This review illustrates the highly variable pharmacokinetics of clavulanic acid in the pediatric population. |
The observed variability can in part be explained by the maturational aspects that characterize these patients, in addition to the disease-specific aspects. |
Both the maturational and disease-specific aspects need to be further addressed, with currently available techniques, as the first step towards pharmacokinetic-pharmacodynamic modeling and subsequent targeted exposure of a very commonly used drug in pediatrics. |
1 Introduction
2 Methods
2.1 Search Strategy and Study Selection
2.2 Quality Assessment
2.3 Data Extraction
2.4 Data Analysis
3 Results
3.1 Search and Included Studies
References | Country | Study design | Study size and setting | Patient characteristics | Type of antibiotic | Primary aim | Primary outcome |
---|---|---|---|---|---|---|---|
Al Roomi et al. [28] | UK | Single-center cohort | n = 32 children (n = 20 included for pharmacokinetics) Setting unknown | 1 mo to 12 y (mean 5.2 y) Urinary tract infection (amoxicillin resistant and amoxicillin sensitive) | Amoxicillin/clavulanic acid (4:1 suspension and 2:1 tablet) dosed on age and body weight Oral suspension; every 8 h | 1. Pharmacokinetics 2. Efficacy | 1. Serum and urine concentrations 2. Clinical response rate 3. Side effects |
Begué [19] | France | Single-center PK study | n = 16 children Hospitalized | 2 mo to 9.5 y (mean 24.3 mo) Acute infection (otitis, pneumonia, bronchitis, rhinitis, sinusitis, UTI) | Amoxicillin/clavulanic acid (4:1) n = 7: 10 + 2.5 mg/kg n = 9: 20 + 5 mg/kg Oral suspension | 1. Pharmacokinetics | 1. Serum concentrations |
Begué [35] | France | Single-center cohort | n = 24 neonates + children (n = 13 included for pharmacokinetics) Hospitalized | 4 d to 14 y Suspected/proven bacterial infection (sepsis, pyelonephritis, pneumonia) | Ticarcillin/clavulanic acid Neonates: 225 + 9 mg/kg/day (25:1) Children age > 3 mo: 250 + 16 mg/kg/day (15:1) iv in 30 min; every 6 h | 1. Pharmacokinetics | 1. Serum and urine concentrations 2. Clinical evolution 3. Side effects |
Burstein [34] | USA | Single-center cohort | n = 11 preterm neonates Hospitalized | Preterms (< 36 wk, < 2200 g) Suspected or proven bacterial infection | Ticarcillin/clavulanic acid (30:1) 72.5 + 2.5 mg/kg iv in 15 min; every 8 h | 1. Pharmacokinetics 2. Development of dosing guidelines | 1. Serum concentrations 2. Adverse reactions |
De Cock [24] | Belgium | Prospective open-label PK study | n = 50 children Pediatric ICU | ICU pts; median age 2.58 y (0.08–15 y) Severe infection | Amoxicillin/clavulanic acid 25–35 mg/kg amoxicillin (10:1 and 5:1) iv in 5–30 min; every 6 h | 1. Pharmacokinetics 2. Efficacy | 1. PK/PD model 2. Clinical outcome |
Fayed et al. [32] | Scotland | Single-center cohort | n = 24 preterm and neonates Hospitalized | BW mean 1700 g (895–3900 g), GA mean 30.7 wk (25–39 wk) Prophylactic because of risk of infection | Ticarcillin/clavulanic acid (15:1) 75 + 5 mg/kg; iv in slow bolus; every 12 h | 1. Pharmacokinetics 2. Clinical/bacteriological efficacy 3. Safety | 1.Serum and urine concentrations 2.Adverse events |
Feldman et al. [21] | USA | Single-center PK study | n = 18 adolescents Hospitalized | Adolescents with malignancies with suspected infection (fever + laboratory signs). Mean age PK cohort 14.8 y (12–19 y) | Ticarcillin/clavulanic acid (30:1) 50 + 1.7 mg/kg iv in 30 min; every 4 h | 1.Clinical efficacy 2.Safety 3.Pharmacokinetics | 1.Serum and urine concentrations |
Fricke et al. [31] | Germany | Single-center cohort | n = 13 preterm and term neonates Hospitalized | GA 34–43 wk, 1400–3750 g Suspected infection | Ticarcillin/clavulanic acid (25:1) < 36 wk: 83.3 + 3.3 mg/kg > 36 wk: 100 + 4 mg/kg iv in 10 min; every 8 h | 1.Pharmacokinetics | 1.Serum concentrations 2.Adverse events |
Hoberman et al. [27] | USA | Open-label study | n = 112 children Home-based treatment | Age: 6–23 mo Acute otitis media | Amoxicillin/clavulanic acid (28:1) Phase I: 45 + 1.6 mg/kg Phase II: 40 + 1.425 mg/kg Oral suspension; every 12 h | 1.Side effects/rate of diarrhea 2.Pharmacokinetics | 1.Side effects 2.Serum concentrations |
Jacobs et al. [22] | USA | Single-center cohort | n = 10 patients with CF Hospitalized | Age (mean + SD) 15.9 y ± 6.5 y Pulmonary exacerbation | Ticarcillin/clavulanic acid (3 + 0.1 g and 3 + 0.2 g) 75 mg/kg iv in 30 min | 1.Pharmacokinetics | 1.Serum and urine concentrations |
Jehl et al. [30] | France | Multicenter PK study | n = 36 children, no neonates Hospitalized | 0–12 y Chronic otitis media with indication for ear tubes | Amoxicillin/clavulanic acid (8:1) 26.7 + 3.3 mg/kg Oral suspension; every 8 h | 1. Pharmacokinetics of blood 2. Pharmacokinetics of middle ear fluid | 1.Serum and middle ear fluid concentrations |
Jones et al. [23] | UK | Single-center PK study | n = 15 children Hospitalized | Age 2–14 y (mean 6.9 y) Known or suspected bacterial infection, seriously ill | Amoxicillin/clavulanic acid (10:1) 50 + 5 mg/kg iv in 30 min | 1. Pharmacokinetics | 1.Serum concentrations |
Miall-Allen et al. [33] | UK | Single-center RCT | n = 89 neonates (n = 46 treated with timentin) hospitalized | GA: 24–40 wk, PNA 1–59 d BW: 620–3860 g Suspected/proven infection | Ticarcillin/clavulanic acid (15:1) 75 + 5 mg/kg iv in 20 min; 2–3 times a day | 1.Efficacy 2.Pharmacokinetics | 1.Clinical outcome 2.Serum concentrations |
Nelson et al. (1982) | USA | Single-center PK study | n = 34 children Setting unknown | No age or weight reported Otitis media/dermatological infections | Amoxicillin/clavulanic acid (4:1) 1. 6.6 + 1.7 mg/kg 2. 13.3 + 3.3 mg/kg Oral suspension; single dose | 1.Pharmacokinetics | 1.Serum concentrations |
Niekerk et al. [29] | South Africa | Single-center PK study | n = 35 children n = 22 clavulanic acid pharmacokinetics Setting unknown | Age: 2.08–9.5 y Weight: 9.5–29 kg Suspected/proven bacterial infection | Amoxicillin/clavulanic acid (4:1) 2–5 y: 125 + 31.25 mg 6–10 y: 250 + 62.5 mg Oral suspension | 1.Pharmacokinetics 2.Clinical efficacy 3.Adverse outcome | 1.Serum concentrations 2.Clinical outcome 3.Side effects |
Reed et al. [18] | USA | Single-center PK study | n = 22 children Hospitalized | Age: 1–111 mo; weight 4–47 kg Suspected/proven bacterial infection | Ticarcillin/clavulanic acid (30:1) 50 + 1.7 mg/kg iv in 20 min; every 4 h | 1.Pharmacokinetics | 1.Serum and urine concentrations |
Schaad et al. [27]) | Switzerland | Single-center PK study | n = 12 children Hospitalized | Age: 2–14.5 y (mean 10 y) Viral or neurological problem | Amoxicillin/clavulanic acid (5:1) 25 + 5 mg/kg iv in 2 min; single dose | 1.Pharmacokinetics | 1.Serum and urine concentrations |
Schaad et al. [20] | Switzerland | Single-center PK study | n = 11 children Hospitalized | Age: 3.1–13.8 y (mean 10.8 ± 3.2 y) Non-infectious reason | Amoxicillin/clavulanic acid (4:1) 20 + 5 mg/kg oral suspension; single dose | 1.Pharmacokinetics | 1.Serum and urine concentrations 2.Side effects |
3.2 Quality Assessment
3.3 Study Population
3.4 Antibiotic Regimen
References | Type of antibiotic | Clavulanic acid (dose) | Administration | Material | Timing of sampling |
---|---|---|---|---|---|
Oral clavulanic acid co-administered with amoxicillin | |||||
Al Roomi et al. [28] | Amoxicillin/clavulanic acid (4:1 C4/C2 suspension; 2:1 tablet) | C4 <1 month: 4.76 mg/dose C4 1–3 month: 6.35 mg/dose C4 3–9 month: 7.9 mg/dose C4 9 month-2 y: 15.9 mg/dose C2 2.5 y: 31.75 mg/dose Tab >5 y: 62.5 mg/dose | Oral Every 8 h After 4–8 h of fast | Blood Urine | T = 30-60-90 min after first dose (mg/L) T = 0–6 h after first dose (mg/L) |
Bégué [19] | Amoxicillin/clavulanic acid (4:1) | 1. 2.5 mg/kg 2. 5 mg/kg | Oral Not with food | Blood | T = 15, 30, 45 min, 1, 2, 4, 8 h |
Hober-man et al. [25] | Amoxicillin/clavulanic acid (28:1) | 1. 1.6 mg/kg 2. 1.425 mg/kg | Oral Every 12 h | Blood | Single sample between 30 min and 4 h after dose (treatment day 1 or day 7) |
Jehl et al. [30] | Amoxicillin/clavulanic acid (8:1) | 3.3 mg/kg | Oral Every 8 h | Blood Middle ear fluid | Single sample per patient 1, 2, 3, 8, 12 h (treatment day 4) |
Nelson et al. [26] | Amoxicillin/clavulanic acid (4:1) | 1. 1.7 mg/kg 2. 3.3 mg/kg | Oral Single dose | Blood | T = 20, 40, 60, 120, 180, 240 min |
Niekerk et al. [29] | Amoxicillin/clavulanic acid (4:1) | 1. 2–5 y: 31.25 mg/dose 2.34 ±0.483 mg/kg 2. 6–10 y: 62.5 mg/dose 3.14 ± 0.6 mg/kg | Oral Every 8 h for 5–7 days | Blood | T = 0, 20, 40, 60, 90, 120, 180, 240, 360 min after first dose |
Schaad et al. [20] | Amoxicillin/clavulanic acid(4:1) 20 + 5 mg/kg | 5 mg/kg | Oral Single dose | Blood Urine | T = 0, 20, 40, 60, 90, 120, 180, 360 min |
Intravenous clavulanic acid co-administered with amoxicillin | |||||
Schaad et al. [27] | Amoxicillin/clavulanic acid(5:1) | 25 + 5 mg/kg | iv in 2 min Single dose | Blood Urine | T = 5, 15, 30, 60, 90, 180, 360 min Every 2 h for 6 h |
Jones et al. [23] | Amoxicillin/clavulanic acid (10:1) | 50 + 5 mg/kg | iv in 30 min Single and repeated dose | Blood | T = 15, 30, 40, 50, 60, 75, 90 min 2, 3, 4, 6 h after beginning infusion |
De Cock [24] | Amoxicillin/clavulanic acid (10:1 and 5:1) | iv in 5–30 min Every 6 h | Blood | ||
Intravenous clavulanic acid co-administered with ticarcillin | |||||
Bégué [35] | Ticarcillin/clavulanic acid Neonates: (25:1) Children aged >3 months: (15:1) | <3 months: 2.25 mg/kg >3 months: 4 mg/kg | iv in 30 min Every 6 h | Blood Urine | T= 0.15, 30, 45 min 1, 2,3, 4, 6 h after third dose Every 2 h for 6 h |
Burstein [34] | Ticarcillin/clavulanic acid (30:1) | 2.5 mg/kg | iv in 15 min Every 8 h | Blood | T = 0.5, 1.5, 4, 8 h after first dose |
Fayed et al. [32] | Ticarcillin/clavulanic acid (15:1) | 5 mg/kg | iv in slow bolus Every 12 h | Blood Urine | T = 0, 15, 90 min, 4, 12 h after first dose 0–6 and 6–12 h after first dose |
Feldman et al. [21] | Ticarcillin/clavulanic acid (30:1) | 1.7 mg/kg | iv in 30 min Every 4 h | Blood | T = 0, 30, 60, 90, 180, 240 min steady-state dose |
Fricke et al. [31] | Ticarcillin/clavulanic acid (25:1) | 1. <36 wk: 3.3 mg/kg 2. >36 wk: 4 mg/kg | iv in 10 min Every 8 h | Blood | T = 15, 30, 60, 120, 240, 480 min after first dose Through level day 4 |
Jacobs et al. [22] | Ticarcillin/clavulanic acid | 1. 5 mg/kg 2. 2.5 mg/kg | iv in 30 min Two consecutive doses | Blood Urine | T = 5, 15, 30, 45 min, 1, 2, 4, 6 h 0–6 h after dose |
Miall-Allen et al. [33] | Ticarcillin/clavulanic acid (15:1) | 5 mg/kg | iv in 20 min Every 8–12 h | Blood | T = 15, 90 min, 4, 8, 12 h after first dose |
Reed et al. [18] | Ticarcillin/clavulanic acid (30:1) | 1.7 mg/kg | iv in 20 min Every 4 h | Blood Urine | 20, 60, 90, 120, 240 min after first dose (1) and steady state (2) 0–4 h after dose |
References | Pharmacokinetic data/concentrations | ||||||
---|---|---|---|---|---|---|---|
Oral clavulanic acid co-administered with amoxicillin | |||||||
Al Roomi et al. [28] | 30 min | 60 min | 90 min | ||||
C4 | 0.9 (0.7; 0–2.0) | 3.1 (1.7; 0.4–5.6) | 3.7 (1.9; 0.5–5.6) | ||||
C2 | 2.13 (1.7; 0.1–4.4) | 4.4 (3.8; 0.2–11) | 2.5 (2.8; 0.5–8) | ||||
Tab | 3.0 (2.4; 0.1–6.6) | 3.4 (3.2; 1.2–11) | 2.6 (0.1–6.6) | ||||
C4 | 0–2 h | 2–4 h | 4–6 h | ||||
C2 | 2.7 (0.75) | 103 (27) | 48.6 (40) | ||||
Tab | 35 (48) | 57.3 (83) | 22 (16) | ||||
61.4 (34.3) | 53 (91) | 22.6 (26.2) | |||||
Bégué [19] | Mean peak + SEM | Serum half-life (h) | |||||
1. 1.26 ± 0.83 (at T = 1 h) | 1.0 | ||||||
2. 3.02 ± 2.9 (at T = 0.75 h) | 1.3 | ||||||
Hober-man et al. [25] | Pharmacokinetics (mean ± SD) | 1. | 2. | ||||
Cmax (µg/mL) | 2.1 | 1.13 ± 0.4 | |||||
Tmax(h) | 1.5 | 2.0 (1.9–2.1) | |||||
AUC (µgh/mL) | 4.9 | 3.8 | |||||
T1/2(h) | 2.9 | 1.4 | |||||
CL/F (L/h/kg) | 0.31 | 0.37 | |||||
Jehl et al. [30] | Mean (SD + range) | ||||||
Serum | Middle ear fluid | ||||||
1 h | 2.60 ± 2.60 (0.09–7.99) | 0.58 ± 0.82 (0–3.07) | |||||
2 h | 1.85 ± 1.21 (0.52–3.75) | 0.94 ± 0.58 (0.17–1.88) | |||||
3 h | 0.64 ± 0.45 (0.12–1.42) | 0.62 ± 0.45 (0.12–1.43) | |||||
8 h | 0.02 ± 0.01 (0–0.04) | 0.11 ± 0.08 (0–0.23) | |||||
12 h | 0.008 ± 0.009 (0–0.02) | 0.11 ± 0.12 (0–0.40) | |||||
Nelson et al. [26] | Mean ± SEM | 20 min | T40 | T60 | T120 | T180 | T240 |
1. | 0.29 ± 0.14 | 0.72 ± 0.22 | 0.67 ± 0.17 | 0.47 ± 0.11 | 0.20 ± 0.04 | 0.09 ± 0.02 | |
2. | 0.42 ± 0.10 | 1.12 ± 0.24 | 1.45 ± 0.22 | 1.02 ± 0.14 | 0.52 ± 0.08 | 0.25 ± 0.03 | |
AUC (µgh/mL) | T1/2(h) | Vd(mL/kg) | Cl (mL/min/1.73 m2) | ||||
1. 1.66 | 1.10 | 1.622 | 478 | ||||
2. 3.54 | 1.17 | 1.575 | 435 | ||||
Niekerk et al. [29] | Mean ± SD | Cmax | Tmax | AUC (µgh/L) | Cl (mL/min/kg) | ||
1. | 1.18 ± 0.63 | 1.39 ± 0.50 | 2.49 ± 1.37 | 17.6 ± 4.7 | |||
2. | 1.31 ± 0.79 | 1.23 ± 0.45 | 2.49 ± 1.53 | 19.1 ± 8.3 | |||
Schaad et al. [20] | Mean ± SD | ||||||
20 min | 40 min | 1 h | 1.5 h | 2 h | 3 h | 6 h | |
0.85 ± 0.89 | 1.72 ± 1.21 | 2.00 ± 1.02 | 2.04 ± 0.71 | 1.60 ± 0.65 | 0.79 ± 0.50 | 0.12 ± 0.10 | |
AUC (mgh/L) | T1/2 (h) | Cl (mL/min) | Renal Cl | ||||
5.6 ± 1.5 | 1.02 ± 0.4 | 789 ± 249 | 135 ± 48 | ||||
0–2 h (%) | 2–4 h (%) | 4–6 h (%) | 0–6 h (%) | ||||
9.5 ± 4.0 | 5.4 ± 2.5 | 3.5 ± 2.9 | 18.4 ± 8.7 | ||||
Intravenous clavulanic acid co-administered with amoxicillin | |||||||
Schaad et al. [27] | T1/2 (h) | AUC (μgh/mL) | Vd (mL/kg) | Cl (mL/min/1.73 m2) | |||
0.81 ± 0.04 | 15.9 ± 0.7 | 368 ± 14 | 254 ± 13 | ||||
Jones et al. [23] | AUC (μgh/mL) | T1/2(h) | Vd (mL/kg) | Cl (mL/min/ 1.73 m2) | |||
13.82 ± 4.39 | 0.786 h | 434 ± 179 | 298.16 ± 138.05 | ||||
De Cock [24] | Cl (L/h/70kg) | Vd (L/70 kg) | |||||
12.20 | 11.60 | ||||||
Intravenous clavulanic acid co-administered with ticarcillin | |||||||
Bégué [35] | Cmax (mg/L) | T1/2 (h) | Vd(mL/kg) | ||||
4.7 ± 0.9 | 2.5 ± 2.4 | 488 ± 172 | |||||
4.78 ± 0.8 | 1.06 ± 0.3 | 661 ± 192 | |||||
0–2 h (mg/L) | 2–4 h | 4–6 h | |||||
129 | 94 | 95 | |||||
Burstein [34] | AUC (μgh/kg/L) | Cmax: (mg/L) | Vd (L/kg) | Cl (L/h/kg) | T1/2(h) | ||
21 (6-42) | 6.8 (2.9–13) | 0.28 (0.14–0.47) | 0.12 (0.057–0.42) | 2.0 (1.1–3.7) | |||
Fayed et al. [32] | (mg/L) Mean ± SD | T1/2 2 ± 1.6 h | |||||
15 min | 90 min | 4 h | 12 h | ||||
2.4 ± 2.7 (0.65–9.2) | 1.5 ± 1.3 (0.65–5) | 0.7 ± 0.6 (0–2.1) | 0.3 ± 0.3 (0–0.65) | ||||
0–6 h 112 ± 258 | 6–12 h 15.4 ± 24.4 | ||||||
Feldman et al. [21] | Time (h) | Mean serum level (mg/L) | Trough/before (T = 0) 0.97 ± 0.19 | ||||
0 | 0.97 ± 0.19 | Peak: 7.2 ± 2.1 | |||||
0.5 | 7.2 ± 2.1 | Through (end): 0.84 ± 0.16 | |||||
1 | 3.2 ± 0.7 | Mean concentration: 2.9 ± 0.6 | |||||
1.5 | 1.9 ± 0.4 | ||||||
2 | 1.4 ± 0.3 | ||||||
3 | 1.2 ± 0.3 | ||||||
4 | 0.84 ± 0.16 | ||||||
T1/2 (h): 1.30 | |||||||
AUC (μgh/mL):11.7 ± 2.0 | |||||||
Vd (L/kg): 0.35 ± 0.05 L/kg | |||||||
Cl (mL/min/kg): 2.93 ± 0.58 | |||||||
Fricke et al. [31] | Cmax(mg/L) | Tmax(min) | Vd(mL/kg) | T1/2(h) | AUC (μgh/mL) | Cl (mg/L) | |
1. 15.0 ± 1.2 | 19.3 ± 2.8 | 263 ± 22 | 1.39 ± 0.12 | 30.1 ± 1.7 | 0.61 ± 0.07 | ||
2. 8.4 ± 0.56 | 19.3 ± 2.8 | 414 ± 29 | 2.56 ± 0.18 | 27.1 ± 2.0 | 0.92 ± 0.15 | ||
Jacobs et al. [22] | T = 15 min | T = 6 h | T1/2(h) | AUC (μgh/mL) | Vd(L/kg) | Cl (L/h/kg) | |
13.84 ± 8.69 | 0.33 ± 0.15 | 0.78 | 8.71 ± 2.18 | 0.364 | 0.305 | ||
5.24 ± 2.05 | 0.22 ± 0.03 | 0.82 | 21.02 ± 13.10 | 0.321 | 0.140 | ||
50% excreted unchanged in urine | |||||||
Miall-Allen et al. [33] | Peak concentration: 6.2–15.6 μg/mL (data solely presented in graphs) | ||||||
Reed et al. [18] | T1/2(h) | Vd(L/kg) | Cl (mL/min/kg) | Fe0–4 h(% dose) | |||
0.87 ± 0.4 | 0.39 ± 0.1 | 6.1 ± 2.5 50 ± 21 | 50 ± 21 Fe | ||||
0.92 ± 0.4 | 0.39 ± 0.1 | 5.8 ± 2.2 |
3.5 Sampling Methods
3.6 Sample Analysis
3.7 Methods for the Pharmacokinetic Analysis
3.8 Pharmacokinetic Results
Pharmacokinetic parameters (range) | Intravenous clavulanic acid | Oral clavulanic acid |
---|---|---|
T1/2 (h) all studies | 0.78–2.56 | 1.0–2.9 |
T1/2, studies in neonates | 1.39–2.5 | n.a. |
AUC (mg × h/L) | 1.7–30.1 | 1.66–5.6 |
AUC (mg × h/L), studies in neonates | 21–30 | n.a. |
AUC (mg × h/L) corrected for dose | 2.76–9.12 | 0.73–2.67 |
AUC (mg × h/L) corrected for dose, studies in neonates | 6.75–9.09 | n.a. |
Vd (mL/kg) | 263–661 | Not reported |
Vd (mL/kg), studies in neonates | 280–488 | n.a. |
Cl (L/h/kg)a | 0.12–0.37 | 0.31–1.15 |