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Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report
J Infect Chemother xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case Report
Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report* Khalid Eljaaly a, b, *, Samah Alshehri a, b a b
Department of Pharmacy Practice, College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia Pharmacy Practice and Science Department, College of Pharmacy, University of Arizona, Tucson, AZ, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 June 2019 Received in revised form 9 August 2019 Accepted 21 August 2019 Available online xxx
This case report describes a 4-year-old girl with food aversion who received three separate courses of cefdinir mixed with PediaSure®, an iron-fortified nutritional formula. The patient's stool turned red with variable onset during all three courses of treatment. Moreover, the PediaSure® formula turned purple after mixed with cefdinir, an interaction that has not been previously reported. We recommend that medication counseling for pediatric patients taking cefdinir include a mention of these possible discolorations. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Cefdinir Red Stool Purple Violet Formula
1. Introduction Cefdinir is an oral third-generation cephalosporin that is commonly used as an alternative in pediatric patients with penicillin allergy for the treatment of bacterial infections, particularly otitis media and streptococcal pharyngitis. PediaSure® is an oral milk-based nutritional formula for children. In this case report, we describe a child with food aversion who was administered cefdinir mixed with PediaSure® and who on three different courses experienced variable-onset red-stool discolorations that resolved after completing cefdinir therapy. In addition, in this case, the PediaSure® formula turned a purple color once mixed with cefdinir, a phenomenon that to our knowledge has not previously been reported in medical literature. 2. Case report A 4-year-old girl weighing 15 kg with food aversion received three separate courses of same generic cefdinir oral suspension 14 mg/kg once daily for 10 days. During each course, the patient * All authors meet the ICMJE authorship criteria. * Corresponding author. Department of Pharmacy Practice, King Abdulaziz University, P.O. Box 80200, Jeddah, 21589, Saudi Arabia. E-mail address: [email protected] (K. Eljaaly). Twitter: http://twitter.com/khalideljaaly (K. Eljaaly)
experienced stool redness, without diarrhea, vomiting, or abdominal pain, that lasted until cefdinir therapy was completed. The patient had a history of erythematous maculopapular rash due to amoxicillin, but cefdinir was tolerated. At the time of therapy, the patient was drinking vanilla PediaSure® with Fiber (Grow & Gain) and not consuming any other food or medication except for acetaminophen suppositories as needed. Due to the patient's food aversion and refusal to drink any medication, cefdinir was mixed with PediaSure® in a colorless bottle every morning. Prior to the first course of cefdinir treatment, a rapid strep test was performed and tested positive following a two-day history of fever and throat pain. The PediaSure® turned light purple once mixed with cefdinir. At first, the patient's parents were concerned that the mixture might have lost its efficacy and/or become toxic. They attempted to mix cefdinir with another bottle of PediaSure® and observed the same discoloration, which did not happen when mixing cefdinir with regular milk. After pharmacist consultation, cefdinir therapy was started as it was thought it is probably a benign interaction similar to red stool discoloration and this was the only antibiotic that this autistic child accepts its taste. On day 4 of therapy, the patient had her first bowel movement. The stool was red in color but therapy was not interrupted. On day 6, a guaiac test to rule out bleeding was performed in a pediatric clinic and was negative. Two days after completing the cefdinir therapy, the patient's stool color returned to normal.
https://doi.org/10.1016/j.jiac.2019.08.014 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Eljaaly K, Alshehri S, Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.014
2
K. Eljaaly, S. Alshehri / J Infect Chemother xxx (xxxx) xxx
Prior to the second course of cefdinir treatment, and approximately 5 weeks after completing the first course, the patient experienced a new incidence of fever and had again a positive rapid strep test. The patient's family reported normal-colored stools on days 3, 5, and 7, and red stool on day 9 of treatment. Stool color returned to normal the day after completing cefdinir therapy. Prior to the third course of cefdinir treatment and approximately 8 weeks after completing the second course, the patient was diagnosed with otitis media. The family reported normal-colored stools on days 2 and 5 and red stool on day 6. Stool color again returned to a normal the day after completing cefdinir therapy. On all three occasions, the infection symptoms, including pain and fever, resolved within 48 hours of starting cefdinir therapy. 3. Discussion Cefdinir-induced red- or maroon-colored stool when administering cefdinir with iron-containing products is listed as a possible side effect in the package insert [1]. We conducted a systematic search in Pubmed on 5 June, 2019 using the terms “cefdinir AND (stool* OR red OR maroon)”, which produced19 articles. Of these, six articles including cases of cefdinir-induced red stool were found. These six articles included 7 cases of cefdinir-induced red stool [2e7]. Including 2 additional articles of 3 cases from a manual search, a total of 10 cases of cefdinir-induced red stool were found to have been reported in the pediatric literature [8,9]. This red discoloration of stool is due to the formation of a nonabsorbable complex between iron and cefdinir or its metabolites in the gastrointestinal tract [1]. Administration of cefdinir with products containing 60 mg and 10 mg of elemental iron can reduce the absorption of cefdinir by approximately 80% and 31%, respectively. According to manufacturer prescribing information, cefdinir must be spaced at least 2 hours from iron supplements. In contrast, formulas fortified for infants that contain 2.2 mg of elemental iron have not been shown to significantly affect the pharmacokinetics of cefdinir. Therefore, cefdinir can be mixed with these formulas [1]. The iron content/100 kcal of each of the formulas with which red stools have been observed in the literature are as follows: 0.77 mg for the discontinued Neocate One Plus (Nutricia North America, Gaithersburg, MD); 1.8 mg for the discontinued Enfamil with Iron (Mead Johnson Nutritionals, Evansville, IN); 1.8 mg for Similac Alimentum (Abbott Nutrition, Columbus, OH); 2.7 mg for PediaSure® with Fiber Grow & Gain (Abbott Nutrition, Columbus, OH) [3,10,11]. Using the Naranjo scale for estimating the probability of adverse drug reactions, cefdinir-induced red stool in our case report was estimated as highly probable [12]. Another strength in our case report is that we investigated and clearly stated that the child was not taking any products which could discolor her stool. The food aversion was severe resulting in not taking anything, not even water, other than PediaSure® and cefdinir except the acetaminophen suppository. This was a major limitation in previous case reports of stool discoloration due to interaction of cefdinir with nutritional formula. It is interesting to note that in this case report, the onset of stool redness was variable for a single patient, ranging from the fourth to ninth day. In this case, the family monitored the stool very closely, unlike many of the previously reported cases, in which only the day of stool redness was observed without providing detail on each bowel movement or specific timing. For example, in some cases, it is unclear if the red stool was the first stool or if the patient had experienced normal-colored bowel movements before the red stool. If the red stool was the first one, then stool redness in the colon could have happened earlier but was not known until the patient had their first bowel movement. However, the onset of stool redness in these case reports was between 2 and 6 days of cefdinir
Fig. 1. Picture of PediaSure® and regular milk/iron with and without cefdinir.
use; however, in our case, for two of the courses, it did not occur until day 9 of treatment despite several previous bowel movements. Future studies could seek to further explore the incidence of cefdinir-induced red stool and its onset. It is interesting that our Pubmed search did not reveal any reports in the medical literature of formulas like PediaSure® turning purple, nor is this phenomenon listed on the package insert of cefdinir. Therefore, this could be the first report of this type of interaction. Such a discoloration might confuse and concern patients, including not only small children but also older patients with food aversion, and family members leading to interruption of therapy. In addition, the possibility of interaction should be listed in the package insert for cefdinir products. Under the Drug Interaction Probability Scale (DIPS), cefdinir-induced purple iron-fortified nutritional formula was estimated as probable [13]. To further strengthen our case, we mixed a regular milk with cefdinir and crushed white iron tablet. The milk color also turned purple confirming iron to be the cause rather than other ingredients [Fig. 1]. We recommend that medication counseling include a mention of the possibility of purple discoloration when mixing cefdinir with an iron-containing formula. Despite lack of data of clinical failure due to this drug-interaction, avoidance of mixing when possible might be reasonable. However, nutritional formula does not seem to be concerning like iron supplements, particularly in patients with autism and food aversion who might not accept taking cefdinir except with their nutritional formula. 4. Conclusion A child experienced variable-onset red stools on three occasions and the iron-containing nutritional formula turned purple after mixing with cefdinir. Declaration of interest The authors report no declarations of interest.
Please cite this article as: Eljaaly K, Alshehri S, Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.014
K. Eljaaly, S. Alshehri / J Infect Chemother xxx (xxxx) xxx
References [1] Omnicef® [package insert]. North Chicago, IL: AbbBie Inc; 2015. [2] Nelson JS. Red stools and omnicef. J Pediatr 2000;136(6):853e4. [3] Lancaster J, Sylvia LM, Schainker E. Nonbloody, red stools from coadministration of cefdinir and iron-supplemented infant formulas. Pharmacotherapy 2008;28(5):678e81. [4] Graves R, Weaver SP. Cefdinir-associated “bloody stools” in an infant. J Am Board Fam Med 2008;21(3):246e8. [5] Lowers J, Jaffe A, Zenel JA, Cabana MD, Donahue C, Uba A. Visual diagnosis: four infants who have red, “bloody” stools. Pediatr Rev 2009;30(4):146e9. [6] Mookadam M, Eisenhart A. Infant male with blood-colored stools. Ann Emerg Med 2009;54(2):308e14. [7] Roath MC, Di palma JA. Correspondence: cefdinir and red stool. Gastroenterol Hepatol (N Y) 2013;9(6):338.
3
[8] Cefdinir. Red stools in a child and an infant: 2 case reports. Reactions 2000;813(1):6. [9] Nelson JS, McCracken GH. Red stools and omnicef. Ped Infect Dis J 2002;21(4): A7e8. [10] Abbott Nutrition. Similac Alimentum product information. http://abbottnutrition. com/brands/products/similac-expert-care-alimentum. [Accessed 4 September 2019]. [11] Abbott Nutrition. Pediasure with fiber Grow and Gain product information. http://abbottnutrition.com/brands/products/pediasure-with-fiber-grow-gain. [Accessed 4 September 2019]. [12] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30(2):239e45. [13] Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41(4):674e80.
Please cite this article as: Eljaaly K, Alshehri S, Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.014
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case Report
Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report* Khalid Eljaaly a, b, *, Samah Alshehri a, b a b
Department of Pharmacy Practice, College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia Pharmacy Practice and Science Department, College of Pharmacy, University of Arizona, Tucson, AZ, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 June 2019 Received in revised form 9 August 2019 Accepted 21 August 2019 Available online xxx
This case report describes a 4-year-old girl with food aversion who received three separate courses of cefdinir mixed with PediaSure®, an iron-fortified nutritional formula. The patient's stool turned red with variable onset during all three courses of treatment. Moreover, the PediaSure® formula turned purple after mixed with cefdinir, an interaction that has not been previously reported. We recommend that medication counseling for pediatric patients taking cefdinir include a mention of these possible discolorations. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Cefdinir Red Stool Purple Violet Formula
1. Introduction Cefdinir is an oral third-generation cephalosporin that is commonly used as an alternative in pediatric patients with penicillin allergy for the treatment of bacterial infections, particularly otitis media and streptococcal pharyngitis. PediaSure® is an oral milk-based nutritional formula for children. In this case report, we describe a child with food aversion who was administered cefdinir mixed with PediaSure® and who on three different courses experienced variable-onset red-stool discolorations that resolved after completing cefdinir therapy. In addition, in this case, the PediaSure® formula turned a purple color once mixed with cefdinir, a phenomenon that to our knowledge has not previously been reported in medical literature. 2. Case report A 4-year-old girl weighing 15 kg with food aversion received three separate courses of same generic cefdinir oral suspension 14 mg/kg once daily for 10 days. During each course, the patient * All authors meet the ICMJE authorship criteria. * Corresponding author. Department of Pharmacy Practice, King Abdulaziz University, P.O. Box 80200, Jeddah, 21589, Saudi Arabia. E-mail address: [email protected] (K. Eljaaly). Twitter: http://twitter.com/khalideljaaly (K. Eljaaly)
experienced stool redness, without diarrhea, vomiting, or abdominal pain, that lasted until cefdinir therapy was completed. The patient had a history of erythematous maculopapular rash due to amoxicillin, but cefdinir was tolerated. At the time of therapy, the patient was drinking vanilla PediaSure® with Fiber (Grow & Gain) and not consuming any other food or medication except for acetaminophen suppositories as needed. Due to the patient's food aversion and refusal to drink any medication, cefdinir was mixed with PediaSure® in a colorless bottle every morning. Prior to the first course of cefdinir treatment, a rapid strep test was performed and tested positive following a two-day history of fever and throat pain. The PediaSure® turned light purple once mixed with cefdinir. At first, the patient's parents were concerned that the mixture might have lost its efficacy and/or become toxic. They attempted to mix cefdinir with another bottle of PediaSure® and observed the same discoloration, which did not happen when mixing cefdinir with regular milk. After pharmacist consultation, cefdinir therapy was started as it was thought it is probably a benign interaction similar to red stool discoloration and this was the only antibiotic that this autistic child accepts its taste. On day 4 of therapy, the patient had her first bowel movement. The stool was red in color but therapy was not interrupted. On day 6, a guaiac test to rule out bleeding was performed in a pediatric clinic and was negative. Two days after completing the cefdinir therapy, the patient's stool color returned to normal.
https://doi.org/10.1016/j.jiac.2019.08.014 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Eljaaly K, Alshehri S, Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.014
2
K. Eljaaly, S. Alshehri / J Infect Chemother xxx (xxxx) xxx
Prior to the second course of cefdinir treatment, and approximately 5 weeks after completing the first course, the patient experienced a new incidence of fever and had again a positive rapid strep test. The patient's family reported normal-colored stools on days 3, 5, and 7, and red stool on day 9 of treatment. Stool color returned to normal the day after completing cefdinir therapy. Prior to the third course of cefdinir treatment and approximately 8 weeks after completing the second course, the patient was diagnosed with otitis media. The family reported normal-colored stools on days 2 and 5 and red stool on day 6. Stool color again returned to a normal the day after completing cefdinir therapy. On all three occasions, the infection symptoms, including pain and fever, resolved within 48 hours of starting cefdinir therapy. 3. Discussion Cefdinir-induced red- or maroon-colored stool when administering cefdinir with iron-containing products is listed as a possible side effect in the package insert [1]. We conducted a systematic search in Pubmed on 5 June, 2019 using the terms “cefdinir AND (stool* OR red OR maroon)”, which produced19 articles. Of these, six articles including cases of cefdinir-induced red stool were found. These six articles included 7 cases of cefdinir-induced red stool [2e7]. Including 2 additional articles of 3 cases from a manual search, a total of 10 cases of cefdinir-induced red stool were found to have been reported in the pediatric literature [8,9]. This red discoloration of stool is due to the formation of a nonabsorbable complex between iron and cefdinir or its metabolites in the gastrointestinal tract [1]. Administration of cefdinir with products containing 60 mg and 10 mg of elemental iron can reduce the absorption of cefdinir by approximately 80% and 31%, respectively. According to manufacturer prescribing information, cefdinir must be spaced at least 2 hours from iron supplements. In contrast, formulas fortified for infants that contain 2.2 mg of elemental iron have not been shown to significantly affect the pharmacokinetics of cefdinir. Therefore, cefdinir can be mixed with these formulas [1]. The iron content/100 kcal of each of the formulas with which red stools have been observed in the literature are as follows: 0.77 mg for the discontinued Neocate One Plus (Nutricia North America, Gaithersburg, MD); 1.8 mg for the discontinued Enfamil with Iron (Mead Johnson Nutritionals, Evansville, IN); 1.8 mg for Similac Alimentum (Abbott Nutrition, Columbus, OH); 2.7 mg for PediaSure® with Fiber Grow & Gain (Abbott Nutrition, Columbus, OH) [3,10,11]. Using the Naranjo scale for estimating the probability of adverse drug reactions, cefdinir-induced red stool in our case report was estimated as highly probable [12]. Another strength in our case report is that we investigated and clearly stated that the child was not taking any products which could discolor her stool. The food aversion was severe resulting in not taking anything, not even water, other than PediaSure® and cefdinir except the acetaminophen suppository. This was a major limitation in previous case reports of stool discoloration due to interaction of cefdinir with nutritional formula. It is interesting to note that in this case report, the onset of stool redness was variable for a single patient, ranging from the fourth to ninth day. In this case, the family monitored the stool very closely, unlike many of the previously reported cases, in which only the day of stool redness was observed without providing detail on each bowel movement or specific timing. For example, in some cases, it is unclear if the red stool was the first stool or if the patient had experienced normal-colored bowel movements before the red stool. If the red stool was the first one, then stool redness in the colon could have happened earlier but was not known until the patient had their first bowel movement. However, the onset of stool redness in these case reports was between 2 and 6 days of cefdinir
Fig. 1. Picture of PediaSure® and regular milk/iron with and without cefdinir.
use; however, in our case, for two of the courses, it did not occur until day 9 of treatment despite several previous bowel movements. Future studies could seek to further explore the incidence of cefdinir-induced red stool and its onset. It is interesting that our Pubmed search did not reveal any reports in the medical literature of formulas like PediaSure® turning purple, nor is this phenomenon listed on the package insert of cefdinir. Therefore, this could be the first report of this type of interaction. Such a discoloration might confuse and concern patients, including not only small children but also older patients with food aversion, and family members leading to interruption of therapy. In addition, the possibility of interaction should be listed in the package insert for cefdinir products. Under the Drug Interaction Probability Scale (DIPS), cefdinir-induced purple iron-fortified nutritional formula was estimated as probable [13]. To further strengthen our case, we mixed a regular milk with cefdinir and crushed white iron tablet. The milk color also turned purple confirming iron to be the cause rather than other ingredients [Fig. 1]. We recommend that medication counseling include a mention of the possibility of purple discoloration when mixing cefdinir with an iron-containing formula. Despite lack of data of clinical failure due to this drug-interaction, avoidance of mixing when possible might be reasonable. However, nutritional formula does not seem to be concerning like iron supplements, particularly in patients with autism and food aversion who might not accept taking cefdinir except with their nutritional formula. 4. Conclusion A child experienced variable-onset red stools on three occasions and the iron-containing nutritional formula turned purple after mixing with cefdinir. Declaration of interest The authors report no declarations of interest.
Please cite this article as: Eljaaly K, Alshehri S, Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.014
K. Eljaaly, S. Alshehri / J Infect Chemother xxx (xxxx) xxx
References [1] Omnicef® [package insert]. North Chicago, IL: AbbBie Inc; 2015. [2] Nelson JS. Red stools and omnicef. J Pediatr 2000;136(6):853e4. [3] Lancaster J, Sylvia LM, Schainker E. Nonbloody, red stools from coadministration of cefdinir and iron-supplemented infant formulas. Pharmacotherapy 2008;28(5):678e81. [4] Graves R, Weaver SP. Cefdinir-associated “bloody stools” in an infant. J Am Board Fam Med 2008;21(3):246e8. [5] Lowers J, Jaffe A, Zenel JA, Cabana MD, Donahue C, Uba A. Visual diagnosis: four infants who have red, “bloody” stools. Pediatr Rev 2009;30(4):146e9. [6] Mookadam M, Eisenhart A. Infant male with blood-colored stools. Ann Emerg Med 2009;54(2):308e14. [7] Roath MC, Di palma JA. Correspondence: cefdinir and red stool. Gastroenterol Hepatol (N Y) 2013;9(6):338.
3
[8] Cefdinir. Red stools in a child and an infant: 2 case reports. Reactions 2000;813(1):6. [9] Nelson JS, McCracken GH. Red stools and omnicef. Ped Infect Dis J 2002;21(4): A7e8. [10] Abbott Nutrition. Similac Alimentum product information. http://abbottnutrition. com/brands/products/similac-expert-care-alimentum. [Accessed 4 September 2019]. [11] Abbott Nutrition. Pediasure with fiber Grow and Gain product information. http://abbottnutrition.com/brands/products/pediasure-with-fiber-grow-gain. [Accessed 4 September 2019]. [12] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30(2):239e45. [13] Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41(4):674e80.
Please cite this article as: Eljaaly K, Alshehri S, Cefdinir-induced red stool and purple discoloration of nutritional formula: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.08.014