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

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