What is the data to support metronidazole 30 mg/kg/day (max of 1500 mg/day) in pediatric appendicitis?

What is the data to support metronidazole 30 mg/kg/day (max of 1500 mg/day) in pediatric appendicitis?

Comment by InpharmD Researcher

Clinical guidelines recommend the use of metronidazole 30-40 mg/kg/day in combination with an advanced-generation cephalosporin for management of complicated intra-abdominal infections, including appendicitis, in pediatric patients. Limited studies reporting the use of metronidazole in dosages of 30 mg/kg/day for the management of appendicitis in pediatrics cite maximum dosages; one retrospective study reports a maximum of 1,500 mg, while a pharmacokinetic study lists a maximum dosage of 1,000 mg for patients below 80 kg and 1,500 mg for patients above 80 kg. In general, dosing of metronidazole at 30 mg/kg/day for pediatric appendicitis appears to be beneficial in infection control with a tolerable safety profile, although it should be noted that all identified studies provided a combination of metronidazole and ceftriaxone.

Background

Guidelines published in 2010 by the Surgical Infection Society and Infectious Diseases Society of America for the management of complicated intra-abdominal infections (including appendicitis) recommend broad-spectrum antimicrobial regimens for pediatric patients with complicated intra-abdominal infections. Recommended regimens include a carbapenem, a beta-lactam/beta-lactamase inhibitor combination, or an advanced-generation cephalosporin in combination with metronidazole. The recommended dose of metronidazole is 30-40 mg/kg/day divided every 8 hours. For children with severe allergies to beta-lactam antibiotics, ciprofloxacin plus metronidazole or an aminoglycoside-based regimen is recommended. [1]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the data to support metronidazole 30 mg/kg/day (max of 1500 mg/day) in pediatric appendicitis?

Please see Tables 1-4 for your response.

A Standardized Protocol for the Management of Appendicitis in Children Reduces Resource Utilization
Design	Retrospective and prospective, pre-post study N= 640
Objective	To determine whether delivering a standardized protocol (SP) to children with appendicitis would improve healthcare resource utilization and clinical outcomes
Study Groups	pre-SP (n= 343) post-SP (n= 297)
Inclusion Criteria	Patients under the age of 21 with uncomplicated or complicated appendicitis
Exclusion Criteria	Not explicitly stated
Methods	The study was conducted at a free-standing children's hospital and implemented an SP for managing pediatric appendicitis. The SP involved preoperative administration of ceftriaxone (50 mg/kg, maximum 2,000 mg) and metronidazole (30 mg/kg, maximum 1,500 mg) for a minimum of 3 days, followed by prompt appendectomy by a designated pediatric surgeon. Postoperative care was tailored based on the classification of appendicitis. Uncomplicated cases were discharged without postoperative antibiotics if they met discharge criteria, while complicated cases received intravenous antibiotics for at least 3 days. Complicated cases were discharged on oral antibiotics (amoxicillin/clavulanic acid 45 mg/kg, maximum 875 mg), with the duration determined by white blood cell (WBC) count; a full course of 5 days was utilized if the WBC count was normal or 7 days if it was abnormal. If discharge criteria were not met on postoperative day 3, intravenous (IV) antibiotics were continued, and the child was reassessed daily until postoperative day 7. During the post-SP period, a temporary shortage of metronidazole led to the use of clindamycin (10 mg/kg, maximum 900 mg) in the modified regimen.
Duration	pre-SP: January 2015 to November 2016 post-SP: January 2017 to November 2018
Outcome Measures	Primary: length of stay (LOS), antibiotic days, discharge on intravenous (IV) antibiotics, utilization of peripherally inserted central catheter (PICC) lines, and postoperative imaging Secondary: protocol adherence and rates of adverse events (postoperative abscess, return to emergency department [ED] or operating room [OR], surgical site infection, and readmission within 30 days)
Baseline Characteristics		Uncomplicated Appendicitis		Complicated Appendicitis		p-Value
		pre-SP (n= 224)	post-SP (n= 188)	pre-SP (n= 119)	post-SP (n= 109)	Uncomplicated	Complicated
	Age*, years	11.4 (8.8–15.1)	12.1 (9.7–15.4)	10.4 (7.5–14.0)	10.4 (8.0–14.2)	0.124	0.521
	Male	56.7%	62.8%	58.0%	63.3%	0.211	0.412
	White	22.8%	20.2%	20.2%	20.2%	--	--
	Admission WBC*	13.7 (9.8–16.9)	13.9 (10.3–16.8)	16.4 (13.5–19.4)	15.1 (12.1–19.8)	0.610	0.284
	*Values reported as medians with interquartile ranges
Results	Endpoint	Uncomplicated Appendicitis		Complicated Appendicitis		p-Value
		pre-SP (n= 224)	post-SP (n= 188)	pre-SP (n=119)	post-SP (n= 109)	Uncomplicated	Complicated
	Length of stay*, days	1.0 (1.0–2.0)	1.0 (1.0–1.0)	5.0 (3.0–6.0)	4.0 (3.0–5.0)	0.010	0.015
	PICC	0.0	0.0	26.9%	1.8%	--	< 0.001
	Discharge on IV antibiotics	0.0	0.0	17.6%	0.9%	--	< 0.001
	Postoperative antibiotic days*	0.0 (0.0–1.0)	0.0 (0.0–0.0)	6.0 (4.0–10.0)	5.0 (5.0–7.0)	< 0.001	0.525
	Imaging Ultrasound CT scan	0.4% 0	0.5% 0.5%	8.4% 4.2%	1.8% 1.8%	0.705 0.456	0.027 0.449
	*Values reported as medians with interquartile ranges
Adverse Events	pre-SP vs. post-SP: Uncomplicated - rate of any adverse event (6.7% vs. 2.7%; p= 0.058), postoperative abscesses (0.4% vs. 0.0%; p= 0.544), readmissions within 30 days (1.8% vs. 0.5%; p= 0.245), return to ED (6.3% vs. 2.7%; p= 0.084), and return to OR (0.4% vs. 0.5%; p= 0.705) Complicated - rate of any adverse event (16.0% vs. 18.3%; p= 0.633), postoperative abscess (9.2% vs. 3.7%; p= 0.090), readmission within 30 days (3.4% vs. 3.7%; p= 0.899), return to ED (10.0% vs. 14.7%, p= 0.291), and return to OR (0.8% vs. 0.0%; p= 0.522)
Adverse Events	Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions	We successfully implemented an SP for treating appendicitis in children. The uniform care provided by this protocol reduced resource utilization, and, by inference, costs to the healthcare system, for uncomplicated and complicated appendicitis without compromising clinical outcomes.
InpharmD Researcher Critique	The study's strengths include the implementation of a standardized protocol that led to improved resource utilization and clinical outcomes in pediatric appendicitis management. Weaknesses may include the non-randomized study design and potential biases in retrospective data collection. The study highlights the importance of standardized protocols in enhancing care delivery and reducing healthcare costs in pediatric surgical settings.

References:

Pennell C, Meckmongkol T, Arthur LG, et al. A Standardized Protocol for the Management of Appendicitis in Children Reduces Resource Utilization. Pediatr Qual Saf. 2020;5(6):e357. Published 2020 Oct 26. doi:10.1097/pq9.0000000000000357

Pharmacokinetic and Pharmacodynamic Properties of Metronidazole in Pediatric Patients With Acute Appendicitis: A Prospective Study
Design	Prospective pharmacokinetic study N= 100
Objective	To determine whether metronidazole (MDZ) 30 mg/kg once daily dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis (B fragilis), which is the most common organism implicated in infectious complications of appendicitis
Study Groups	Aged 4–7 years (n= 26) Aged 8–11 years (n= 40) Aged 12–17 years (n= 34)
Inclusion Criteria	Aged 4–17 years; admitted for suspected acute appendicitis, perforated or nonperforated, with or without abscess; treated with once-daily ceftriaxone and MDZ
Exclusion Criteria	Did not receive once-daily dose of MDZ; currently receiving rifampin, cimetidine, phenytoin, fosphenytoin, or phenobarbital (due to potential cytochrome P-450 interactions); pregnant or medically complex by history (e.g., Children’s Hospital Association clinical risk groups 5 or greater)
Methods	Antimicrobial therapy was given by intravenous (IV) infusion, MDZ 30 mg/kg per dose (actual body weight) once daily with a maximum dose of 1000 mg for less than 80 kg and 1500 mg for patients over 80 kg, in conjunction with ceftriaxone 50 mg/kg per dose once daily with a maximum dose of 2000 mg. After the initial dose of MDZ, plasma samples were collected at up to 5 time points surrounding the first dose: before infusion, 10 minutes, 3–4 hours, 6–8 hours, and 23–24 hours post-infusion. MDZ and its metabolite hydroxy-MDZ (MDZOH) were quantified by validated liquid chromatography-tandem mass spectrometry methodology. One and 2 compartmental models were evaluated for MDZ.
Duration	July 2014 to April 2016
Outcome Measures	AUC/MIC ratio for B. fragilis; percentage of patients meeting the AUC/MIC efficacy target ratio of ≥70:1
Baseline Characteristics		Patients (n = 100)
	Male, n	66
	White, n	44
	Median weight, kg	37.5
	Median body mass index, kg/m²	17.8
	Antimicrobial therapy, n Maximum of 1000-mg dose for less than 80 kg Maximum of 1500-mg dose for over 80 kg Greater than 80 kg but received 1000 mg instead of 1500 mg	51 2 1
	Number of samples, n 4- to 7-year-old group 8- to 11-year-old group 12- to 17-year-old group	26 40 34
Results	Percentage of Patients Whose Metronidazole Area Under the Curve/Mean Inhibitory Concentration Achieves Target for Efficacy (≥70:1) Based on Monte Carlo Simulation
	Age, years	Median AUC (mg×h/L)	MIC = 1	MIC = 2	MIC = 4	MIC = 8
	4	732	100	100	97.6	71.6
	5	612	100	100	94.6	57
	6	555	100	99.2	93	49
	7	530	100	99.4	89.2	46
	8	588	100	100	92.7	53.6
	9	520	100	99.6	89.7	42.5
	10	478	100	99.3	88	36.2
	11	456	100	98.7	84.5	32.6
	12	419	100	98.7	78.4	26.2
	13	369	100	97.7	75.5	20
	14	361	100	96.5	73.3	14.1
	15	360	100	97.1	71.1	19.4
	16	341	100	97.8	68	19
	17	313	100	96.5	61	9.5
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	The target AUC/MIC = 70:1 was obtained in more than 95% of patients with organisms having an MIC ≤ 2 mcg/mL. Because 90% of B. fragilis isolates in the United States and Europe report an MIC ≤ 2 mcg/mL, and this is the most common anaerobe to complicate appendicitis, success with MDZ is expected to provide adequate source control (for example, surgical drainage). Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing than 30 mg/kg per dose once daily in this population.
InpharmD Researcher Critique	This study has inherent limitations. Study findings cannot be extrapolated across the entire spectrum of illness, patient complexity, diagnoses (in particular, central nervous system infections), or the adult population as only healthy children with acute appendicitis were enrolled. Additionally, only 2 participants received the max dose of 1500 mg, which is the dose that may be more predictive of the appropriate dose to meet goal AUC in the older age groups. The robustness of clearance and AUC calculations are limited, particularly for the metabolite as the study only had an average of 3 samples per patient.

References:

Child J, Chen X, Mistry RD, et al. Pharmacokinetic and Pharmacodynamic Properties of Metronidazole in Pediatric Patients With Acute Appendicitis: A Prospective Study. J Pediatric Infect Dis Soc. 2019;8(4):297-302. doi:10.1093/jpids/piy040

Once Daily Dosing of Ceftriaxone and Metronidazole in Children With Perforated Appendicitis
Design	Single-center, retrospective analysis N= 123
Objective	To evaluate the efficacy of once-daily ceftriaxone and metronidazole regimen for children with perforated appendicitis
Study Groups	Ceftriaxone and metronidazole (n= 66) Other antibiotic regimens (n= 57)
Inclusion Criteria	Patients less than 18 years of age with perforated appendicitis, procedures executed at the University of Florida Health Shands Hospital
Exclusion Criteria	Diagnosis of non-perforated appendicitis or treated with a prolonged course of antibiotics prior to surgery, diagnosied with a condition (e.g., leukemia on chemotherapy) or infection (e.g., shunt infection) not related to the appendectomy that might influence antibiotic selection and duration, and documentation was inadequate
Methods	A group of patients treated with ceftriaxone and metronidazole was compared with a cohort of patients treated with other antibiotic regimens. Patients were given ceftriaxone (50 mg/kg/day up to 2000 mg/dose) every 24 hours and metronidazole (30 mg/kg/day up to 1000 mg/dose) divided every 6, 8, or 24 hours. Patients receiving other antibiotics were dosed using recommendations for intra-abdominal infections, outlined in standard pediatric drug references.
Duration	Enrollment: procedures from January 2008 to July 2013 Intervention: 4.6 to = 15.7 days (dependent on regimen)
Outcome Measures	Primary outcome: postoperative length of stay Secondary outcomes: total length of intravenous antibiotic treatment, rate of wound infection, and abscess formation
Baseline Characteristics		Ceftriaxone and metronidazole (n= 66)	Other antibiotic regimens (n= 57)
	Age, years	9.0 ± 3.9	9.8 ± 4.3
	Male	48 (73%)	43 (74%)
	Weight, kg	41.1 ± 22.1	42 ± 20.6
	Maximum temperature on admission, C°	38.5 ± 0.88	38.2 ± 0.89
Results	Endpoint	Ceftriaxone and metronidazole (n= 66)	Other antibiotic regimens (n= 57)	p-value
	Postoperative length of stay, days	5.7 ± 2.96	5.8 ± 2.46	0.83
	Postoperative duration of intravenous antibiotic treatment, days	6.0 ± 3.1	5.9 ± 2.4	0.96
	Rate of wound infection	3 (5%)	1 (2%)	0.73
	Postoperative abscess rate	5 (8%)	2 (4%)	0.57
Adverse Events	Common Adverse Events: Not disclosed
	Serious Adverse Events: Not disclosed
	Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions	There were no statistically significant differences in the outcomes evaluated. A prospective, randomized, controlled trial is warranted to better understand the benefits and risks of this regimen, including the rate of infectious complications such as abscess formation.
InpharmD Researcher Critique	Strengths of this study include similarities in baseline characteristics, the standardization of procedure, and that all patients received intraoperative antibiotics prior to incision. The retrospective nature of the study relied on each surgeon's assessment and classifications of a patient diagnosis/complications. Each surgical sterilization practice may have been different and influenced the outcomes. While there were no statistically significant differences in the outcomes evaluated, the twofold greater risk of infectious complications in the ceftriaxone and metronidazole group may be worth reexamining before implementing into practice.

References:

Lee JY, Ally S, Kelly B, Kays D, Thames L. Once Daily Dosing of Ceftriaxone and Metronidazole in Children With Perforated Appendicitis. J Pediatr Pharmacol Ther. 2016;21(2):140-145. doi:10.5863/1551-6776-21.2.140

Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial
Design	Prospective, randomized trial N= 99
Objective	To compare the efficacy of ceftriaxone and metronidazole compared to a standard triple antibiotic regimen of ampicillin, gentamicin, and clindamycin in children with perforated appendicitis
Study Groups	Ceftriaxone and metronidazole (CM) (n= 49) Ampicillin, gentamicin, and clindamycin (AGC) (n= 49)
Inclusion Criteria	Children with perforated appendicitis
Exclusion Criteria	Allergies to any medication used in the trial, abscess identified before surgery
Methods	Patients were randomized to receive either once-daily ceftriaxone 50 mg/kg and metronidazole 30 mg/kg (CM) or triple antibiotic therapy of ampicillin 50mg/kg every 6 hours, gentamicin 2.5 mg/kg every 8 hours, and clindamycin 10 mg/kg every 6 hours (AGC). All patients received a 5-day course of intravenous antibiotics. Patients could receive up to 10 days of antibiotic therapy.
Duration	Enrollment: April 2005 to November 2006 Intervention: at least 5 days
Outcome Measures	Primary: maximum daily temperatures, time to initial oral intake, time to regular diet, length of hospitalization, length of antibiotic therapy, abscess rate, and wound infection rate
Baseline Characteristics		CM (n= 49)	AGC (n= 49)	p-value
	Age, years	9.9 ± 4.0	7.3 ± 4.2	0.02
	Female	43%	35%	0.60
	Weight, kg	39.0 ± 22.2	29.9 ± 20.1	0.03
	Max temperature, °C	37.8	37.8	--
	Duration of symptoms, days	3.2 ± 2.2	3.0 ± 1.9	0.70
Results	Endpoint	CM (n= 49)	AGC (n= 49)	p-Value
	Time to regular diet, hr:min	75:56 ± 47:40	78:03 ± 39:27	0.82
	Length of stay after operation, h-min	154:50 ± 68:56	151:59 ± 81.01	0.85
	Postoperative abscess	20%	16%	0.6
	Wound infection	0	2%	0.99
	Data presented in graphs: There was no difference in maximum daily temperatures between groups. Time to initial oral intake was not reported. Length of therapy in the overall population was also not reported; among patients with abscesses, there was no difference in days of additional therapy (p= 0.4).
Adverse Events	Common Adverse Events: Not disclosed
	Serious Adverse Events: Not disclosed
	Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions	Once daily dosing with the 2-drug regimen (CM) offers a more efficient, cost-effective antibiotic management in children with perforated appendicitis without compromising infection control when compared to a traditional 3-drug regimen.
InpharmD Researcher Critique	This study was limited in part by differences in baseline characteristics between groups. In the CM group, the patients were significantly older and heavier than the AGC group, which could confounded results; although, the researchers claim that it was due to true randomization of patients, and patients were dosed based on weight.

References:

St Peter SD, Tsao K, Spilde TL, et al. Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial. J Pediatr Surg. 2008;43(6):981-985. doi:10.1016/j.jpedsurg.2008.02.018