Is the standard dose of amoxicillin-clavulanic acid sufficient?

BMC Clinical Pharmacology

Annelies Verbon³  Cathrien Bruggeman⁴  Cees Neef¹  Leo Stolk¹  Thomas Havenith¹  Michiel Haeseker² 

[1] Department of Clinical Pharmacy, Maastricht University Medical Centre, Maastricht, the Netherlands;Present address: Maastricht University Medical Centre, P. Debyelaan 25, PO Box 58006202 AZ Maastricht, the Netherlands;Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands;Care and Public Health Research Institute (CAPHRI), Maastricht, the Netherlands

关键词: Age;    Pharmacokinetics;    Clavulanic acid;    Amoxicillin;   

Others  :  1084947
DOI  :  10.1186/2050-6511-15-38

 received in 2014-03-24, accepted in 2014-07-14,  发布年份 2014

【 摘 要 】

Background

The pharmacodynamic (PD) efficacy target of amoxicillin is 40% time above the minimal inhibition concentration (40%T > MIC). Recent studies of other antibiotics have shown that PD-efficacy targets are not always reached. The aim of this study was to evaluate the percentage of hospitalised patients, using amoxicillin/clavulanic acid intravenously (iv), that reach the pharmacodynamic efficacy target 40%T > MIC. Additionally, the association of demographic anthropomorphic and clinical parameters with the pharmacokinetics and pharmacodynamics of amoxicillin were determined.

Methods

In serum of 57 hospitalised patients amoxicillin concentrations were measured using high performance liquid chromatography. Patients were older than 18 years and most patients had an abdominal infection. The standard amoxicillin/clavulanic acid dose was 4 times a day 1000/200 mg iv. Pharmacokinetic parameters were calculated with maximum a posteriori Bayesian estimation (MW\Pharm 3.60). A one-compartment open model was used. Individual dosing simulations were performed with MW\Pharm.

Results

In our study population, the mean (±SD) age was 67 (±16) years and the mean clearance corrected for bodyweight was 0.17 (±0.07) L/h/kg. Only, 65% of the patients reached the proposed amoxicillin 40%T > MIC with amoxicillin/clavulanic acid for bacterial MICs of 8 mg/L. A computer simulated increase of the standard dose to 6 times daily, increased this percentage to 95%. In this small study group 40%T > MIC was not associated with clinical or microbiological cure.

Conclusion

A substantial proportion of the hospitalised patients did not reach the 40%T > MIC with the standard dose amoxicillin/clavulanic acid for a bacterial MIC of 8 mg/L. Therefore, we suggest increasing the standard dose of amoxicillin/clavulanic acid to 6 times a day in patients with severe Enterobacteriaceae infections.

Trial registration

Trial registration number: NTR1725 16^th march 2009.

【 授权许可】

   
2014 Haeseker et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Craig WA: Antimicrobial resistance issues of the future. Diagn Microbiol Infect Dis 1996, 25(4):213-217.
• [2]Vogelman B, Craig WA: Kinetics of antimicrobial activity. J Pediatr 1986, 108(5 Pt 2):835-840.
• [3]Craig WA: Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis 1995, 22(1–2):89-96.
• [4]Adam D, de Visser I, Koeppe P: Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination. Antimicrob Agents Chemother 1982, 22(3):353-357.
• [5]Sjovall J, Alvan G, Huitfeldt B: Intra- and inter-individual variation in pharmacokinetics of intravenously infused amoxycillin and ampicillin to elderly volunteers. Br J Clin Pharmacol 1986, 21(2):171-181.
• [6]Matsuura M, Nakazawa H, Hashimoto T, Mitsuhashi S: Combined antibacterial activity of amoxicillin with clavulanic acid against ampicillin-resistant strains. Antimicrob Agents Chemother 1980, 17(6):908-911.
• [7]van Zanten AR, Polderman KH, van Geijlswijk IM, van der Meer GY, Schouten MA, Girbes AR: Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study. J Crit Care 2008, 23(3):422-430.
• [8]Haeseker M, Stolk L, Nieman F, Hoebe C, Neef C, Bruggeman C, Verbon A: The ciprofloxacin target AUC : MIC ratio is not reached in hospitalized patients with the recommended dosing regimens. Br J Clin Pharmacol 2013, 75(1):180-185.
• [9]Aubert G, Carricajo A, Coudrot M, Guyomarc’h S, Auboyer C, Zeni F: Prospective determination of serum ceftazidime concentrations in intensive care units. Ther Drug Monit 2010, 32(4):517-519.
• [10]Rea RS, Capitano B, Bies R, Bigos KL, Smith R, Lee H: Suboptimal aminoglycoside dosing in critically ill patients. Ther Drug Monit 2008, 30(6):674-681.
• [11]EUCAST: Amoxicillin Rationale for the EUCAST clinical breakpoints. http://www.eucast.org/documents/rd/ webcite
• [12]Nederlands Trial Register. Antibiotic blood levels elderly http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1725 webcite
• [13]FDA: Guidance for Industry. Bioanalytical Method Validation, U.S. Department of Health and Food Science. Rockville, MD, USA: Food and Drug Administration (FDA); 2001.
• [14]Martinez MN, Riviere JE: Review of the 1993 veterinary drug bioequivalence workshop, held on march 29–31, 1993, in Rockville, Maryland. J Vet Pharmacol Ther 1994, 17(2):85-119.
• [15]Pullen J, Stolk LM, Neef C, Zimmermann LJ: Microanalysis of amoxicillin, flucloxacillin, and rifampicin in neonatal plasma. Biomed Chromatogr 2007, 21(12):1259-1265.
• [16]Proost JH, Meijer DK: MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring. Comput Biol Med 1992, 22(3):155-163.
• [17]van der Meer AF, Marcus MA, Touw DJ, Proost JH, Neef C: Optimal sampling strategy development methodology using maximum a posteriori Bayesian estimation. Ther Drug Monit 2011, 33(2):133-146.
• [18]Turnidge JD: The pharmacodynamics of beta-lactams. Clin Infect Dis 1998, 27(1):10-22.
• [19]Blaettler L, Mertz D, Frei R, Elzi L, Widmer AF, Battegay M, Fluckiger U: Secular trend and risk factors for antimicrobial resistance in Escherichia coli isolates in Switzerland 1997–2007. Infection 2009, 37(6):534-539.
• [20]SWAB: Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands. http://www.swab.nl/swab/cms3.nsf/viewdoc/20BCD3983B5C390AC12575850031D33D webcite
• [21]de Abajo FJ, Montero D, Madurga M, Garcia Rodriguez LA: Acute and clinically relevant drug-induced liver injury: a population based case–control study. Br J Clin Pharmacol 2004, 58(1):71-80.
• [22]Garcia Rodriguez LA, Stricker BH, Zimmerman HJ: Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Med 1996, 156(12):1327-1332.
• [23]Salvo F, Polimeni G, Moretti U, Conforti A, Leone R, Leoni O, Motola D, Dusi G, Caputi AP: Adverse drug reactions related to amoxicillin alone and in association with clavulanic acid: data from spontaneous reporting in Italy. J Antimicrob Chemother 2007, 60(1):121-126.
• [24]Bolzan H, Spatola J, Castelletto R, Curciarello J: Intrahepatic cholestasis induced by amoxicillin alone. Gastroenterol Hepatol 2000, 23(5):237-239.
• [25]Schwarze C, Schmitz V, Fischer HP, Sauerbruch T, Spengler U: Vanishing bile duct syndrome associated with elevated pancreatic enzymes after short-term administration of amoxicillin. Eur J Gastroenterol Hepatol 2002, 14(11):1275-1277.
• [26]Aguilar L, Martin M, Balcabao IP, Gomez-Lus ML, Dal-Re R, Prieto J: In vitro assessment of the effect of clavulanic acid at concentrations achieved in human serum on the bactericidal activity of amoxicillin at physiological concentrations against Staphylococcus aureus: implications for dosage regimens. Antimicrob Agents Chemother 1997, 41(6):1403-1405.
• [27]Cooper CE, Slocombe B, White AR: Effect of low concentrations of clavulanic acid on the in-vitro activity of amoxycillin against beta-lactamase-producing Branhamella catarrhalis and Haemophilus influenzae. J Antimicrob Chemother 1990, 26(3):371-380.
• [28]Mouton JW, Punt N, Vinks AA: Concentration-effect relationship of ceftazidime explains why the time above the MIC is 40 percent for a static effect in vivo. Antimicrob Agents Chemother 2007, 51(9):3449-3451.