67.
3. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk for invasive pneumococcal disease. N Engl J Med. 2005;352:2082-2090.
4. National Heart Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health; 1991:11.
5. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Available at: www.ginasthma.org/Guidelineitem.asp?l1=2&l2=1&intId=60. Accessed December 10, 2007.
6. Centers for Disease Control and Prevention. Recommended adult immunization schedule—United States, 2009. MMWR Morb Mortal Wkly Rep. 2008;57(53):Q1-Q4.
7. Department of Health. Immunisation Against Infectious Disease 2006: The Green Book. London, England: Department of Health; 2007. Available at: www.dh.gov.uk/en/Policyandguidance/Healthandsocialcaretopics/Greenbook/DH_4097254. Accessed December 10, 2007.
ADULTS BETWEEN THE AGES OF 19 AND 64 YEARS who have chronic lung disease, including asthma, should get the vaccine, as should all patients 65 years and older (strength of recommendation [SOR]: C, consensus guidelines). Evidence doesn’t support routine vaccination of children with asthma or adults younger than 65 years who don’t have chronic lung disease to decrease asthma-related or pneumonia-related hospitalizations (SOR: B, 1 retrospective cohort study and 1 retrospective, case-controlled cohort study).
Evidence summary
A 5-year retrospective cohort study of 9170 patients evaluated the effect of pneumococcal vaccination on incidence and length of all-cause hospitalizations and hospitalizations related to respiratory and otorhinolaryngologic syndromes, including asthma and pneumonia.1 The vaccine was given to all patients older than 64 years (7834 patients [85%]) and any patient at risk for pneumococcal infection or complications, including patients with asthma, chronic obstructive pulmonary disease (COPD), bronchitis, chronic respiratory disease, cardiovascular disease, chronic renal failure, diabetes mellitus, immunodeficiency, and functional or anatomic asplenia (1336 patients [15%]).
The number of all-cause hospitalizations was reduced by 58% in patients who received the pneumococcal vaccine (relative risk [RR]=0.96; 95% confidence interval [CI], 0.94-0.98). In vaccinated patients with asthma (793 patients [8.7%]), asthma-related hospitalizations decreased by 78% (RR=1.82; 95% CI, 1.35-2.45; NNT=49) and average asthma-related length of hospital stay was shortened by about 2 days (P=.039). The study found no difference in pneumonia-related hospitalizations among all vaccinated patients.
Effect on younger patients is unclear
Because the investigators didn’t analyze asthma-related or pneumonia-related hospitalizations among asthmatic patients 64 years and younger, the effect of pneumococcal vaccination on this younger subgroup can’t be differentiated from the entire group of patients with asthma.1
What about pneumococcal hospitalization?
A retrospective, case-controlled cohort study examined the impact of pneumococcal vaccination on any pneumococcal-related hospitalization in patients with COPD or asthma.2 The study included 2746 adults with asthma (74.2% younger than 64 years) who were followed for about 2.1 years before and 2.6 years after vaccination.
Investigators found no significant differences in risk of pneumococcal-related hospitalization between asthma patients and controls throughout the study. They didn’t evaluate asthma-related hospital admissions.
Impact of vaccine on invasive disease in younger asthma patients?
A retrospective, nested, case-controlled study examined the relationship between asthma and invasive pneumococcal disease (IPD) in 6985 patients enrolled in Tennessee’s Medicaid program.3 Patients 2 to 49 years of age with any IPD diagnosis were identified using International Classification of Diseases (ICD-9-CM) codes and followed for 8 years.
Asthma patients without coexisting conditions that confer a high risk of IPD (such as diabetes, cardiac disease, and infection with human immunodeficiency virus) had a 14.7% risk of IPD compared with a risk of only 7.4% in age-matched controls (adjusted odds ratio=2.4; 95% CI, 1.7-3.4). The authors concluded that this Medicaid population with asthma had an increased incidence of IPD of 1 to 3 cases annually per 10,000 people. The effect of pneumococcal vaccination on the incidence of IPD in these younger asthma patients is unknown, however.3
Recommendations
The National Asthma Education and Prevention Program (NAEPP)4 and the Global Initiative for Asthma (GINA)5 make no recommendations regarding the administration of the pneumococcal vaccine.
The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all adults 65 years and older and adults 19 years and older with chronic lung disease, including asthma, or other chronic medical conditions such as cardiovascular diseases, diabetes, chronic liver diseases, chronic alcoholism, chronic renal failure, asplenia, and other immunocompromising conditions.6
The British Department of Health recommends vaccination with either the 7-valent conjugate or the 23-valent polysaccharide pneumococcal vaccine for all asthma patients taking systemic steroids longer than 1 month at a dose equivalent to prednisolone 20 mg daily and for children weighing less than 20 kg who take daily steroids at a dose of ≥1 mg/kg. Efficacy studies aren’t available to support this recommendation.7
ADULTS BETWEEN THE AGES OF 19 AND 64 YEARS who have chronic lung disease, including asthma, should get the vaccine, as should all patients 65 years and older (strength of recommendation [SOR]: C, consensus guidelines). Evidence doesn’t support routine vaccination of children with asthma or adults younger than 65 years who don’t have chronic lung disease to decrease asthma-related or pneumonia-related hospitalizations (SOR: B, 1 retrospective cohort study and 1 retrospective, case-controlled cohort study).
Evidence summary
A 5-year retrospective cohort study of 9170 patients evaluated the effect of pneumococcal vaccination on incidence and length of all-cause hospitalizations and hospitalizations related to respiratory and otorhinolaryngologic syndromes, including asthma and pneumonia.1 The vaccine was given to all patients older than 64 years (7834 patients [85%]) and any patient at risk for pneumococcal infection or complications, including patients with asthma, chronic obstructive pulmonary disease (COPD), bronchitis, chronic respiratory disease, cardiovascular disease, chronic renal failure, diabetes mellitus, immunodeficiency, and functional or anatomic asplenia (1336 patients [15%]).
The number of all-cause hospitalizations was reduced by 58% in patients who received the pneumococcal vaccine (relative risk [RR]=0.96; 95% confidence interval [CI], 0.94-0.98). In vaccinated patients with asthma (793 patients [8.7%]), asthma-related hospitalizations decreased by 78% (RR=1.82; 95% CI, 1.35-2.45; NNT=49) and average asthma-related length of hospital stay was shortened by about 2 days (P=.039). The study found no difference in pneumonia-related hospitalizations among all vaccinated patients.
Effect on younger patients is unclear
Because the investigators didn’t analyze asthma-related or pneumonia-related hospitalizations among asthmatic patients 64 years and younger, the effect of pneumococcal vaccination on this younger subgroup can’t be differentiated from the entire group of patients with asthma.1
What about pneumococcal hospitalization?
A retrospective, case-controlled cohort study examined the impact of pneumococcal vaccination on any pneumococcal-related hospitalization in patients with COPD or asthma.2 The study included 2746 adults with asthma (74.2% younger than 64 years) who were followed for about 2.1 years before and 2.6 years after vaccination.
Investigators found no significant differences in risk of pneumococcal-related hospitalization between asthma patients and controls throughout the study. They didn’t evaluate asthma-related hospital admissions.
Impact of vaccine on invasive disease in younger asthma patients?
A retrospective, nested, case-controlled study examined the relationship between asthma and invasive pneumococcal disease (IPD) in 6985 patients enrolled in Tennessee’s Medicaid program.3 Patients 2 to 49 years of age with any IPD diagnosis were identified using International Classification of Diseases (ICD-9-CM) codes and followed for 8 years.
Asthma patients without coexisting conditions that confer a high risk of IPD (such as diabetes, cardiac disease, and infection with human immunodeficiency virus) had a 14.7% risk of IPD compared with a risk of only 7.4% in age-matched controls (adjusted odds ratio=2.4; 95% CI, 1.7-3.4). The authors concluded that this Medicaid population with asthma had an increased incidence of IPD of 1 to 3 cases annually per 10,000 people. The effect of pneumococcal vaccination on the incidence of IPD in these younger asthma patients is unknown, however.3
Recommendations
The National Asthma Education and Prevention Program (NAEPP)4 and the Global Initiative for Asthma (GINA)5 make no recommendations regarding the administration of the pneumococcal vaccine.
The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all adults 65 years and older and adults 19 years and older with chronic lung disease, including asthma, or other chronic medical conditions such as cardiovascular diseases, diabetes, chronic liver diseases, chronic alcoholism, chronic renal failure, asplenia, and other immunocompromising conditions.6
The British Department of Health recommends vaccination with either the 7-valent conjugate or the 23-valent polysaccharide pneumococcal vaccine for all asthma patients taking systemic steroids longer than 1 month at a dose equivalent to prednisolone 20 mg daily and for children weighing less than 20 kg who take daily steroids at a dose of ≥1 mg/kg. Efficacy studies aren’t available to support this recommendation.7
1. Ansaldi F, Turello V, Lai P, et al. Effectiveness of a 23-valent polysaccharide vaccine in preventing pneumonia and non-invasive pneumococcal infection in elderly people: a large-scale retrospective cohort study. J Int Med Res. 2005;33:490-500.
2. Lee TA, Weaver FM, Weiss KB. Impact of pneumococcal vaccination on pneumonia rates in patients with COPD and asthma. J Gen Intern Med. 2007;22:62-67.
3. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk for invasive pneumococcal disease. N Engl J Med. 2005;352:2082-2090.
4. National Heart Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health; 1991:11.
5. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Available at: www.ginasthma.org/Guidelineitem.asp?l1=2&l2=1&intId=60. Accessed December 10, 2007.
6. Centers for Disease Control and Prevention. Recommended adult immunization schedule—United States, 2009. MMWR Morb Mortal Wkly Rep. 2008;57(53):Q1-Q4.
7. Department of Health. Immunisation Against Infectious Disease 2006: The Green Book. London, England: Department of Health; 2007. Available at: www.dh.gov.uk/en/Policyandguidance/Healthandsocialcaretopics/Greenbook/DH_4097254. Accessed December 10, 2007.
1. Ansaldi F, Turello V, Lai P, et al. Effectiveness of a 23-valent polysaccharide vaccine in preventing pneumonia and non-invasive pneumococcal infection in elderly people: a large-scale retrospective cohort study. J Int Med Res. 2005;33:490-500.
2. Lee TA, Weaver FM, Weiss KB. Impact of pneumococcal vaccination on pneumonia rates in patients with COPD and asthma. J Gen Intern Med. 2007;22:62-67.
3. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk for invasive pneumococcal disease. N Engl J Med. 2005;352:2082-2090.
4. National Heart Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health; 1991:11.
5. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Available at: www.ginasthma.org/Guidelineitem.asp?l1=2&l2=1&intId=60. Accessed December 10, 2007.
6. Centers for Disease Control and Prevention. Recommended adult immunization schedule—United States, 2009. MMWR Morb Mortal Wkly Rep. 2008;57(53):Q1-Q4.
7. Department of Health. Immunisation Against Infectious Disease 2006: The Green Book. London, England: Department of Health; 2007. Available at: www.dh.gov.uk/en/Policyandguidance/Healthandsocialcaretopics/Greenbook/DH_4097254. Accessed December 10, 2007.
Evidence-based answers from the Family Physicians Inquiries Network
Is there much risk in using fluoroquinolones in children?
No, the risks seem to be minimal. Arthralgias and myalgias have been observed clinically in children and adolescents exposed to fluoroquinolones, but they’re transient, disappear when the drug is discontinued, and appear to be no more prevalent than with other antibiotics (strength of recommendation [SOR]: B, 1 structured review and 2 prospective cohort studies). No apparent long-term risk of developmental skeletal growth delay is associated with fluoroquinolone exposure (SOR: B, 1 prospective controlled study). Fluoroquinolone use in children isn’t associated with tendonopathy (SOR: B, 1 prospective controlled study), but it probably carries a very low risk of tendon rupture (SOR: C, extrapolation from a national passive postmarketing monitoring system study predominantly in adults).
Be Judicious
Stefan M. Groetsch, MD
Naval Branch Health Clinic, Atsugi, Japan
Just because you can do something doesn’t mean you should. It’s reassuring that quinolones can be given to pediatric patients if necessary inasmuch as the drugs don’t appear to cause long-term skeletal side effects, and the infrequent arthralgias and myalgias they produce seem to be transient and benign. However, in an era of increasing microbial drug resistance and escalating pharmaceutical costs, we should strive for rational prescribing and reserve quinolones for patients who truly need them.
Evidence summary
Few short-term joint complaints, no long-term skeletal harm
A 1997 database review compiled reports of skeletally immature patients ranging in age from 4 days to 26 years who were exposed to quinolones.1 Thirty-one reports met search term criteria, for a total of 7045 patients. No incidences of quinolone-associated arthralgia were documented in 30 reports (>5000 patients). The review didn’t report the incidence of tendonopathy. One report of 1795 pediatric patients documented a small incidence of arthralgias (~1.5%), which was considered to be reversible and no more than expected for a comparable quinolone-naïve population.
Follow-up data on safety and adverse findings, from as long as 12 years after treatment, were reported for 530 (28%) of the 7045 patients. Changes in skeletal growth were evaluated using various diagnostic techniques. Clinical observation was the most common method of assessment (N=357), however. The follow-up data revealed no arthropathy or abnormal skeletal growth (rate=0%; estimated 95% confidence interval [CI]=0%-0.04%).
A prospective study published in 2006 monitored joint toxicities (swelling, tenderness, or restricted movement) during acute treatment with ciprofloxacin as well as skeletal growth at follow-up based on physical examination.2 Preterm neonates with septicemia were treated with either ciprofloxacin (n=48) or other antibiotics (n=66). Forty infants in the ciprofloxacin group completed an average of 28 months of follow-up. No complaints or physical findings of osteoarticular joint abnormalities or skeletal growth delay were noted in either group during acute treatment or at follow-up. The incidence of tendonopathy was not reported.
Arthralgias, myalgias are transient
A large multicenter, prospective, non-blinded cohort study evaluated adverse effects in children receiving fluoroquinolones versus other antibiotics.3 Duration of fluoroquinolone use was 1 to 23 days. Arthralgias or myalgias, which were only evaluated clinically, occurred more often in children receiving fluoroquinolones—10 of 276 children (3.6%) vs 1 of 249 (0.3%), respectively (odds ratio [OR]=9.3; 95% CI, 1.2-195; P=.02). All events occurred within the first 2 weeks of fluoroquinolone treatment and resolved within 20 days. No tendonopathies were reported.
Tendon rupture is rare, especially in children
A 1996 study reported the incidence of tendon disorders related to fluoroquinolones using drug surveillance data from the general population. The average age of the patients was 55 years.4
The author estimated the risk of tendon rupture associated with norfloxacin or ofloxacin to be 1 case per 23,130 days of treatment and only 1 case per 779,600 days of ciprofloxacin treatment. The estimated risk would likely be even lower in children, the author noted, because the risk of tendon rupture increases with age.
Recommendations
Ciprofloxacin is the only fluoroquinolone approved by the US Food and Drug Administration for pediatric indications. The FDA recently ordered the addition of a Boxed Warning to fluoroquinolones regarding the increased risk of tendonitis and tendon rupture. The FDA made no comments specifically about children or adolescents, and stated that the risks are increased in people older than 60.
The American Academy of Pediatrics recommends limiting fluoroquinolone use to children with infections caused by multidrug-resistant pathogens or children for whom parenteral therapy is not feasible and no other effective oral medication is available.5
The Agency for Healthcare Research and Quality (AHRQ) recommends fluoroquinolones as first-line treatment for children with uncomplicated gonorrhea who weigh more than 45 kg,6 and second-line therapy for children with bacterial meningitis,7 nongonococcal urethritis, chlamydia,6 or pelvic inflammatory disease.8
Acknowledgments
The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government.
1. Burkhardt JE, Walterspiel JN, Schaad RB. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997;25:1196-1204.
2. Ahmed AS, Khan NZ, Saha SK, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh. Pediatr Infect Dis J. 2006;25:1137-1141.
3. Chalumeau M, Tonnelier S, D’Athis P, et al. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics. 2003;111:e714-e719.
4. Royer RJ. Adverse drug reactions with fluoroquinolones. Therapie. 1998;51:414-416.
5. Committee on Infectious Diseases. The use of systematic fluoroquinolones. Pediatrics. 2006;118:1287-1292.
6. Workowski KA, Berman SM. and the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. Diseases characterized by urethritis and cervicitis. MMWR Morb Mortal Wkly Rep. 2006;55(RR-11):35-49.
7. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-1284.
8. Workowski KA, Berman SM. and the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. Pelvic inflammatory disease. MMWR Morb Mortal Wkly Rep. 2006;55(RR-11):56-61.
No, the risks seem to be minimal. Arthralgias and myalgias have been observed clinically in children and adolescents exposed to fluoroquinolones, but they’re transient, disappear when the drug is discontinued, and appear to be no more prevalent than with other antibiotics (strength of recommendation [SOR]: B, 1 structured review and 2 prospective cohort studies). No apparent long-term risk of developmental skeletal growth delay is associated with fluoroquinolone exposure (SOR: B, 1 prospective controlled study). Fluoroquinolone use in children isn’t associated with tendonopathy (SOR: B, 1 prospective controlled study), but it probably carries a very low risk of tendon rupture (SOR: C, extrapolation from a national passive postmarketing monitoring system study predominantly in adults).
Be Judicious
Stefan M. Groetsch, MD
Naval Branch Health Clinic, Atsugi, Japan
Just because you can do something doesn’t mean you should. It’s reassuring that quinolones can be given to pediatric patients if necessary inasmuch as the drugs don’t appear to cause long-term skeletal side effects, and the infrequent arthralgias and myalgias they produce seem to be transient and benign. However, in an era of increasing microbial drug resistance and escalating pharmaceutical costs, we should strive for rational prescribing and reserve quinolones for patients who truly need them.
Evidence summary
Few short-term joint complaints, no long-term skeletal harm
A 1997 database review compiled reports of skeletally immature patients ranging in age from 4 days to 26 years who were exposed to quinolones.1 Thirty-one reports met search term criteria, for a total of 7045 patients. No incidences of quinolone-associated arthralgia were documented in 30 reports (>5000 patients). The review didn’t report the incidence of tendonopathy. One report of 1795 pediatric patients documented a small incidence of arthralgias (~1.5%), which was considered to be reversible and no more than expected for a comparable quinolone-naïve population.
Follow-up data on safety and adverse findings, from as long as 12 years after treatment, were reported for 530 (28%) of the 7045 patients. Changes in skeletal growth were evaluated using various diagnostic techniques. Clinical observation was the most common method of assessment (N=357), however. The follow-up data revealed no arthropathy or abnormal skeletal growth (rate=0%; estimated 95% confidence interval [CI]=0%-0.04%).
A prospective study published in 2006 monitored joint toxicities (swelling, tenderness, or restricted movement) during acute treatment with ciprofloxacin as well as skeletal growth at follow-up based on physical examination.2 Preterm neonates with septicemia were treated with either ciprofloxacin (n=48) or other antibiotics (n=66). Forty infants in the ciprofloxacin group completed an average of 28 months of follow-up. No complaints or physical findings of osteoarticular joint abnormalities or skeletal growth delay were noted in either group during acute treatment or at follow-up. The incidence of tendonopathy was not reported.
Arthralgias, myalgias are transient
A large multicenter, prospective, non-blinded cohort study evaluated adverse effects in children receiving fluoroquinolones versus other antibiotics.3 Duration of fluoroquinolone use was 1 to 23 days. Arthralgias or myalgias, which were only evaluated clinically, occurred more often in children receiving fluoroquinolones—10 of 276 children (3.6%) vs 1 of 249 (0.3%), respectively (odds ratio [OR]=9.3; 95% CI, 1.2-195; P=.02). All events occurred within the first 2 weeks of fluoroquinolone treatment and resolved within 20 days. No tendonopathies were reported.
Tendon rupture is rare, especially in children
A 1996 study reported the incidence of tendon disorders related to fluoroquinolones using drug surveillance data from the general population. The average age of the patients was 55 years.4
The author estimated the risk of tendon rupture associated with norfloxacin or ofloxacin to be 1 case per 23,130 days of treatment and only 1 case per 779,600 days of ciprofloxacin treatment. The estimated risk would likely be even lower in children, the author noted, because the risk of tendon rupture increases with age.
Recommendations
Ciprofloxacin is the only fluoroquinolone approved by the US Food and Drug Administration for pediatric indications. The FDA recently ordered the addition of a Boxed Warning to fluoroquinolones regarding the increased risk of tendonitis and tendon rupture. The FDA made no comments specifically about children or adolescents, and stated that the risks are increased in people older than 60.
The American Academy of Pediatrics recommends limiting fluoroquinolone use to children with infections caused by multidrug-resistant pathogens or children for whom parenteral therapy is not feasible and no other effective oral medication is available.5
The Agency for Healthcare Research and Quality (AHRQ) recommends fluoroquinolones as first-line treatment for children with uncomplicated gonorrhea who weigh more than 45 kg,6 and second-line therapy for children with bacterial meningitis,7 nongonococcal urethritis, chlamydia,6 or pelvic inflammatory disease.8
Acknowledgments
The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government.
No, the risks seem to be minimal. Arthralgias and myalgias have been observed clinically in children and adolescents exposed to fluoroquinolones, but they’re transient, disappear when the drug is discontinued, and appear to be no more prevalent than with other antibiotics (strength of recommendation [SOR]: B, 1 structured review and 2 prospective cohort studies). No apparent long-term risk of developmental skeletal growth delay is associated with fluoroquinolone exposure (SOR: B, 1 prospective controlled study). Fluoroquinolone use in children isn’t associated with tendonopathy (SOR: B, 1 prospective controlled study), but it probably carries a very low risk of tendon rupture (SOR: C, extrapolation from a national passive postmarketing monitoring system study predominantly in adults).
Be Judicious
Stefan M. Groetsch, MD
Naval Branch Health Clinic, Atsugi, Japan
Just because you can do something doesn’t mean you should. It’s reassuring that quinolones can be given to pediatric patients if necessary inasmuch as the drugs don’t appear to cause long-term skeletal side effects, and the infrequent arthralgias and myalgias they produce seem to be transient and benign. However, in an era of increasing microbial drug resistance and escalating pharmaceutical costs, we should strive for rational prescribing and reserve quinolones for patients who truly need them.
Evidence summary
Few short-term joint complaints, no long-term skeletal harm
A 1997 database review compiled reports of skeletally immature patients ranging in age from 4 days to 26 years who were exposed to quinolones.1 Thirty-one reports met search term criteria, for a total of 7045 patients. No incidences of quinolone-associated arthralgia were documented in 30 reports (>5000 patients). The review didn’t report the incidence of tendonopathy. One report of 1795 pediatric patients documented a small incidence of arthralgias (~1.5%), which was considered to be reversible and no more than expected for a comparable quinolone-naïve population.
Follow-up data on safety and adverse findings, from as long as 12 years after treatment, were reported for 530 (28%) of the 7045 patients. Changes in skeletal growth were evaluated using various diagnostic techniques. Clinical observation was the most common method of assessment (N=357), however. The follow-up data revealed no arthropathy or abnormal skeletal growth (rate=0%; estimated 95% confidence interval [CI]=0%-0.04%).
A prospective study published in 2006 monitored joint toxicities (swelling, tenderness, or restricted movement) during acute treatment with ciprofloxacin as well as skeletal growth at follow-up based on physical examination.2 Preterm neonates with septicemia were treated with either ciprofloxacin (n=48) or other antibiotics (n=66). Forty infants in the ciprofloxacin group completed an average of 28 months of follow-up. No complaints or physical findings of osteoarticular joint abnormalities or skeletal growth delay were noted in either group during acute treatment or at follow-up. The incidence of tendonopathy was not reported.
Arthralgias, myalgias are transient
A large multicenter, prospective, non-blinded cohort study evaluated adverse effects in children receiving fluoroquinolones versus other antibiotics.3 Duration of fluoroquinolone use was 1 to 23 days. Arthralgias or myalgias, which were only evaluated clinically, occurred more often in children receiving fluoroquinolones—10 of 276 children (3.6%) vs 1 of 249 (0.3%), respectively (odds ratio [OR]=9.3; 95% CI, 1.2-195; P=.02). All events occurred within the first 2 weeks of fluoroquinolone treatment and resolved within 20 days. No tendonopathies were reported.
Tendon rupture is rare, especially in children
A 1996 study reported the incidence of tendon disorders related to fluoroquinolones using drug surveillance data from the general population. The average age of the patients was 55 years.4
The author estimated the risk of tendon rupture associated with norfloxacin or ofloxacin to be 1 case per 23,130 days of treatment and only 1 case per 779,600 days of ciprofloxacin treatment. The estimated risk would likely be even lower in children, the author noted, because the risk of tendon rupture increases with age.
Recommendations
Ciprofloxacin is the only fluoroquinolone approved by the US Food and Drug Administration for pediatric indications. The FDA recently ordered the addition of a Boxed Warning to fluoroquinolones regarding the increased risk of tendonitis and tendon rupture. The FDA made no comments specifically about children or adolescents, and stated that the risks are increased in people older than 60.
The American Academy of Pediatrics recommends limiting fluoroquinolone use to children with infections caused by multidrug-resistant pathogens or children for whom parenteral therapy is not feasible and no other effective oral medication is available.5
The Agency for Healthcare Research and Quality (AHRQ) recommends fluoroquinolones as first-line treatment for children with uncomplicated gonorrhea who weigh more than 45 kg,6 and second-line therapy for children with bacterial meningitis,7 nongonococcal urethritis, chlamydia,6 or pelvic inflammatory disease.8
Acknowledgments
The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government.
1. Burkhardt JE, Walterspiel JN, Schaad RB. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997;25:1196-1204.
2. Ahmed AS, Khan NZ, Saha SK, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh. Pediatr Infect Dis J. 2006;25:1137-1141.
3. Chalumeau M, Tonnelier S, D’Athis P, et al. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics. 2003;111:e714-e719.
4. Royer RJ. Adverse drug reactions with fluoroquinolones. Therapie. 1998;51:414-416.
5. Committee on Infectious Diseases. The use of systematic fluoroquinolones. Pediatrics. 2006;118:1287-1292.
6. Workowski KA, Berman SM. and the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. Diseases characterized by urethritis and cervicitis. MMWR Morb Mortal Wkly Rep. 2006;55(RR-11):35-49.
7. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-1284.
8. Workowski KA, Berman SM. and the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. Pelvic inflammatory disease. MMWR Morb Mortal Wkly Rep. 2006;55(RR-11):56-61.
1. Burkhardt JE, Walterspiel JN, Schaad RB. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997;25:1196-1204.
2. Ahmed AS, Khan NZ, Saha SK, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh. Pediatr Infect Dis J. 2006;25:1137-1141.
3. Chalumeau M, Tonnelier S, D’Athis P, et al. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics. 2003;111:e714-e719.
4. Royer RJ. Adverse drug reactions with fluoroquinolones. Therapie. 1998;51:414-416.
5. Committee on Infectious Diseases. The use of systematic fluoroquinolones. Pediatrics. 2006;118:1287-1292.
6. Workowski KA, Berman SM. and the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. Diseases characterized by urethritis and cervicitis. MMWR Morb Mortal Wkly Rep. 2006;55(RR-11):35-49.
7. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-1284.
8. Workowski KA, Berman SM. and the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. Pelvic inflammatory disease. MMWR Morb Mortal Wkly Rep. 2006;55(RR-11):56-61.
Evidence-based answers from the Family Physicians Inquiries Network