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Magister Farmasi Klinik Universitas Airlangga2012Drugs Information ServiceReview :Ceftriaxone dosage regimentation(1 gram twice daily & 2 grams once daily)

Microbial mappingInternal medicine department, RSUD Dr. Soetomo2011-2012

No.Gram Negative Bacterial%1. Pseudomonas spp22%2.Acinetobacter spp22%3.E coli16,9%4.Klebsiella pneumoniae11,8%5.Enterobacter aerogenes10,1%No.Gram Positive Bacterial%1.Staphylococcus coagulase negative82,32.Staphylococcus aureus7,23.Streptococcus spp3,94.Corynebacterium spp3,95.Enterococcus2,6

Escherichia coli SensitivityAntibiotic%Amikacin100Meropenem88,8Ceftazidime88,8Gentamycine77,7Cefotaxime77,7Imipenem77,7Piperacilline tazobactam77,7Ampi sulbactam66,6Tobramycin66,6Ceftriaxone66,6Cefoperazone sulbactam55,5Amoxyclav55,5Ciprofloxacin55,5Cotrimoxazole55,5

Acinetobacter spp sensitivityAntibiotic%Meropenem100Amikacin100Cefoperazone sulbactam83,3Ciprofloxacine83,3Levofloxacin83,3Imipenem66,6Cotrimoxazole66,6Ampicillin Sulbactam66,6Gentamycine50Ceftazidim50Piperacillin tazobactam33,3Cefotaxime33,3Amoxyclav16,7Ceftriaxone16,7

Pseudomonas spp. sensitivityAntibiotic%Meropenem100Amikacin83,3Cotrimoxazole83,3Gentamycin50,0Ceftazidime50,0Cefoperazone sulbactam33,3Levofloxacin33,3Imipenem33,3Ampicillin Sulbactam16,7Piperacillin tazobactam16,7Cefotaxime16,7Ceftriaxone-

beta Lactam CompoundsFOCUS

Mechanism of action of beta lactamLullmann et al. 2005. Color Atlas of Pharmacology 3rd edition

Related with PD Characteristic TIME DEPENDENT KILLER

0MICAUC:MIC

T>MIC

Cmax:MIC

Concentration

Time (hours)

PAEPK/PD Parameters Affecting Antibiotic Efficacy in vivoLodise & Drusano, Pharmacokinetics & Pharmacodynamics : Optimal Antimicrobial Therapy in the Intensive Care Unit. Crit Care Clin 27 (2011). 1-18

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Antibiotic ClassificationPK/PD IndexDefinition of PK/PD IndexExamples of AntibioticTime-dependentT > MICPercentage time for which the concentration of a drug remains more than MIC during a dose intervalBETA-LACTAMCarbapenems LincosamidesConcentration-dependentCmax/ MICRatio of the peak drug concentration of the MIC of the pathogenAminoglycosidesConcentration-dependent with time-dependentAUC 0-24 / MICRatio of the area under the concentration time-curve (AUC) during a 24-h period to the MIC of the pathogen FluoroquinolonesGlycopeptidesTigecycline

The Pattern of Antimicrobial Activity Varghese et al, Antimicrobial Pharmacokinetic and Pharmacodynamic Issues in the Critically Ill with Severe Sepsis and Septic Shock. Crit Care Clin 27 (2011) 19-34

Concentration vs Time DependentFigure 1. Time-kill curves, ranging from one-fourth to 64 times the MIC, that show the bactericidal pattern of activity of tobramycin, ciprooxacin, and ticarcillin against Pseudomonas aeruginosa American Type Culture Collection (ATCC) 27853.

Ambrose et al, Pharmacokinetics Pharmacodynamics of Antimicrobial Therapy: Its Not Just for Mice Anymore. Clinical Infectious Diseases 2007; 44:7986

Pharmacokinetic /Pharmacodynamic beta lactam Optimization of Beta Lactam Therapy :

Maximize the f T/ MIC

Manipulation of Dosing Interval

Manipulation of Infusion Time

Crandon & Nicolau, Pharmacodynamic Approaches to Optimizing Beta-Lactam Therapy. Crit Care Clin 27 (2011) 77-93

1st Generation2nd Generation3rd Generation4th GenerationAgentscefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradinecefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, cefoxitin, cefmetazole,cefotetancefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime,cefdinir, ceftibutencefepime

Cephalosporin AgentsFOCUSLacy et al, 2009. Drug Information Handbook 17th EditionSweetman, 2009. Martindale : The Complete Drug Reference 36th Edition

CeftriaxoneCefotaxime

CefoperazoneCeftazidime

CeftriaxoneCefotaxime

CefoperazoneCeftazidime

Chemical stRucture of Third Generation CephalosporinSweetman, 2009. Martindale : The Complete Drug Reference 36th Edition

Pharmacokinetic Characteristics of Third Generation CephalosporinDrugsVolume distribution (Vd)Protein bindingT normalT ESRDExcretionCEFTRIAXONE0,08-0,3 L/kg85-95 % 5-9 hr16 hrUrine (33-67 % as unchanged drug); Feces (as inactive drug)Cefoperazone0,17 L/kg82-93% 1.5-3 hr2,4 hrUrine (20-30 % as unchanged drug); Mainly in the bileCefotaxime0,25 L/kg30-40 %1-1.5 hr15 hrMainly in urine (40-60 % as unchanged drug; also as metabolites)Ceftazidime0,36 L/kg10 % 1-2 hr21 hrMainly in urine (80-90 % as unchanged drug)

Lacy et al, 2009. Drug Information Handbook 17th EditionSweetman, 2009. Martindale : The Complete Drug Reference 36th EditionCunha, 2010. Antibiotic Essentials ninth edition

Pharmacokinetic /Pharmacodynamic ceftriaxoneGarot et al, Population pharmacokinetics of ceftriaxone in critically ill septic patients. British Journal of Clinical Pharmacology . Vol 72, No.5, p. 758767

Pharmacokinetic /Pharmacodynamic ceftriaxonePerry & Schentag, Clinical Use of Ceftriaxone. Clin Pharmacokinet 2001; 40 (9): 685-694

Dosage regimentation of ceftriaxoneLacy et al, 2009. Drug Information Handbook 17th EditionMartin, 2011. British National Formulary 61st Edition

Dosage regimen of ceftriaxone in Patients with Renal and Hepatic Impairment

CrCl 50-80 ml/minNo changeCrCl 10-50ml/minNo changeCrCl < 10ml/minNo changePost HD doseNonePost HFHD doseNo changePost PD doseNoneCVVH doseNo changeModerate hepatic insufficiencyNo changeSevere hepatic insufficiencyNo change(max dose 2 g/day)

Cunha, 2010. Antibiotic Essentials 9th Edition. Physicians Press.

Problem?

CalculationCeftrixones PK characteristics :Vd = 6-14 LT = 5 9 hrDo 1-2 g Cp = 0.5 300 mg/LFormula :

Do = 1 g ; = 12 hr Css = 77.30 mg/L (0.5 300 mg/L)Do= 2 g; = 24 hr Css = 77.30 mg/L (0.5 300 mg/L)

Css = F x Do Vd x 0.693 x t

Calculation

%T> MIC = percentage of the dosing interval for which levels exceed the MIC = dosing interval (h)MIC = minimum inhibitory concentration (mg/L)

Do = 1 g ; = 12 hr %T> MIC = 236.88 %Do= 2 g; = 24 hr %T> MIC = 155.94 %

% T > MIC = ln Do x t x 100 Vd x MIC ln 2

calculationCeftrixones PK characteristics :Vd = 6-14 LT = 5 9 hrProtein binding = 95 % free drug = 5 %Do = 1000 mg; = 12 jam Co = Do x %free Vd= 3.57 mg/L After the first-twelve hours ( t = 12 hr)Cp = Co x e kt= 1.42 mg/L

calculationThen , the second injection is administered Cp = Co + CpCp = 3.57 + 1.42 = 4, 99 mgPlasma concetration at 24 hr (Cp ) is assumed as MIC.e.g Ceftriaxones MIC = 1 g/ mL Cp = Cp x e kt t = 20.88 hrCefriaxone 2 x 1 g To reach its MIC, the time needed is : (12 + 20.88) = 32.88 hr

calculationDo = 2000 mg; = 24 jam Co = Do x % free Vd= 7.14 mg/L Plasma concetration at 24 hr (Cp ) is assumed as MIC.e.g Ceftriaxones MIC = 1 g/ mL Cp = Co x e kt t = 25.53 hrCefriaxone 1 x 2 g To reach its MIC, the time needed is : 25.53 hr

Clinical consideration

Pea et al, 2005. Antimicrobial Therapy in Critically Ill Patients. Clin Pharmacokinet page 1009-1030Varghese et al, Antimicrobial Pharmacokinetic and Pharmacodynamic Issues in the Critically Ill with Severe Sepsis and Septic Shock. Crit Care Clin 27 (2011) 19-34

SummaryCeftriaxone is time-dependent antibiotic which can be adminestered 1-2 g every 12-24 hoursDo = 1 g ; = 12 hr Css = 77.30 mg/L (0.5 300 mg/L)%T> MIC = 236.88 % To reach its MIC, the time needed is 32.88 hrDo= 2 g; = 24 hr Css = 77.30 mg/L (0.5 300 mg/L)%T> MIC = 155.94 %To reach its MIC, the time needed is 25.53 hrIn particular clinical condition such as hypoalbuminemia and fever, shortening the dosage interval ensures optimal ceftriaxone concentrations over the entire dosage interval

ReferencesAmbrose et al, Pharmacokinetics Pharmacodynamics of Antimicrobial Therapy: Its Not Just for Mice Anymore. Clinical Infectious Diseases 2007; 44:7986Crandon & Nicolau, Pharmacodynamic Approaches to Optimizing Beta-Lactam Therapy. Crit Care Clin 27 (2011) 77-93 Cunha, 2010. Antibiotic Essentials, 9th editionGarot et al, Population pharmacokinetics of ceftriaxone in critically ill septic patients. British Journal of Clinical Pharmacology . Vol 72, No.5, p. 758767Lacy et al, 2009. Drug Information Handbook 17th EditionLodise & Drusano, Pharmacokinetics & Pharmacodynamics : Optimal Antimicrobial Therapy in the Intensive Care Unit. Crit Care Clin 27 (2011). 1-18 Lullmann, H, Mohr, K, Ziegler, A & Bieger, D 2005, Color Atlas of Pharmacology, 3rd Ed., Thieme,New York.Pagani et al, 2011. Year in review 2010 : Critical Care-Infection. BioMed Central Ltd page 1-7.Pea et al, 2005. Antimicrobial Therapy in Critically Ill Patients. Clin Pharmacokinet page 1009-1030Perry & Schentag, Clinical Use of Ceftriaxone. Clin Pharmacokinet 2001; 40 (9): 685-694Shargel, L, Wu-Pong, S & Yu, ABC 2007, Applied Biopharmaceutics & Pharmacokinetics, 5th Ed.,The McGraw-Hill Companies.Sweetman, 2009. Martindale : The Complete Drug Reference 36th EditionVarghese et al, Antimicrobial Pharmacokinetic and Pharmacodynamic Issues in the Critically Ill with Severe Sepsis and Septic Shock. Crit Care Clin 27 (2011) 19-34