PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital

Volume 1 2 Number 6 June 200 6

Ertape nem for Prophylaxis and Treatment of Infections in Children Marcia L. Buck, Pharm.D., FCCP

rtapenem, the newest of the carbapenem (penicillin -intermediate strains onl y), Citrobacter E antibiotics, was approved by the Food and freundii, Citrobacter koseri, Enterobacter Drug Administration on November 29, 2001. 1 aerogenes, Enterobacter cloacae , Haemophilus Initially approved for use in adults, it received an species, Klebsiella oxytoca (not all strains), indication for use in children on February 11, Morganella morganii, Proteus vulgaris, 2005 and was relabeled with pediatric dosing Providencia rettgeri, Proidencia stuartii, guidelines on May 18, 2005. 2 Merck, the Serratia marcescens, Ba cteriodes vulgatus, manufacturer of e rtapenem, received a patent Clostridium perfringens , and Fusobacterium extension under the Pediatric Exclusivity species . Unlike other carbapenems, ertapenem Program w hich encourages the pharmaceutical has poor Pseudomonas coverage .1,3 -5 industry to study their products in children who might benefit from their use. This issue of Indications Pediatric Pharmacotherapy will review the Ertapenem is indicated for the treatment of antimicrobial spectrum and pharmacology of patients 3 months of age and older with ertapenem and describe the pediatric studi es complicated in tra -abdominal infections, conducted by the manufacturer. compli cate d skin and skin struction infections, community acquired pneumonia (CAP) , Mechanism of Action complicated urinary tract infections (UTI) , and As with other carbapenems, the bactericidal acute pelvic infections. Ertapenem is not activity of ertapenem is the result of inhibition of recommended for the treatment of meningitis due cell wall synthesis, produced through binding to to the inability to achieve sufficient drug penicillin binding proteins. Ertapenem is stab le concentrations in the cerebrospinal fluid. 3 against hydrolysis by m any beta -lactamases, with the exception of metallo -beta -lactamases. 1,3 -5 Clinical Experience in Children The manufacturer has conducted two pediatric Antimicrobial Spectrum clinical trials with ertapenem. Neither of the Ertapenem has demonstrated both in vivo and in trials has been published in the medical vitro activity against a wide variety of gram - literat ure, but details may be obtained from the positive, gram -negative, and anaerobic prescribing information or the FDA website. 3,4, 6 microorganisms. It is active against Staph . aureus (methicillin -susceptible strains), St rep . The first study (Protocol 036) was a double - agalactiae, Strep. pneumoniae (penicillin - blind, randomized, multicenter comparative susceptible stains), and Strep. pyogenes . It is study of ertapenem and ceftriaxone in 404 also effective against many gram -negative children with complicated UTI, skin and soft microorganisms, including E. coli, H. influenzae tissue infection, or CAP. Patients were (non -beta -lactamase strains), Klebsiella randomized to receive either ertapenem (15 pneumoniae , and Moraxella catarrhalis . mg/kg every 12 hours in patients 3 months to 12 Ertapenem is also active against Bacteroides years and 1 g ram once daily in patients 13 to 17 species, Clostridium clostridioforme, years of age ) or ceftriaxone (50 mg/kg/day given Eubacterium lentum, Peptostreptococcus species, in two divided d oses to patients 3 month s to 12 Porphyromonas asaccharo lytica, and Prevotella years and 50 mg/kg given once daily in children bivia .1,3 -5 13 to 17 years of age ). Both groups were treated for up to 14 days. The clinical response rates in In vitro testing with ertapenem has demonstrated the evaluable patients with skin and soft tissue activity (a minimum inhibitory concentration less infections were 95.5% (64/ 67) for ertapenem and than or equal to the susceptible breakpoint for 100% (26/26) for ceftriaxone . In CAP patients, ertapenem) against Str ep . pneumoniae response rates were 96.1% (74/77) for ertapenem and 96.4% (27/28) for ceftriaxone. In the included diarr hea (in 10.3% of patients ), nausea children with UTI, the microbiologic response (8.5%), infusion site complications (7.1%), rates were 87% (40/46) for ertapenem and 90% headache ( 5.6 %), agitation/confusion (5.1%), (18/ 20) with ceftriaxone. 3,6 fever (5%), constipation (4%), vomiting ( 3.7 %) , abdominal pain (3.6%), edema (3.4%), insomnia In the second study (Protocol 038) , an open - (3.2%), dyspepsia (2.6%), rash (2.5%), dea th/not label, randomized, multicenter comparative drug -related (2.5%), dizziness (2.1%), study, ertapenem was compared to hypotension (2%), pruritus (2%) , ticarcillin/clavulanate in 112 children with extravasation/phlebitis (1.9%), hypotension, complicated intra -abdominal infections or acute tachycardia, reflux, cough, erythema (all 1.6%), pelvic infections . Patients were treated with chest pain (1.5%), vaginitis (1.4%), anxiety either ertapenem, using the dosing regimens (1.4%), fatigue (1.2%), dyspepsia, leg pain, and described in the previous study, or rales ( all 1.1%) . These values were similar in ticarcillin/clavulanate at doses of 50 mg/kg in the comparison group of 774 adults given patients less than 60 kg and 3 gram s in patients piperacillin/tazobactam. 3 weighing greater than 60 kg given four to six tim es daily. The clinical response rates in the Similar results were found in the two clinical children with intra -abdominal infections were trials conducted in pediatric patients . In the 384 83.7% (36/43) for ertapenem and 63.6% (7/11) children receiving ertapene m, the most common for ticarcillin/clavulanate. In the patients with reactions were diarrhea (11.7%), vomiting pelvic infections, the response rates were 100% (10.2%), infusion site pain (7%), fever (4.9%), (23/23) for ertapene m and 100% (4/4) for diaper rash, abdominal pain (both 4.7%), ticarcillin/clavulanate. 3,6 headache and cough (4.4%), redness at the infusion site (3.9%), rash (2.9%), constipation Pharmacokinetics and upper respi ratory tract infection (2.3%), Ertapenem may be administered by intravenous loose stools (2.1%), infusion site phlebitis or (IV) or intramuscular (IM) routes. After a 1 swelling (1.8%), nausea, nasopharyngitis, gram IV dose, the mean peak plasma hypothermia, dizziness (all 1.6%), infusion site concentration is achieved within 2 to 3 hours. warmth (1.3%), infusion site induration, upper Ertapenem exhibi ts non -linear pharmacokinetics abdominal pain, abdominal abscess, herp es as a result of its concentration -dependent protein simplex, viral pharyngitis, wheezing, and binding. The percentage of drug bound to serum dermatitis (all 1.0%). The incidence of adverse albumin ranges from 95% at concentrations less effects was similar to that seen with the than 100 mcg/mL to 85% at concentrations comparison groups receiving ceftriaxone or greater than 300 mcg/mL. In adults, t he apparent ticarcillin/clavulanate. 3 volume of distribution is approximately 0.12 L/kg, compared to 0.2 L/kg in patients 3 months Hypersensitivity reactions, including to 12 years of age and 0.16 L/kg in pediatric anaphylaxis, have been reported after ertapenem patients 13 to 17 years of age. 1,3,6 Ertapenem is administration. Patients with a history of metabolized through hydrolysis of the beta - sensitivity to other beta -lactam antibiotics may lactam ring and then renally excreted. The mean be at greater risk for severe hypersensitivity half -life is approximately 4 hours in adults and reactions to ertapenem. Seizures have been children over 12 years of age. In patients 3 reported in patients receiving ertap enem, and months to 12 years of age, the half -life is may be more likely in patients with an underlying significantly shorter, with a mean value of 2.5 seizure disorder, brain lesions, or decreased renal hours . The half -life is prolong ed in patients with function. As with other antibiotics, ertapenem renal insufficiency .1,3 ,6 use has been associated with the development of pseudomembranous colitis. 1,3,4 Drug Interactions Administration of probenecid with ertapenem Dosing Recommend ations will prolong the half -life of ertapenem from 4 to The recommended dose of ertapenem in patients 4.8 hours in adults. Because of this small effect, 3 months to 12 years of age is 15 mg/kg given IV co -administration of probenecid in an effor t to or IM twice daily, up to a maximum dose of 1 prolong ertapenem clearance is not gram/day. In older children and adults, the recommended. No other clinically significant recommended dose is 1 gram given once daily. drug interactions hav e been reported. 1,3 ,4 When administered IV, the dose should be infused over 30 minutes. The recommended Adverse Effects duration of therapy is up to 14 days for IV In a study of 802 adults receiving ertapenem, administration and up to 7 days for IM use. 3 adverse effects observed in > 1% of subjects The dose of ertapenem should be reduced in Pharmacology Literature Review patients with renal insufficiency. In adults with a Bupropion concentration -response relationship crea tinine clearance less than 30 mL/min/1.73 The relationship between bupropion plasma m2, the recommended dose is 500 mg concentrations and antidepressant response was administered once daily. Patients undergoing studied in 16 adolescents (11 to 17 years of age). hemodialysis who have received a 500 mg dose All patients were receiving the drug (1 00 to 200 within 6 hours of a dialysis session should mg/day) for depression. Steady -state plasma receive a supplemental dose of 150 mg after the levels were obtained during a 24 -hour period. session. If the last regular dose was more than 6 Clinical Global Impression Improvement scale hours prior to hemodialysis, no supplemental (CGI -I) scores were assessed by the patient’s dose is needed. There are no data in pediatric treating psychiatrist. In the nine children patients with renal insufficiency. 3 considered to be responders (CGI -I < 2), mean area under the concentration curves for Ertapenem may be mixed in sodium chloride or bupropion and its metabolites were significantly Ringer’s solution, but sho uld not be mixed or higher than in those children considered to be infused with dextrose -containing fluids. It is also nonresponders. The authors suggest that plasma unstable when mixed with mannitol. Ertapenem levels of bupropion and its hydroxybupropio n may be infused with hetastarch, heparin, and metabolite may be useful in predicting response potassium chloride solutions. 7 to therapy. Daviss WB, Perel JM, Brent DA, et al. Acute antidepressant response and plasma Availability and Cost levels of bupropion and metabolites in a Ertapenem (Invanz ®; Merck & Co., Inc. ) is pediatric -aged sample: an exploratory study. available in 1 gram vials . The average wholesale Ther Drug Monit 2006;28:190 -8. price for ertapenem is $58.85 per vial. 8 Buspirone pharmacokinetics in autistic children Summary Buspirone, a serotonin 5 -HT -1A agonist , may be Ertapenem offers pediatric health care useful in the treatment of children with pervasive professionals another option for broad spectrum developmental disorder and autism. In this study antimicrobial coverage. While little clinical trial ,the pharmacokinetics of buspirone were studied informatio n is available, this agent appears to be in 21 chi ldren with autism. Patie nts 2 -3 years of an effective therapy that is generally well age were given 2.5 mg and patients 4 -6 years of tolerated in children. More research is needed to age were given 5 mg. The authors found a mean define the role of ertapenem in treating pediatric peak serum concentration of 1,141 +748 pg/mL, infections. with a time to maximum concentration of 0.8 hours. Elimination half -life w as 1.6 +0.3 hours. References Peak concentrations of the primary metabolite (1 - 1. Ertapenem. Drug Facts and Comparisons . Efacts pyrimidinylpiperazine) were 4.5 -fold higher than [online]. 2006. Available from Wolters Kluwer Health, Inc. the corresponding buspirone concentration. Girls (accessed 5/13 /06). 2. Food and Drug Administration Center for Drug Evaluation had significantly higher peak buspirone and Research. Pediatric Exclusivity Labeling Charnges. concentrations and a lower metabolite/parent Available at: www.fda.gov/cder/pediatric/labelchange.htm drug ratio. The authors concluded from these (accessed 5/12/06) data that buspirone is rapidly absorbed and 3. Invanz ® pr escribing information. Merck & Co., Inc., October 2005. eliminated in young children, with peak plasma 4. Keating GM, Perry CM. Ertapenem: a review of its use in concentrations similar to that observed in older the treatment of bacterial infections . Drugs 2005;65:2151 - children receiving higher doses. Edward DJ, 78. Chugani DC, Chugani HT, et al. 5. Shah PM, Isaacs RD. Ertapenem, the first of a new group of carbapenems. J Antimicrob Chemother 2003;52:538 -42. Pharmacokinetics of buspirone in autistic 6. Executive summary, Division of Anti -infective and children. J Clin Pharmacol 2006;46:508 -14. ophthalmology products. Summary of clinical review of studies su bmitted in response to a pediatric written request. Busulfan concentrations in saliva and plasma Ertapenem (Invanz) -BPCA pediatric studies summary. Available at Measurement of busulfan concentrations in www.fda.gov/cder/pediatric/Summaryreview.htm (accessed children may be used to optimize response and 5/13/06). minimize the risk for toxicity. In this study, t he 7. Mc Quade MS, Van Nostrand V, Schariter J, et al. Stability pharmacokinetic parameters of busulfan were and compatibility of reconstituted ertapenem with commonly evaluated in 10 children (1.3 to 19 years of age) used IV infusion and coinfusion solutions. Am J Health -Syst Pharm 2004;61:38 -45. undergoing hematopoietic stem cell 8. 2005 Red Book. Montvale, NJ. Medical Economics, 2005. transplantation using both plasma and saliva samples . Liquid chromatography -tandem mass spectrometry was used to quantify busulfan concentrations in 69 pairs of samples. The correlation between samples from the two sites errors in 1,678 orders. In a prospective review of was highly significant (r = 0.958). The apparent drugs used in 8 mock codes, there were 4 errors plasma clearance was higher than the apparent in 125 orders. The authors concluded that saliva clearance (202 +31 mL/hr/kg versus spontaneous medication error reporting systems 189 +28 mL/hr/kg; p = 0.001) , but th e mean may significantly underestimate the rate of 10 - elimination half -life was not significantly fold dosing errors in children and that the error different (2.31 +0.46 hours in the plasma samples rate during code situations may be particularly and 2.30 +0.36 hours in the saliva samples). high. Kozer E, Scolnik D, Jarvis AD, et al. The Based on their results, the authors conclude d that effect of detection approaches on the reported busulfan analysis using saliva s amples could be a incidence of tenfold errors. Drug Safety useful alternative to plasma samples for assessing 2006;29:169 -74. concentrations in children undergoing treatment. Rauh M, Stachel D, Kuhlen M, et al. NSA IDs during pregnancy Quantification of busulfan in saliva and plasma Nonsteroidal anti -inflammatory drugs (NSAIDs) in haematopoietic stem cell transplantation in are known to produce closure of the patent childre n: validation of liquid chromatography ductus arteriosus in neonates. The authors tandem mass spectrometry method. Clin present the findings of their meta -analysis of Pharmacokinet 2006;45:305 -16. reports of NSAID use during the third trimester and th e risk of premature closure of the ductus. Cisplatin dosing adjustment They compared 217 patient exposures to The authors of this paper introduce a new indomethacin and 221 controls and found that the method for adjusting cisplatin dosing in children. risk of ductal closure was 15 -fold higher in the It has previously been sho wn that adjustment of women exposed to indomethacin. The authors dose based on body surface area can lead to conclude d that short -term use o f NSAIDs in late significant variability in area under the pregnancy is associated with an increased risk for concentration versus time curve (AUC). Using ductal closure. Koren G, Florescu A, Costei AM, plasma cisplatin concentrations from 19 children, et al. Nonsteroidal anti -inflammatory drugs the authors investigated various combinations of during third trimester and the risk of premature pat ient parameters in order to reduce variability closure of the ductus arteriosus: a meta -analys is. in AUC. The combination of height, weight, age, Ann Pharmacother 2006;40:824 -9. maximum serum concentration, and half -life was used to create a dosing formula that gives a more Oxycodone pharmacokinetics constant AUC. Further studies will be needed to The authors of this study used population assess the cli nical utility of this new method. pharmacokinetic modeling to develop a profile of Goodisman J, Souid A. Constancy in integrated oxycodone pharmacokinetics in children between cisplatin plasma concentrations among pediatric 6 months and 7 years of age. Using data from patients. J Clin Pharmacol 2006;46:443 -8. several small studies, the data were fit to a two - compartment linear model. Weight was found to Extended release dexmethylphenidate have a significant affect on clearance and volume This review describes the studies conducted with of distribution , confirming the need for weight - extended release dexmethylphenidate (Focalin ™ based dosing in young children . El -Tahtawy A, XR) , the active d -enantiomer of methylphenidate. Kokki H, Reidenberg BE . Population The authors include information on the pharmacokinetics of oxycodone in children 6 pharmacokinetics, efficacy , and safety of this months to 7 years old. J Clin Pharmacol new product . The studies are presented in a 2006;46:433 -42. concise, bu llet -list format, allowing readers to quickly review the litera ture. Robinson DM, There was no P&T Committee meeting in May. Keating GM. Dexmethylphenidate extended release in attention -deficit hyperactivity disorder. Contributing Editor:Marcia L. Buck, Pharm.D. Drugs 2006;66:661 -8. Editorial Board: Kristi N. Hofer, Pharm.D. Michelle W. McCarthy, Pharm.D. Medication Errors If you have comments or suggestions for f uture The objective of this study was to identify the issues, please contact us at Box 800674, UVA source of 10 -fold errors in pediatric medication Health System, Charlottesville, VA 22908 or order s in a large tertiary care hospital. In a by e -mail to mlb3u@virgini a.edu . This review of medication errors reported to the newsletter is also available at hospital’s Medication Incident Committee, the www.healthsystem.virginia.edu/internet/pediatr authors found an incidence rate of 1 error per ics/pharma -news/home.cfm 22,500 doses prescribed. A chart audit of 1,532 patients in the Emergency De partment revealed 2