Dosing of Amoxicillin / Clavulanic Acid in Geriatric Patients at the Emergency Department

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Academiejaar 2018 – 2019

DOSING OF AMOXICILLIN / CLAVULANIC ACID IN GERIATRIC PATIENTS AT THE EMERGENCY DEPARTMENT.

Tania DESMET

Promotor 1: Prof. dr. P. De Paepe

Promotor 2: Apr. dr. P. De Cock

Masterproef voorgedragen in de master in de specialistische geneeskunde Urgentiegeneeskunde

Academiejaar 2018 – 2019

DOSING OF AMOXICILLIN / CLAVULANIC ACID IN GERIATRIC PATIENTS AT THE EMERGENCY DEPARTMENT.

Tania DESMET

Promotor 1: Prof. dr. P. De Paepe

Promotor 2: Apr. dr. P. De Cock

Masterproef voorgedragen in de master in de specialistische geneeskunde Urgentiegeneeskunde PREFACE

I would like to use this preface to gratefully acknowledge all the people who supported me to write this thesis.

First, I would like to thank my promoters Prof. De Paepe and Apr. De Cock because, despite their busy schedule, I could always rely on their expertise and they steered me in the right direction whenever I needed it.

I would like to express my special thanks to Prof. Petrovic and Prof. Buylaert. I am gratefully indebted to their valuable comments regarding this thesis over the past two years.

My gratitude also goes out to Bram Van Braeckel, Tim Krols, Helena Verhasselt and Frederick Libeer without whose participation and input this research could not have been successfully conducted.

I would also like to acknowledge the laboratory staff who have guaranteed the smooth operation of this research.

Finally, I am grateful to the nurses from the emergency department and the geriatric department for their unfailing support and assistance in this study. They were always patient, kind and willing to help. TABLE OF CONTENTS

TABLE OF CONTENTS ...... i

ABSTRACT ...... 1

INTRODUCTION ...... 2

A. OBJECTIVE ...... 2

B. PHARMACOLOGY IN THE ELDERLY ...... 3

B.1. PHARMACOKINETICS ...... 4

B.2. INTERACTIONS AND ADVERSE DRUG REACTIONS ...... 6

C. PHARMACOLOGY OF BETA-LACTAM ANTIBIOTICS – AMOXICILLIN/CLAVULANIC ACID...... 7

C.1. AMOXICILLIN/CLAVULANIC ACID ...... 7

C.2. BETA-LACTAM ANTIBIOTICS IN DIFFERENT POPULATIONS ...... 9

C.2.1. BETA-LACTAM ANTIBIOTICS IN ELDERLY ...... 10

METHODS ...... 13

A. LITERATURE SEARCH ...... 13

B. STUDY DESIGN ...... 13

C. INCLUSION CRITERIA ...... 14

D. DRUG ADMINISTRATION ...... 14

E. DATA COLLECTION ...... 14

F. DATA ANALYSIS ...... 16

RESULTS ...... 19

A. STUDY POPULATION ...... 19

B. CONCENTRATION/TIME CURVE OF AMOXICILLIN ...... 21

B.1. FIRST DOSE RESULTS: GENERAL ...... 21

B.2. FIRST DOSE RESULTS: TARGET ATTAINMENT ...... 22

B.3. STEADY STATE DOSE RESULTS: GENERAL ...... 23

B.4. STEADY STATE DOSE RESULTS: TARGET ATTAINMENT ...... 23

C. CONCENTRATION/TIME CURVE OF CLAVULANIC ACID ...... 25

C.1. FIRST DOSE RESULTS: GENERAL ...... 25

C.2. FIRST DOSE RESULTS: TARGET ATTAINMENT ...... 25

C.3. STEADY STATE DOSE RESULTS: GENERAL ...... 27

C.4. STEADY STATE DOSE RESULTS: TARGET ATTAINMENT ...... 28

D. CLEARANCE OF AMOXICILLIN/CLAVULANIC ACID ...... 29

E. OUTCOME STUDY POPULATION ...... 31

DISCUSSION ...... 32

REFERENCES ...... 37

NEDERLANDSTALIGE SAMENVATTING ...... 44

ABSTRACT

Introduction: Frail geriatric patients may present with altered pharmacokinetics (PK) due to aging and comorbidity. The objectives of this study were (i) to evaluate fT>MIC target attainment rates in this vulnerable patient population receiving amoxicillin/clavulanic acid, (ii) to investigate the correlation between drug clearance and commonly used estimators for renal function.

Methods: Prospective, monocentric, observational PK study. Geriatric hospitalized patients, admitted through the emergency department in whom treatment with intravenous amoxicillin/clavulanic acid (1G/0.2G q6h) was indicated, were enrolled. Plasma samples were collected during first (FD) and/or assumed steady-state (SS) dose intervals. Mid-dose (CMD) concentrations, corrected for plasma protein binding, were compared to the EUCAST MIC clinical breakpoint of Escherichia coli (8 mg/L) to evaluate the fT>MIC 50% target. As this EUCAST breakpoint was determined using a fixed concentration of 2 mg/liter clavulanic acid, this was chosen as the target concentration for clavulanic acid. Noncompartmental PK-analysis was used to estimate drug clearance (PKsolver®, Excel Office 365). Renal function was estimated by the Cockcroft-Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular filtration rate (eGFR) formula. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (R).

Results: Eighteen patients were included (median age: 88 years; interquartile range (IQR): 83- 91.2 years; median CG eGFR at FD: 41.5 ml/min; IQR 28.0 – 46.8 ml/min and 45.0 ml/min at

SS dose; IQR: 38-55 ml/min). After the first amoxicillin dose, median CMD was 13.0 mg/L

(IQR: 8.5-15.4 mg/L). CMD remained above 8 mg/L in 80% of patients. In SS conditions, median CMD was 13.2 mg/L (IQR: 9.8-20.9 mg/L). CMD remained above 8 mg/L in 88% of patients. A correlation was observed between CG eGFR and amoxicillin/clavulanic acid clearance respectively. (R = 0.6; p = 0.05 and R = 0.7; p = 0.00 in FD; R = 0.8; p = 0.02 and R = 0.7; p = 0.03 in SS dose).

Discussion: This pilot study suggests that the current dosing regimen of amoxicillin/clavulanic acid seems adequate in most patients. A correlation was found between Cockcroft Gault eGFR and both amoxicillin and clavulanic acid clearance, suggesting an opportunity of providing dosing recommendations for amoxicillin/clavulanic acid based on CG in elderly.

INTRODUCTION

A. OBJECTIVE

Throughout most of the world we are witnessing an increasing number of aged people. (1) In 2018, 125 million people are aged 80 years or older. By 2050, there will be almost 434 million people in this age group worldwide. The number of people aged 60 years and older will outnumber children younger than 5 years. (2)

There is, however, scarce evidence to suggest that older people today are experiencing their later years in better health than their parents. Rates of severe disability have declined in high- income countries but there has been no significant change in mild to moderate disability. The rates of dependence and frailty amongst elderly are likely to double in the next years. (2)

Infections are a major cause of death in elderly people, and they are a challenge for the practicing physician. Urinary tract infections are the most common infectious complication in residents of long-term care facilities. Prospective observational studies in residents of long-term care facilities report an incidence of symptomatic urinary infections that varies from 0.1 to 2.4 cases per 1,000 resident-days. (3, 4) One of the most frequent life-threatening infections is community-acquired pneumonia (CAP). The incidence of CAP is on average 4 times higher in elderly than in younger people and increases stepwise with every decade. (5) The mortality rate for CAP in elderly subjects rises to 30% and is hence 3 times as high as in younger persons. The mortality is even 57% in elderly patients with health-care-associated pneumonia. (6)

At the same time, the world is facing an alarming scenario in which we are rapidly losing treatment options due to resistance against multiple currently available antibiotics. (7) This issue is even more important in frail older patients who have been frequently admitted to the hospital due to their multiple comorbidities or who live in nursing home facilities and have been exposed to multi-resistant bacteria.

Not only is there an increasing rate of resistance when dosing too low, there is also a higher susceptibility to adverse drug reactions in this age-group which makes it dangerous to dose higher than strictly necessary.

For the above-mentioned reasons, adequate dosing of antibiotics is of most importance in the elder population.

In drug research studies, older people – and especially patients with a geriatric profile or frailty risk - are very frequently excluded. Therefore, drug dosing is often extrapolated from studies in younger adults with failure to consider potential differences in pharmacokinetics (PK) and pharmacodynamics (PD). (8-13)

To date, only limited data on the pharmacokinetics of antibiotic treatment are available in sick older people. The few data on antibiotic dosing in older patients are obtained from studies including patients from 65 years onwards. Data are mostly limited to single dose measurements and a lot of exclusion criteria are applied such as comorbidities, organ system restrictions, limited life expectancy, concomitant drug use, etc. (14-16) Studies on dosing of beta-lactam antibiotics (often life-saving in sick elderly), more specific amoxicillin-clavulanic acid, in geriatric or frail patients aged 75 years or older have, to the best of our knowledge, never been performed.

In this pilot study, we investigated whether - with the current amoxicillin/clavulanic acid dosing regimen, used at the Ghent University Hospital – pharmacokinetic and pharmacodynamic targets are attained in frail geriatric patients. Secondary, we investigate the correlation between renal function and antibiotic clearance.

Before investigating above study aims we would like to elaborate about some pharmacological aspects.

B. PHARMACOLOGY IN THE ELDERLY

When a drug is administered two aspects are of major importance: pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetics refer to the disposition of a drug in the body (what the body does to the drug). Pharmacodynamics is the study of the physiologic and biochemical effects that drugs have on the body (what the drug does to the body) (17, 18)

B.1. PHARMACOKINETICS

Absorption – Various anatomical and physiological changes that occur with normal aging could potentially affect drug absorption. Secretion of gastric acid decreases with advancing age (hypochlorhydria due to atrophic gastritis). Gastric emptying and intestinal transit rates are decreased due to region-specific loss of neurons. In addition, elderly persons have a 30% decrease in the mucosal surface area of the small intestine due to flattening of intestinal villi and there is about 40% reduction of blood flow in the small intestine. These changes could all influence the absorption of mostly acid medium dependent medications and supplements. Polypharmacy commonly occurs in elderly. Concomitant administration of drugs may lead to a reduced drug absorption, e.g. antacids and anticholinergics. Of the four pharmacokinetic parameters, absorption appears to be the least affected by the physiological changes that occur with age. (17, 19-26)

Distribution – The proportion of adipose tissue increases with aging. This increase results in a larger volume of distribution (Vd) for lipid-soluble drugs, causing the half-life of many lipid- soluble agents to be considerably prolonged in elderly patients. The total body water (both intracellular and extracellular) decreases. Consequently, the Vd of water-soluble drugs is decreased. This reduced Vd can result in an increased serum concentration of water-soluble drugs. Older persons have a decreased lean body mass with a reduced muscle mass leading to a higher concentration of muscle binding compounds (e.g. digoxin). Changes in plasma protein concentration as well as alterations in plasma protein binding can occur with advancing age and my influence the distribution of drugs. The concentration of plasma proteins such as albumin tends to decrease in many elderly patients. This change may result in a reduced protein-bound fraction of many medications and a larger amount of free (active) drug. Alterations in plasma protein binding that occur in the elderly are generally not attributed to age, but rather to physiological and pathophysiological changes or disease states that may occur more frequently in the elderly. Drugs may also compete for protein-binding sites. A newly added drug can displace a drug from its protein binding sites and thus potentially result in toxicity. α1 Acid glycoprotein is an acute-phase reactant that can increase with advancing age in the presence of inflammation, but the serum concentration is not altered per se by aging. This increase in α1 acid glycoprotein can causes a decrease in unbound active basic drugs. (17, 19, 21-27)

Metabolism – Hepatic mass decreases with advancing age, and the number of functioning hepatocytes is reduced. This difference results in a major reduction in first-pass metabolism of drugs. Hepatic metabolism occurs by two mechanisms, referred to as phase I and phase II reactions. Phase I metabolism occurs in the microsomal enzyme mixed-function oxidase system (cytochrome P450) and produces metabolites that may be pharmacologically active. A decline in phase I metabolism is often noted in elderly persons. (17, 19-26, 28) Phase II metabolism involves the conjugation of a drug molecule by glucuronidation, sulfation, or acetylation, usually resulting in a pharmacologically inactive metabolite. Phase II metabolism is generally unaffected by aging. (17, 19-26, 28)

Elimination – Drug elimination is mainly determined by renal function, which, in general, declines steadily with normal aging. The magnitude of this decline, however, varies greatly and depends on whether chronic conditions such as hypertension have caused further renal impairment. Serum creatinine (Cr) is not a reliable indicator of renal function in the elderly population since creatinine is a product of muscle breakdown and elderly people have a decreased muscle mass. The glomerular filtration rate (GFR) is a more exact measure of renal function, either measured by urine sampling and e.g. inulin clearance or predicted by formulas (estimated GFR = eGFR). The latter seems most useful in clinical practice. From the prediction formulas the Cockcroft-Gault equation (rather than the Modification of Diet in Renal Disease – MDRD formula or Chronic Kidney Disease Epidemiology Collaboration - CKD-EPI formula) is widely used for dose adjustment of renally eliminated drugs in older people, especially in elderly patients with impaired renal function or with concomitant diseases. The most common used formulas in adults are summarised in Table 1. (17, 19, 20, 22-26, 28-35)

Table 1 - eGFR formulas referred to in this thesis.(33-35) eGFR formula Equation

Cockcroft – Gault [((140 - age) x weight (kg)) / (72 x serum creatinine (mg/dl))] (ml / min) (x 0.85 for females) 141 x min (Scr/κ, 1)α x max (Scr/κ, 1)-1.209 x 0.993Age x 1.018 (if female) x 1.159 (if black). Chronic Kidney Scr = serum creatinine in mg/dL. Disease Epidemiology κ = 0.7 if female / = 0.9 is male. Collaboration α = -0.329 if female / = -0.411 if male. (CKD – EPI) Min = the minimum of Scr/κ or 1. (ml / min / 1.73 m²) Max = the minimum of Scr/κ or 1 Modification of Diet in Renal Disease 186 x (Scr)-1.154 x (age)-0.203 x 0.742 (if female) x 1.112 (if black). (MDRD) Scr = serum creatinine in mg/dL. (ml / min / 1.73 m²)

PHARMACODYNAMICS

Pharmacodynamics refer to the pharmacological mechanism of action of a drug at its specific targets, which includes its therapeutic effects as well as any adverse effect. Elderly respond differently to drugs than do younger people. The physiological response is much more variable, and predictability of drug action is much less certain. Changes occur in end-organ responsiveness to medications with aging. These pharmacodynamic changes may be due to a change in receptor binding, a decrease in receptor number, or altered translation of a receptor-initiated cellular response into a biochemical reaction. These changes may result in either an increased or decreased receptor response. (19, 23, 25, 29, 36, 37)

B.2. INTERACTIONS AND ADVERSE DRUG REACTIONS

Drug interactions as a broad category include drug – disease interactions, drug – food or – herb interactions and drug – drug interactions. Elderly have an increased risk of drug interactions. This may be caused by patient factors, prescriber factors, or difficulties within the health-care system such as inefficient communication between health professionals and patients. (38) Age- related pharmacokinetic and pharmacodynamic changes can potentially increase the risk of adverse events from drug interactions. The risk of drug interactions increases with the number of drugs prescribed, and elderly people use more drugs than do younger adults. Physicians are often not aware of all the drugs their elderly patients are taking. Furthermore, atypical presentation of disease or vague presenting complaints such as confusion, falls, urinary incontinence, and weakness could mask or confuse the detection of drug interactions. (38, 39)

Several studies have measured the prevalence of drug interactions in elderly patients. In a European study of 1601 elderly outpatients living in six European countries, 46% of patients had at least one potential clinically significant drug – drug interaction, and 10% of these interactions were regarded as of high severity. Lindblad and colleagues (2005) assessed drug – disease interactions in a group of frail elderly patients in-hospital. They reported that 15 – 40% of the patients had a potential drug – disease interaction. (38-41)

Adverse drug reactions (ADR) are responsible for considerable morbidity and mortality in the elderly population and are a financial burden to the health care system. ADR in older adults are more likely to be severe and tend to be underreported. They are observed 2–3 times more frequently in geriatric patients than in younger adults. Apart from senescence, this problem is attributed in part to multimorbidity and polypharmacy in old individuals. Caranasos et al. (1974) found that the incidence of ADR was higher in the age-group of 61 to 80 years and even higher in the group aged 71 to 80 years in comparison to patients younger than 60 years.

At least 10% of hospital admissions for elderly patients may be caused by ADR, and the mortality rate as a result of ADR is significantly higher than in younger patients. Drugs taken to treat the same condition, e.g. hypertension, predictably have synergistic effects that may lead to adverse effects such as dizziness and light-headedness, increasing the risk for falls. Other commonly experienced ADR associated with polypharmacy in an elderly population are QT interval prolongation and hypoglycaemia. Elderly people may develop adverse drug reactions that differ completely in manifestation in comparison with younger people. (17, 18, 42-46)

C. PHARMACOLOGY OF BETA-LACTAM ANTIBIOTICS – AMOXICILLIN/CLAVULANIC ACID

Appropriate antibiotic treatment is a cornerstone in the pharmacological treatment of sick older people admitted at the emergency department. Due to their broad antimicrobial spectrum and relatively low toxicity, beta-lactams are the most commonly prescribed class of antimicrobials, routinely recommended as first-line therapy in many guidelines. Amoxicillin/clavulanic acid is frequently used as first-line therapy for treatment of (community acquired) respiratory, urinary, gastro-intestinal and soft tissue infections caused by Gram-positive and Gram-negative organisms including anaerobe organisms. (7, 47-51)

C.1. AMOXICILLIN/CLAVULANIC ACID

Amoxicillin is a semisynthetic penicillin that inhibits one or more enzymes (penicillin-binding proteins) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam structurally related to penicillin.

It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

The pharmacokinetic parameters of amoxicillin and clavulanic acid, after intravenous administration of a single dose of 1000 / 200 mg, are shown in Table 2. Steady state concentrations are achieved after minimum 5 times the elimination half-life. (52, 53)

Table 2 - Pharmacokinetic parameters of amoxicillin and clavulanic acid after administration of a single intravenous dose of 1000 / 200 mg. (52, 53) Amoxicillin Clavulanic acid Mean elimination half-life - T ½ 0.9 0.9 (h)

Apparent volume of distribution - VD 0.3 – 0.4 0.2 (L/kg) Area under the curve – AUC 76.3 27.9 (h x mg/L) Total clearance – CL 25 25 (L / h) Mean peak serum concentration 105.4 28.5 (mg/L) Excretion in urine first 6 h after administration 60 – 70 40 – 65 (%) Protein bound form 18 25 (%)

The most commonly reported adverse drug reactions are diarrhoea, nausea and vomiting. Very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100) drug reactions are listed in Table 3. (52, 54)

Table 3 – Adverse drug reactions of amoxicillin-clavulanic acid Very common Common Uncommon ≥ 1/10 ≥ 1/100 to < 1/10 ≥ 1/1000 to < 1/100 None Mucocutaneous candidiasis Dizziness Diarrhoea Headache Nausea Vomiting Indigestion Rises in AST and/or ALT Skin rash Pruritus Urticaria

Interactions are described with oral anticoagulants, methotrexate and probenecid. A brief overview is given in Table 4. (52, 54)

Table 4 – Amoxicillin/clavulanic acid interactions (52-54)  Oral anticoagulants Cases of increased international normalized ratio in patients on acenocoumarol or warfarin who were prescribed a course of amoxicillin.  Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.  Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

Amoxicillin/clavulanic acid is, as all beta-lactam antibiotics, a time-dependent antibiotic. This means that the time interval (fT), in which the unbound drug concentration is above the minimal inhibitory concentration (MIC), is the measure best linked to the ability to kill the target micro- organism (= PD target outcome) (Figure 2). Satisfactory outcome has been achieved with fT > MIC (= Time Above MIC) during minimum 50% of the dosing interval. Some authors advocate for a fT > MIC of 100%, particularly against gram negative bacteria. Maximum antibiotic activity is achieved during fT > 4 x MIC. (1, 8, 55-57)

The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the total dose. Clavulanic acid is extensively metabolized in humans and eliminated in urine and faeces and as carbon dioxide in expired air. (52)

C.2. BETA-LACTAM ANTIBIOTICS IN DIFFERENT POPULATIONS

The pharmacology of beta-lactam antibiotics has been studied in different patient populations, e.g. critically ill patients, obese patients, children etc.

Monte Carlo simulation has shown that for beta-lactams, the probability of obtaining fT > MIC targets can be improved in critically ill adults by increasing the dose, shortening the dosing interval or prolonging the infusion time of the drug. (7, 58) Patients with very high creatinine clearance need more frequent dosing or alternate dosing strategies to achieve the minimal pharmacodynamic target of 50% fT > MIC (8 mg/L), with little accumulation of clavulanic acid. To achieve higher targets, such as 100% fT > MIC, in patients with high creatinine clearance, the administration of higher doses as a prolonged infusion is necessary. (7, 59)

Obese patients are a subgroup continuously increasing in developed countries. Because of their special clinical situation, antibiotic pharmacokinetic parameters are significantly influenced by physiologic changes. Piperacillin and tazobactam clearance (CL) and Vd were altered in obese patients, and larger doses might be needed to achieve the same PD exposures as in non-obese patients. (7, 60) Obesity is a significant risk for antibiotic treatment failure. In fact, obesity is not commonly a standalone disease but linked to other pathologies (such as diabetes, hypercholesterolemia, cardiac failure, renal and hepatic impairment). (61)

Concerning children, a first pharmacokinetic study conducted at the paediatric ICU of the Ghent University Hospital, Ghent, Belgium revealed that current recommendations for amoxicillin- clavulanic acid can result in subtherapeutic treatment. Due to a state of “augmented renal clearance” (similar to critically ill adults) a minimal dosing regimen of 25 mg/kg (based on the amoxicillin component) every 4 h is warranted in serious infections. (62)

C.2.1. BETA-LACTAM ANTIBIOTICS IN ELDERLY

Only a few trials studied the PK/PD modelling of beta-lactam antibiotics in elderly.

1.a PENICILLINS In 1986 Fourtillan et al. published a study in which 15 elderly patients with ages ranging from 66 – 90 years (mean 79.8 years) received a single dose of 4g piperacillin. Pharmacokinetic results suggested that the mean residence time was practically doubled as compared to younger volunteers. There was no information given about the type of patients (healthy, sick, critically ill). (63)

In 1991 Meyers and his group published results on 8 healthy elderly volunteers with an age range of 65 – 68 years (mean 73.9 years) receiving ampicillin-sulbactam intravenously. Serum concentrations following a first dose were significantly higher in the older group in comparison to the younger groups (< 65 years). Moreover, the urinary amount excreted antibiotic was also significantly higher in the elder group. (64) Similar results in a healthy study population of 12 elderly volunteers (65 – 93 years) were reported in 1989 by Rho et al. (65)

Majcher-Peszynski et al. (2014) published data regarding 13 patients with community acquired pneumonia aged 65 years or older. However, they give no information on frailty risk or the geriatric profile. The mean age was 77.4 years.

All patients were treated with ampicillin 1 g and sulbactam 2 g thrice a day. In this trial also, no data were collected regarding the first dose of antibiotic treatment. The authors found that, due to renal impairment dosing regimens in this study seemed adequate. However, in elderly patients without renal impairment more frequent dosing (> 3 times daily) may be necessary. (8)

One study from Janknegt et al. (1992) studied PK/PD modelling of amoxicillin in 8 frail older participants. The participants, however, were healthy volunteers. No information was provided regarding the frailty profile. Furthermore, combined intravenous and oral amoxicillin- administration were studied without distinction between first and steady state dose, and no conclusions were made regarding antibiotic activity related to time above the MIC. The mean clearance after intravenous administration of amoxicillin was 109 ml/min with a huge range of 54 ml/min – 255 ml/min. In its conclusion the study focused especially on the difficulties in performing a study on pharmacokinetics in a group of frail elderly. (66)

1.b CEPHALOSPORINS

In 1980 Douglas et al. published a study in which 16 convalescent patients with ages ranging from 71 – 88 years (mean 77.4 years) were treated with intravenous cefuroxime. They suggested that dose and dosage intervals should depend upon renal function rather than age per se. They suggested a dose reduction in elderly with a creatinine clearance of 20 ml/min or less. (67)

1.c MONOBACTAMS

Two years after the first trial in 1991 (cfr. above) Meyers et al. published a trial in which aztreonam was administered in an older (> 65 years, mean 72.8 years) and a younger group (18 - 30 years) of healthy volunteers. High serum levels of aztreonam were maintained in the elder group for a greater period of time in comparison to younger patients. A lower clearance of aztreonam was noted in the older group. This was associated with a decrease in creatinine clearance also observed in the same group. (68)

1.d CARBAPENEMS

A very interesting and large trial (75 patients) on meropenem pharmacokinetics and pharmacodynamics was carried out by Zhou et al. (2011) They collected data on steady state and first doses of meropenem. However, the mean age in their population of elderly was 75.6 years and information regarding frailty was not available.

Furthermore, both critically ill patients and ward patients were included in this study. This study developed a population pharmacokinetics model in an elderly Chinese population for the use of meropenem in the treatment of low respiratory tract infections. Creatinine clearance and age had the most significant impact on meropenem pharmacokinetics in patients. (69)

A recent study in 2013, performed on 10 sick elderly patients with an age range from 64 – 89 years (mean 77.0 years) revealed that creatinine clearance was the most important covariate to determine optimal pharmacotherapy following a one-hour infusion of 500mg doripenem, which is a carbapenem that is not available in Belgium. However, data for evaluation were limited and further research in a larger population was recommended. (70) These results were similar to results published by Musson et al. (2004) in a group of 14 older subjects > 65 years (mean 73.1 years). They found that the concentrations in plasma and the half-life of ertapenem were higher and longer respectively in the older group in comparison to a younger control group (mean age 32.8 years). However, the older group in this study consisted of healthy volunteers. (71) Namkoong et al. (2014) also published a trial on carbapenems (biapenem) in 25 older (> 65 years, mean 78.5 years) sick patients with pneumonia. Time above MIC in this study was 100%. Four patients developed an adverse drug reaction (liver dysfunction or nausea). None of these, however, necessitated treatment modification. The standard dosing regimen of biapenem was used in this trial. No dose adjustment suggestions were made. (15)

Finally, Usman et al. (2017) recently published a large trial in 178 elderly patients > 65 years (mean 75 years) treated with meropenem. Data were collected from 3 different authors. A population pharmacokinetic (2-compartmental) model was developed and the influence of different covariates on meropenem clearance and distribution was observed. They found that body weight and creatinine clearance had a significant influence on meropenem clearance. There was no direct influence of age. Meropenem clearance was significantly lower in the elderly compared to younger patients due to the reduced renal function. (72)

To our knowledge no studies have been published concerning intravenous amoxicillin/clavulanic acid in elderly.

METHODS

A. LITERATURE SEARCH

An extensive literature search has been done before the start of this trial. Pubmed, EMBASE, MEDLINE and Google Scholar have been used.

Following search strategies have been used:  ((("Pharmacokinetic") AND ("Pharmacodynamic")) OR ("PK/PD")) AND (("aged") OR ("ELDERLY") OR ("GERIATRIC") OR ("FRAIL")) AND (("Antibiotic") OR ("antibacterial"))  ((("pharmacokinetic") AND ("pharmacodynamic")) OR ("PK/PD")) AND (("aged") OR ("elderly") OR ("geriatric") OR ("FRAIL")) AND (("modelling") OR ("modeling"))  (("penicillins"[Majr]) OR ("piperacillin" [Majr]) OR ("Amoxicillin"[Majr]) OR ("Clavulanic acid" [Majr])) AND (("Aged"[Majr]) OR("elderly") OR ("geriatric") OR ("FRAIL"))  (("amoxicillin") OR ("piperacillin") OR ("penicillin") OR ("clavulanic acid")) AND (("PK/PD") OR (("pharmacokinetic") AND ("pharmacodynamic")))  ((amoxicillin) OR (Piperacillin) OR (penicillin) OR (clavulanic acid)) AND ((elderly) OR (geriatric) OR (aged) OR (frail)) AND ((PK/PD) OR ((pharmacokinetic) AND (pharmacodynamic)))  ((amoxicillin) OR (Piperacillin) OR (penicillin) OR (clavulanic acid)) AND ((elderly) OR (geriatric) OR (aged) OR (frail)) AND ((PK/PD) OR ((pharmacokinetic) AND (pharmacodynamic)))  ((amoxicillin) OR (piperacillin) OR (penicillin) OR (clavulanic acid)) AND ((PK/PD) OR ((pharmacokinetic) AND (pharmacodynamic))) AND ((modeling) OR (modelling))  ((amoxicillin) OR (piperacillin) OR (penicillin) OR (clavulanic acid)) AND ((PK/PD) OR ((pharmacokinetic) AND (pharmacodynamic))) AND ((modeling) OR (modelling))  ("Pharmacokinetics"[Majr:noexp] OR "PK/PD"[All Fields]) AND ("Aged"[Majr] OR "geriatric"[All Fields] OR "elderly"[All Fields] OR "frail"[All Fields])

Duplicates were excluded. The search was repeated every week during the past two years (starting July 2017). Every relevant new publication was added to the literature study until 01/02/2019.

203 unique publications were withheld (only in English, Dutch or French) of which 153 articles were online available or could be requested in full text (Library Ghent University).

B. STUDY DESIGN

This monocentric, prospective, observational trial was conducted at the emergency department and geriatric department of the Ghent University Hospital. The first patient was included in April 2018.

Written informed consent was obtained from the patient or a legally authorized representative before enrolment. Informed consent was obtained at the emergency department by the treating physician. In case of legally incapable / incapacitated patients, informed consent was obtained from the children or other legal representatives. Informed consent forms can be found in the appendix.

Approval from the human ethics committee of Ghent University Hospital was obtained in January 2018 (research project 2017/1369).

C. INCLUSION CRITERIA

Patients were eligible for inclusion if they were at least 75 years old, presented themselves at the emergency department with an infection that necessitated intravenous amoxicillin- clavulanic acid treatment and hospitalization at the geriatric ward. Patients who had received oral amoxicillin/clavulanic acid before admission or were allergic to amoxicillin-clavulanic acid were excluded.

D. DRUG ADMINISTRATION

Amoxicillin/clavulanic acid 1000/200mg was infused intravenously over 30 minutes using a syringe pump every 4 to 6 hours. The standard dosing protocol can be found in the appendix.

E. DATA COLLECTION

An infusion catheter of minimum 18-gauge was placed in the contralateral arm to the arm in which the antibiotic dose was administered. Blood samples were collected from this catheter at first dose and assumed steady state conditions. Steady state was assumed to be reached after minimal 24h (> 4 doses at four – six hourly interval) of therapy. The goal was to obtain 5 first dose and 5 steady dose samples in every patient. The catheter was removed after collection of the steady state dose or in case of malfunction; in this case no more additional sampling was performed for that patient. Both sampling scheme and terminology are given in Figure 1.

Blood samples were collected just before start of infusion (time zero) and after 30, 90, 180 and 360 minutes in both a first and a steady state dose (Figure 1

Figure 2). Samples were collected in 4 mL Lithium - heparin tubes and were kept on ice during transport to the laboratory.

Samples were centrifuged during 8 minutes at 1885g. Plasma was then collected, divided in two separate labelled Eppendorf tubes of 1.5 ml and immediately frozen at -80 °C. In some cases, freezing was started at -20 °C and minimum 12 hours later transferred to a freezer at -80 °C.

Figure 1 - Definition of first and steady state dose incl. sampling times. First dose Steady state dose = sampling after the = sampling after a dose first antibiotic dose at admission > 24 h after start treatment

END END END Baseline = = Baseline = = Time zero zero Time = = Time Zero Zero Time = MID - DOSE DOSE MID - DOSE MID - dosing interval interval dosing interval dosing

Sampling time (min) 0 30 90 180 360 0 30 90 180 360

Material for bacteriological analysis, such as blood cultures, urine samples, sputum ea., were collected in every patient according to standard care. In case of bacterial growth, MIC’s were measured on the reported strains when possible.

Amoxicillin and clavulanic acid were measured using a validated ultra-performance liquid chromatographic method with tandem mass spectrometric detection. (73) This method has an accuracy of 85 – 115% and a precision within 15%. The limit of quantification is 0.5 mg/L. Serum creatinine, infection parameters (CRP, WBC count) and albumin were obtained from standard blood samples performed in these patients at day one and also later on during their therapy. (73)

Three frailty score systems (KATZ, Geriatric 8 – G8, Cumulative Illness Rating Scale – CIRS) were calculated. Details on the score systems can be found in the appendix.

The following information was obtained during history taking of the patient or his family members or from the electronic patient file:  Age  Weight, length and Body Mass Index where available  CIRS score, Katz Scale, G8 screening test  Reason for admission and indication for antibiotic treatment  Co-medication and comorbidities

 Side-effects

F. DATA ANALYSIS

Data were collected and processed in Excel Office 365 ProPlus version 1808. SPSS 25.0 was used for the normality testing of variables, using the Shapiro Wilk test. SPSS 25.0 was also used for the comparison between two groups using the Wilcoxon signed rank test. Since not all populations in this paper were normally distributed and samples were rather small, median and interquartile ranges (IQR) were reported (instead of mean and standard deviation). MDCalc was used to calculate eGFR according to Cockcroft Gault and CKD-EPI. The correlation between drug clearance and eGFR was assessed using scatter plots and the Pearson correlation coefficient (when both variables were normally distributed) or the Spearman correlation coefficient (when one or more variables were not normally distributed). The null hypothesis was retained at the 0.05 level of significance.

Measured concentrations of the antibiotic were mathematically corrected for plasma protein binding using a fixed percentage: 18% for amoxicillin; 25% for clavulanic acid. In the calculation of antibiotic clearance, the total (measured) antibiotic concentration was used. (52, 62) PKsolver was used as add-in program to calculate the clearance of amoxicillin and clavulanic acid with a non-compartmental PK analysis. Area under the curve (AUC) was calculated using the log – linear trapezoidal method. (74)

The target efficacy exposure was evaluated using PK/PD targets of 50% fT>MIC and 100% fT>MIC. A target MIC of 8 mg/liter for amoxicillin was chosen as the worst-case scenario, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints for Escherichia coli. (75) As the EUCAST clinical breakpoint for amoxicillin was determined using a fixed concentration of 2 mg/liter clavulanic acid, this was chosen as the target concentration for clavulanic acid. (62, 75, 76) (

Figure 2)

Figure 2 - Example of a Concentration / Time curve of amoxicillin (blue) & clavulanic acid (grey) incl. sampling times in hours in blue and gray squares. A non-compartmental PK analysis was used. EUCAST threshold for amoxicillin (green; 8 mg/L) and clavulanic acid (purple; 2 mg/L).

RESULTS

A. STUDY POPULATION

Between 1 April 2018 and November 2018 elderly (> 75 years) patients were enrolled. All patients presented themselves at the emergency department with a subsequent hospitalization at the geriatric ward. The demographic data and patient characteristics are summarized in Table 5. Sampling times are displayed in Table 6.

Table 5 – Clinical, treatment and sampling characteristics. Medians were accompanied by interquartile ranges (brackets). The eGFR in first and steady state dose was compared (p < 0.05). Characteristics All patients (n = 18)

Patients receiving first dose sampling 16 Number of first dose samples 77 Patients receiving steady state dose sampling 11 Number of steady state samples 46 Patients receiving first and steady state dose sampling 9 Patients treated for pneumonia 12 Patients treated for urinary tract infection 3 Patients treated for erysipelas / cholecystitis / liver abscesses Each 1 9 ♂ Gender 9 ♀ Legally incapable 9 Median age (years) 88 (83 – 91.2) Median body weight (kg) 59.2 (55.6 – 66.5) Median SIRS score 2 (1 – 3) Median KATZ score 16 (11 – 19) Median G8 score 10 (8 – 12) Median CIRS score 12.5 (10 – 15) Median CKD-EPI eGFR (ml/min/1.73 m²) At first dose (n = 16) 57.5 (38.8 – 71) p < 0.05 At steady state dose (n = 11) 67.0 (59.0 – 82.0) Median Cockcroft – Gault eGFR (ml/min) At first dose (n = 16) 41.5 (28.0 – 46.8) p < 0.05 At steady state dose (n = 11) 45.0 (38.0 – 55.0)

Fifteen causative microorganisms were cultured from 11 patients; the isolates included Escherichia coli (n = 8), Pseudomonas aeruginosa (n = 3), Klebsiella variicola (n = 1), Aerococcus uriniae (n = 1), Proteus mirabilis (n = 1) and Stenotrophomonas maltophilia (n = 1). The median MIC was 3.5 (IQR 1.3 – 5.5) mg/L (n = 8) for susceptible microorganisms (all but Pseudomonas aeruginosa).

Table 6 - Number of samples at every sampling time in first and in steady state dose. First dose Steady state dose = sampling after the = sampling after a dose first antibiotic dose at admission > 24 h past start of antibiotic therapy

END END END Baseline = = = Baseline Baseline = = Time zero zero Time = = Time Zero Zero Time = MID - DOSE DOSE MID - DOSE MID - dosing interval interval dosing interval dosing

Sampling time (min) 0 30 90 180 360 0 30 90 180 360 Number of patients 16 16 16 15 14 11 10 8 8 9 with sample (n) Number of patients 16 11 in total (n) Number of samples 77 46 in total (n)

B. CONCENTRATION/TIME CURVE OF AMOXICILLIN B.1. FIRST DOSE RESULTS: GENERAL

The concentration/time curve of the first dose is shown Figure 3. An overview of all data can be found in the appendix.

Figure 3 – Concentration/time curve of amoxicillin measured at certain fixed times after administration of a first dose of amoxicillin in 16 patients with the best fitting trend line (blue) in relation to the EUCAST threshold for amoxicillin (orange).

B.2. FIRST DOSE RESULTS: TARGET ATTAINMENT

An overview of the mid-dose amoxicillin concentration (after a first dose of amoxicillin) can be found in Figure 4.

Figure 4 – Fifteen amoxicillin mid-dose concentrations measured 3h after administration of a first dose of amoxicillin in relation to the EUCAST threshold for amoxicillin (orange).

The median first dose concentrations at mid-dose (fT 50%) and at the end of the dosing interval (fT 100%) are summarized in Table 7.

Table 7 – Characteristics of the serum concentration after administration of a first dose of amoxicillin. Data are reported as median (IQR). Median sampling Median amoxicillin Lowest amoxicillin

time (h) concentration (mg/L) concentration (mg/L) Mid-dose (n = 15 samples) 3.0 (3.0 – 3.1) 13.0 (8.5 – 15.4) 6.7 End dosing interval 6.0 (4.5 – 7.8) 4.2 (2.4 – 6.7) 1.0 (n = 14 samples)

The target at mid-dose (50 % fT > MIC 8 mg/L) was achieved in 12 out of the 15 (80 %) patients in whom a mid-dose could be measured. The lowest measured concentration of amoxicillin at mid-dose was 6.7 mg/L.

B.3. STEADY STATE DOSE RESULTS: GENERAL

The concentration/time curve of the steady state dose is shown Figure 5. An overview of all data can be found in the appendix.

Figure 5 – Concentration/time curve of amoxicillin measured at certain fixed times after administration of a steady state dose of amoxicillin in 11 patients with the best fitting trend line (blue) in relation to the EUCAST threshold for amoxicillin (orange).

B.4. STEADY STATE DOSE RESULTS: TARGET ATTAINMENT

An overview of the mid-dose amoxicillin concentration (after a steady state dose of amoxicillin) can be found in Figure 6.

Figure 6 - Eight amoxicillin mid-dose concentrations measured 3h after administration of a steady state dose of amoxicillin in relation to the EUCAST threshold for amoxicillin (orange).

The median steady state dose concentrations at baseline (time zero), mid-dose (fT 50%) and at the end of the dosing interval (fT 100%) are summarized in Table 8. The median mid-dose concentration at steady state was slightly higher in comparison to the first dose (not statistically significant; p > 0.05).

Table 8 - Characteristics of the serum concentration after administration of a steady state dose of amoxicillin. Data are reported as median (IQR). Median sampling Median amoxicillin Lowest amoxicillin

time (h) concentration (mg/L) concentration (mg/L) Baseline (n = 11 samples) 0.0 (0.0 – 0.0) 6.3 (3.9 – 11.2) 3.0

Mid-dose (n = 8 samples) 3.0 (2.9 – 3.0) 13.2 (9.8 – 20.9) 7.5 End dosing interval 5.9 (5.6 – 6.0) 7.4 (3.9 – 9.6) 2.9 (n = 9 samples)

The target at mid-dose (50 % fT > MIC 8 mg/L) was achieved in 7 out of the 8 (88 %) patients in whom a mid-dose could be measured. The lowest measured concentration of amoxicillin at mid-dose was 7.5 mg/L.

C. CONCENTRATION/TIME CURVE OF CLAVULANIC ACID C.1. FIRST DOSE RESULTS: GENERAL

The concentration/time curve of the first dose is shown in Figure 7. An overview of all data can be found in the appendix.

Figure 7 – Concentration/time of clavulanic acid measured at certain fixed times after administration of a first dose of clavulanic acid in 16 patients with the best fitting trend line (blue) in relation to the EUCAST threshold for clavulanic acid (orange).

C.2. FIRST DOSE RESULTS: TARGET ATTAINMENT

An overview of the mid-dose clavulanic acid concentration (after a first dose of clavulanic acid) can be found in Figure 8.

Figure 8 - Fifteen clavulanic acid mid-dose concentrations measured 3h after administration of a first dose of clavulanic acid in relation to the EUCAST threshold for clavulanic acid (orange)

The median first dose concentrations at mid-dose (fT 50%) and at the end of the dosing interval (fT 100%) are summarized in Table 9.

Table 9 - Characteristics of the serum concentration after administration of a first dose of clavulanic acid. Data are reported as median (IQR). Median sampling Median clavulanic acid Lowest clavulanic acid

time (h) concentration (mg/L) concentration (mg/L) Mid – dose (n = 15 samples) 3.0 (3.0 – 3.1) 2.6 (1.6 – 3.3) 0.8 End dosing interval 6.0 (4.5 – 7.8) 0.8 (0.5 – 1.0) 0.0 (n = 14 samples)

The target at mid-dose (50 % fT > 2 mg/L) was achieved in 10 out of the 15 (67 % of the) patients in whom a mid-dose could be measured. The lowest measured concentration of clavulanic acid at mid-dose was 0.8 mg/L.

C.3. STEADY STATE DOSE RESULTS: GENERAL

The concentration/time curve of the steady state dose is shown in Figure 9. An overview of all data can be found in the appendix.

Figure 9 – Concentration/time curve of clavulanic acid measured at certain fixed times after administration of a steady state dose of clavulanic acid in 11 patients with the best fitting trend line (blue) in relation to the EUCAST threshold for clavulanic acid (orange).

C.4. STEADY STATE DOSE RESULTS: TARGET ATTAINMENT

An overview of the mid-dose clavulanic acid concentration (after a steady state dose of clavulanic acid) can be found in Figure 10.

Figure 10 - Eight clavulanic acid mid-dose concentrations measured 3h after administration of a steady state dose of clavulanic acid in relation to the EUCAST threshold for clavulanic acid (orange).

The median steady state dose concentrations at baseline (time zero), mid-dose (fT 50%) and at the end of the dosing interval (fT 100%) are summarized in Table 10. The median mid-dose concentration at steady state was slightly higher in comparison to the first dose (not statistically significant; p > 0.05)

Table 10 - Characteristics of the serum concentration after administration of a steady state dose of clavulanic acid. Data are reported as median (IQR). Median sampling Median clavulanic acid Lowest clavulanic acid

time (h) concentration (mg/L) concentration (mg/L) Baseline (n = 11 samples) 0.0 (0.0 – 0.0) 1.3 (0.7 – 1.5) 0.5

Mid – dose (n = 8 samples) 3.0 (2.9 – 3.0) 2.8 (1.8 – 3.8) 1.6 End dosing interval 5.9 (5.6 – 6.0) 1.3 (0.6 – 1.8) 0.5 (n = 9 samples)

The target at mid-dose (50 % fT > MIC 8 mg/L) was achieved in 6 out of the 8 (75 % of the) patients in whom a mid-dose could be measured. The lowest measured concentration of clavulanic acid at mid-dose was 1.6 mg/L.

D. CLEARANCE OF AMOXICILLIN/CLAVULANIC ACID

Median clearances in first and steady state dose for amoxicillin and clavulanic acid are summarized in Table 3Table 11.

Table 11 - Clearance of amoxicillin and clavulanic acid in first and steady state. Data are reported as median (IQR).

First dose Steady state dose

amoxicillin clavulanic acid amoxicillin clavulanic acid clearance (ml/min) clearance (mL/min) clearance (mL/min) clearance (mL/min) Median 125.9 (97.8 – 109.6 (71.9 – 115.5 (86.7 – 149.9) 111.6 (77.5 – 141.2) (IQR) 163.4) 157.9)

There is no significant difference between the clearance of amoxicillin in first and steady state dose (p = 0.87 using the Wilcoxon signed rank test). There is no significant difference between the clearance of clavulanic acid in first and steady state dose (p = 0.61 using the Wilcoxon signed rank test). There is no significant difference between de clearance of amoxicillin and clavulanic acid in first dose (p = 0.34 using the Wilcoxon signed rank test) and in steady state dose (p = 0.26 using the Wilcoxon signed rank test).

A positive significant correlation was found between renal function according to Cockcroft – Gault and amoxicillin and clavulanic acid clearance both in first and steady state dose. These results are given in Table 12 and Figure 101 – 14. The scatterplots concerning the estimated GFR according to CKD – EPI and amoxicillin and clavulanic acid are displayed in the appendix.

Table 12 - Correlation between amoxicillin clearance / clavulanic acid clearance eGFR. First dose Steady state dose

CKD – EPI Cockcroft – Gault CKD – EPI Cockcroft – Gault

r = 0.386 r = 0.659 r = 0.351 r = 0.770 Amoxicillin Clearance p = 0.14 p = 0.05 p = 0.354 p = 0.02

r = 0.430 r = 0.744 r = 0.244 r = 0.720 Clavulanic acid Clearance p = 0.10 p = 0.00 p = 0.527 p = 0.03

Figure 13 - Scatterplot correlation eGR according to Cockcroft – Gault (CLEDCG) and amoxicillin Figure 12 - Scatterplot correlation eGFR according to Cockcroft – Gault (CLSSCG) and clearance after administration of a first dose of amoxicillin (CLEDamox). amoxicillin clearance after administration of a steady state dose of amoxicillin (CLSSamox).

Figure 11 - Scatterplot correlation eGFR according to Cockcroft - Gault and clavulanic acid Figure 14 - Scatterplot correlation eGFR according to Cockcroft - Gault and clavulanic acid clearance after administration of a first dose of clavulanic acid (CLEDclav). clearance after administration of a steady state dose of clavulanic acid (CLSSclav).

E. OUTCOME STUDY POPULATION

To the best of our knowledge there were no serious adverse events requiring the cessation of amoxicillin/clavulanic acid.

Six patients have been switched to another antibiotic during treatment. Four patients were switched to piperacillin/tazobactam from which two empirically due to clinical failure. One of these two patients died during the hospitalisation. Two other patients were switched due to positive cultures for Pseudomonas aeruginosa.

Two patients were downgraded to levofloxacin but did not experience therapy failure on amoxicillin-clavulanic acid.

All patients except one could be discharged from the hospital.

DISCUSSION

The primary aim of this study was to investigate whether pharmacodynamic targets regarding amoxicillin-clavulanic acid are attained in frail patients admitted to the geriatric department. The secondary aim was to investigate the amoxicillin/clavulanic acid clearance and creatinine clearance in this population of frail elderly.

Our study population has a mean age of 88 years and a rather high KATZ score (median 16, possible range 6 – 24) and moderate CIRS score (median 12.5, possible range 0 – 52), indicating a population with a high care burden and with moderate severe comorbidities. The G8 score was below the cut-off value for frailty (≤ 14). There were no exclusions made based on comorbidity or cognitive impairment. We can conclude that the study population of this study consists of a true geriatric and even frail population. This is innovative in currently available literature, where the mean age is maximum 79.8 years (63), no frailty scores are provided and where in most of the (8 out of 11) studies patients are excluded due to comorbidities.

The target efficacy exposure was evaluated at mid-dose (50% fT> MIC) where a target of 8 mg/L was chosen as the worst-case scenario according to EUCAST en CLSI clinical breakpoints. (75) Eighty percent (12/15) of the patients in first dose and 88 percent (7/8) of the patients in steady state dose reached this target attainment at 50% of the dosing interval. The median mid- dose concentrations of amoxicillin after first and steady state dose are much higher than the chosen cut-off value of 8 mg/L. The lowest mid-dose concentration measured was 6.7 mg/L in first dose and 7.5 mg/L in steady state dose. Considering that the measured MIC for susceptible organisms in this study population was only 3.5 mg/L (IQR 1.3 – 5.5 mg/L) we can state that an adequate serum concentration of amoxicillin was reached during 50% of the dosing interval, according to EUCAST targets as well as according to true resistance patterns in this population.

As stated above, twenty percent (3/15) of the patients in first dose and 12 percent (1/8) of the patient in the steady state dose did not reach the target attainment for amoxicillin at 50% of the dosing interval according to the EUCAST target of 8mg/L. Nevertheless, none of these four patients experienced therapy failure due to this lower serum concentration of the antibiotic. Cultures were available in three out of these four patients; two showed a MIC for amoxicillin of 1 – 2 mg/L. One patient was switched to another antibiotic due to culture of Pseudomonas aeruginosa, a micro-organism that is inherent resistant to amoxicillin/clavulanic acid.

We may assume that the MIC in the fourth patient was also (far) below the EUCAST threshold of 8 mg/L since this patient responded well to antibiotic therapy.

In the total study population of eighteen patients four patients were switched to piperacillin/tazobactam. Two of them were switched due to culture of Pseudomonas aeruginosa (cfr. above). Two other patients (from which 1 patient died) were switched empirically to piperacillin/tazobactam due to signs of therapy failure. In these 2 patients unfortunately, no microbiology cultures were available. The measured serum concentration of amoxicillin/clavulanic acid in those two patients, however, was high enough to presume that a low serum concentration of the antibiotic is probably not the cause of this therapy failure.1

The target attainment for clavulanic acid seems less favorable than that for amoxicillin. The EUCAST target for clavulanic acid concentration is 2 mg/L. (75) Only sixty-seven percent (10/15) of the patients in first dose and 75 percent (6/8) of the patients in steady state dose reached this target during 50% of the dosing interval. The median concentrations of clavulanic acid at 50%fT after a first and steady state dose are higher than the desired target of 2 mg/L. Although these concentrations seem adequate there is a substantial variability in the clavulanic acid concentrations at 50%fT (first dose range: 0.8 mg/L – 6.8 mg/L, steady state dose range: 1.6 mg/L – 4.7 mg/L) resulting in some very low values (Table 9 andTable 10).

Six study patients (from which one patient both in first and in steady state dose) did not reach the target attainment of 2 mg/L clavulanic acid. All the 4 patients (three first, one steady state dose) with an amoxicillin concentration during 50%fT below the target of 8 mg/L had a clavulanic acid concentration below the target of 2 mg/L. However, for the three resulting patients with clavulanic acid concentration below the target (two in first and one in steady state dose) an adequate amoxicillin concentration (8.5 – 12.1 mg/L) was measured. Firstly, this discrepancy could be due to the different clearance pattern of amoxicillin and clavulanic acid. Amoxicillin is almost fully eliminated by the kidneys (70% unchanged metabolite in urine after 6 hours).

1 Patient 1: 13.0 mg/L – 2.8 mg/L amoxicillin – clavulanic acid in first dose. 16.6 mg/L – 3.6 mg/L amoxicillin – clavulanic acid in steady state dose. Patient 2: 14.1 mg/L – 2.2 mg/L amoxicillin – clavulanic acid in first dose. No steady state measurement. 33

In contrast, clavulanic acid is only partially renally cleared (40% unchanged metabolite in urine after 6 hours) which may lead to a higher total clearance (e.g. due to compensation of hepatic clearance), and thus a lower measured serum concentration, of clavulanic acid in patients with a potentially reduced renal function such as the older population in this study. (52, 53) Secondly, in the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration which may lead to lower observed serum concentration at mid-dose (3 hours) and at the end of the dosing interval (6 hours). (52) In this study, however, there was no significant difference between the clearance of amoxicillin and the clearance of clavulanic acid. As a third, pre-analytic problems may be a cause of false low measurement of clavulanic acid in serum. Not much is known about the storage conditions of clavulanic acid in serum, but we do know that clavulanic acid is a thermolabile compound that rapidly degrades at room temperature. Even though it is not a photosensitive compound, Duran T. et al. found in 2015 that clavulanic acid degraded by 40% in 4 hours under classic lamp light conditions. (77-79) This could mean that measured concentrations of clavulanic acid may have been underestimated when the sampling or transportation time was prolonged, two factors that were not monitored in this study. Finally, the evidence for the used clavulanic acid threshold is scarce (in comparison to amoxicillin). As such, it might be that the target threshold used in this study is too conservative.

Mean amoxicillin/clavulanic acid concentrations at 50% of the dosing interval were slightly higher in steady state compared to the first dose (not significant; p > 0.05) despite the fact that patients had a significantly better renal function in steady state presumably resulting in a higher clearance of the antibiotic. However, accumulation of the antibiotic would be the most logic explanation for the apparent higher mid-dose concentrations in steady state compared to the first dose.

The calculated amoxicillin/clavulanic acid clearance in this study is lower than previously reported in literature. We found a mean amoxicillin clearance of 208.3 ml/min in young healthy volunteers (59, 80, 81), 198.3 ml/min in hospitalized patients of all age groups (76) and 163.3 ml/min in hospitalized patient above 70 years (76). All these results are significantly higher than the clearance of amoxicillin in this study (127.5ml/min in first dose – 118.7 ml/min in steady state dose). The mean clavulanic acid clearance in young volunteers was 241.5 ml/min (82), also much higher than the reported clearance of clavulanic acid (131.6 ml/min in first dose – 113.2 ml/min in steady state dose) in this study.

Above literature results imply a declining trend in clearance with older age and in hospitalized patients compared to healthy volunteers. The mean age in our study population is higher than in those studies, indicating that age-related processes, such as decline in renal function, may be the reason for the lower calculated amoxicillin/clavulanic acid clearance in this study. This corresponds to a recent PK study by Lonsdale et al. (2019) who found that the beta-lactam clearance (amoxicillin, piperacillin and meropenem) at 87 years is half of the clearance found in young adults. (83)

As stated above, amoxicillin/clavulanic acid is mostly renally excreted. In this study we observed a rather low eGFR in comparison to a healthy young population, as could be expected due to the older age of the participants. (19, 20) The correlation of amoxicillin/clavulanic acid clearance and renal function was investigated. The latter was estimated using the CKD-EPI and Cockcroft Gault formulas. Several studies showed a better estimation of the renal function in elderly using the Cockcroft Gault formula rather than the CKD-EPI equation. The eGFR estimated using the Cockcroft Gault formula is known to be lower than the CKD-EPI in an older population and the CKD-EPI formula would overestimate the through renal function. The only exception would be obese elderly, who currently still are a minority, especially in our patient population (1 out of 18 patients in this study population). (19, 20) A significant correlation was found between the creatinine clearance according to Cockcroft Gault and the clearance of antibiotic compounds in first and in steady state conditions. There was no correlation between antibiotic clearance and creatinine clearance according to the CKD-EPI formula.

This study has some limitations. The most important problem were the difficulties with blood sampling. It was impossible to obtain 10 samples in every patient due to difficulties in drawing blood from the infusion line. Because of these issues, sampling periods often were long whereby sampling times were not precise. Storage conditions on ice may not have been optimal due to delay in transport and freezing times. Although, there was an agreement on the immediate freezing of the samples, no information nor supervision concerning the time frame was available between sampling and freezing. These logistical problems may have led to an underestimation of the serum concentrations due to degradation of the antibiotic (and especially clavulanic acid) into metabolites ex vivo. Additionally, in our study the reported concentrations were mathematically corrected for protein binding. A fixed protein binding percentage of 18 and 25 was applied for amoxicillin and clavulanic acid respectively.

The concentration of plasma proteins, however, tends to decrease in many elderly. This may result in a reduced protein binding of amoxicillin/clavulanic acid and a greater amount of free (active) drug. Therefore, the use of a fixed percentage of protein binding may possibly result in an underestimation of free drug concentrations in this study. Furthermore, true measured MIC was only available in 11 out of 18 patients. Microbiological cultures were not available in the other 7, making this an uncertain domain in this study. Finally, the time above the MIC is merely an intermediate endpoint. Conclusions made about this are not necessarily connected to clinical outcome. Unfortunately, no information was available concerning clinical and biochemical infection parameters at the end of antibiotic therapy.

Frail geriatric patients are a growing population, frequently in demand of intensive medical care. Nevertheless, they are almost always excluded from drug research. This study manages to focus on this specific patient population. Promising results were obtained concerning antibiotic serum concentrations and the correlation with renal function. In future research we would like to focus even more on this specific patient group. Study goals should extend to hard endpoints as well, such as clinical outcome, time to discharge and normalisation of microbiological cultures.

In conclusion, we can state that the measured serum concentrations of amoxicillin and clavulanic acid in this geriatric population seems adequate in most patients. A correlation was found between creatinine clearance according to Cockcroft Gault and both amoxicillin and clavulanic acid clearance, suggesting an opportunity of providing dosing recommendations for amoxicillin/clavulanic acid based on CG in elderly.

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NEDERLANDSTALIGE SAMENVATTING

Door de toenemende vergrijzing is de proportie oudere patiënten met een geriatrisch profiel en/of een toegenomen risico op frailty sterk toegenomen in de ziekenhuizen en op de spoedopname. Adequate dosering van antibiotica is van cruciaal belang in deze groep van geriatrische patiënten; Door frequente hospitalisatie en/of verblijf in een woonzorgcentrum is dit de groep bij uitstek waar resistentie van kiemen een belangrijke rol zal spelen. Doseringsschema’s werden zelden getest op deze patiëntengroep. Dit is echter van cruciaal belang gezien kwetsbare geriatrische patiënten zich kunnen presenteren met een veranderde farmacokinetiek als gevolg van veroudering en comorbiditeiten.

De doelstellingen van deze studie waren (i) het evalueren van de streefpercentages van fT> MIC in deze kwetsbare patiëntenpopulatie die amoxicilline /clavulaanzuur ontving, (ii) het onderzoeken van de correlatie tussen de klaring van amoxicilline/clavulaanzuur en de nierfunctie binnen deze patiëntengroep.

Deze studie betreft een prospectief, monocentrisch en observationeel farmacokinetisch onderzoek. Geriatrische gehospitaliseerde patiënten, die waren opgenomen via de spoedgevallendienst en bij wie een behandeling met intraveneus amoxicilline/clavulaanzuur (1000mg/200mg per 6 uur) was geïndiceerd, werden geïncludeerd. Serumstalen werden verzameld tijdens de eerste en/of veronderstelde steady-state dosis. Mid-dosis concentraties, gecorrigeerd voor plasma-eiwitbinding, werden vergeleken met het EUCAST klinisch breekpunt voor Escherichia coli (8 mg/L) om de fT > MIC 50% te evalueren. Omdat dit EUCAST-breekpunt werd bepaald met een vaste concentratie van 2 mg/L clavulaanzuur, werd dit gekozen als de doelconcentratie voor clavulaanzuur. Niet-compartimentele PK-analyse werd gebruikt om de klaring van amoxicilline en clavulaanzuur te schatten (PKsolver®, Excel Office 365). De nierfunctie werd geschat aan de hand van de Cockcroft-Gault (CG) en de Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formule. Correlatie werd beoordeeld door middel van een scatterplot en een Pearson Correlation Coefficient (R).

Achttien patiënten werden geïncludeerd. De mediane leeftijd betrof 88 jaar (interkwartiel bereik (IQR): 83-91,2 jaar). De mediane Cockcroft-Gault bij de eerste dosis was 41,5 ml/min (IQR 28,0 - 46,8 ml/min) en 45,0 ml/min bij de steady state dosis (IQR: 38-55 ml/min). Een hoge KATZ en CIRS score en een lage G8 score suggereren een geriatrische en kwetsbare populatie. Na de eerste dosis amoxicilline/clavulaanzuur was de mediane mid-dosis concentratie amoxicilline 13,0 mg/L (IQR: 8,5 - 15,4 mg/L) en van clavulaanzuur 2.6 mg/L (IQR: 1.6 – 3.3 mg/L). Deze mid-dosis concentratie bleef bij 80% van de patiënten boven het target van 8 mg/L voor amoxicilline en bij 67% boven het target van 2mg/L voor clavulaanzuur. In steady state omstandigheden was de mediane mid-dose concentratie 13,2 mg/L (IQR: 9,8-20,9 mg/L) voor amoxicilline en 2.8 mg/L voor clavulaanzuur (IQR: 1.8 – 3.8 mg/L). Deze mid-dosis concentratie bleef bij 88% van de patiënten boven het target van 8 mg/L voor amoxicilline en bij 75% van de patiënten boven het target van 2 mg/L voor clavulaanzuur. Een correlatie werd waargenomen tussen de Cockcroft-Gault en respectievelijk amoxicilline/clavulaanzuurklaring. (Amoxicilline: R = 0,6; p = 0,05 en clavulaanzuur: R = 0,7; p = 0,00 bij een eerste dosis; amoxicilline: R = 0,8; p = 0,02 en clavulaanzuur: R = 0,7; p = 0,03 bij een steady state dosis).

Dit pilootproject suggereert dat het huidige doseringsregime van amoxicilline/clavulaanzuur bij de meeste geriatrische patiënten toereikend is. Er werd een correlatie gevonden tussen de geschatte nierfunctie volgens Cockcroft-Gault en de amoxicilline/clavulaanzuurklaring, wat de mogelijkheid schept om aanbevelingen te geven wat betreft de dosering van amoxicilline/clavulaanzuur op basis van de Cockcroft-Gault bij ouderen.

APPENDIX

TABLE OF CONTENTS

APPENDIX 1 – INFORMED CONSENT AGED STUDY ...... 2 1.1 INFORMED CONSENT AGED STUDY CAPABLE ELDERLY ...... 2 1.2 INFORMED CONSENT AGED STUDY INCAPACITATED ELDERLY ...... 7 APPENDIX 2 – FRAILTY SCORES ...... 12 2.1 CIRS SCORE ...... 12 2.2 KATZ SCORE ...... 13 2.3 G8 SCORE ...... 14 APPENDIX 3 - STANDARD DOSING REGIMEN AMOXICILLIN / CLAVULANIC ACID UNIVERSITY HOSPITAL GHENT ...... 15 APPENDIX 4 – STUDY DATA ...... 16

APPENDIX 1 – INFORMED CONSENT AGED STUDY 1.1 INFORMED CONSENT AGED STUDY CAPABLE ELDERLY

Informatie- en toestemmingsformulier patiënten

1. Titel van de studie

Dosering van antibiotica voor infecties bij kwetsbare ouderen.

2. Informatieformulier

Geachte Heer/Mevrouw,

U werd opgenomen via de afdeling spoedgevallen. Omwille van tekenen van een bacteriële infectie werd door uw arts beslist om u te behandelen met een antibioticum. Tijdens uw verblijf in het ziekenhuis zal dit antibioticum gedurende een aantal dagen via de bloedbaan (via een katheter in de arm of hand) worden toegediend.

De dosis antibioticum die u krijgt werd overgenomen uit internationaal geldende richtlijnen. Om deze richtlijnen te kunnen opstellen werd de dosis van deze antibiotica bestudeerd bij een patiëntengroep jonger dan 75 jaar.

Momenteel is onvoldoende gekend over de snelheid van verschijnen en verdwijnen van deze geneesmiddelen in de bloedbaan bij patiënten ouder dan 75 jaar. In het onderzoek dat uw behandelende arts voorstelt worden daarom een aantal bloedstalen verzameld om na te gaan wat de hoeveelheid antibiotica is in het bloed over verloop van de tijd. Deze gegevens zijn van belang om in kaart te brengen of de standaarddosis van dit antibioticum voldoende is om zijn werking maximaal te kunnen uitoefenen. We weten immers uit vorig onderzoek dat een bepaalde hoeveelheid antibioticum in het bloed nodig is om een optimale werking te hebben tegen de ziekmakende bacteriën.

Om de bloedstalen af te nemen wordt u eenmalig bijkomend geprikt. Hierbij wordt een katheter geplaatst. Langs deze katheter worden tijdens de ziekenhuisopname een aantal bloedafnames uitgevoerd, verspreid over ongeveer 3 – 4 dagen.

In totaal wordt maximaal 10 mL bloed afgenomen (ongeveer hetzelfde volume als bij één standaard bloedafname en minder dan 1/40 van wat bij een bloeddonor per keer wordt afgenomen). Studenten geneeskunde kunnen assisteren bij deze bloedafnames. Na 3 – 4 dagen wordt de katheter verwijderd. Op het einde van uw behandeling met antibiotica, als de infectie genezen is, wordt nog eenmalig een bloedafname uitgevoerd. Hiervoor dient u niet bijkomend geprikt te worden aangezien deze afname wordt gecombineerd met een standaard bloedafname tijdens uw verblijf op geriatrie.

De stalen worden bewaard in een biobank in eigen beheer van de dienst pharmacologie en het labo microbiologie (diepvries Heymans instituut -70°) onder het medisch beheer van Prof. Dr. P. De Paepe.

Verder worden in deze studie een aantal klinische gegevens verzameld. Deze gegevens kunnen we deels terugvinden in uw dossier, andere zullen in een gesprek met u of met uw familie worden bevraagd. Met deze gegevens wordt uiteraard strikt vertrouwelijk omgegaan. Studenten geneeskunde kunnen assisteren in deze dataverzameling en -verwerking.

Aangezien u de antibiotica krijgt volgens de huidige richtlijnen zijn er voor u geen negatieve of positieve gevolgen te verwachten bij deelname aan de studie. Wanneer u deelneemt aan deze studie is uw behandeling exact dezelfde als wanneer u niet deelneemt. De resultaten van deze studie kunnen in de nabije toekomst echter wel een voordeel betekenen voor andere patiënten mocht blijken dat de hoeveelheid antibioticum in het bloed onvoldoende of te hoog is.

Deelname aan deze studie brengt geen extra kosten mee. Tevens is er geen onkostenvergoeding of bezoldiging voorzien voor patiënten die deelnemen aan dit onderzoek.

Dit onderzoek werd goed gekeurd door het Ethisch Comité van het UZ Gent. De studie wordt uitgevoerd volgens de richtlijnen voor de goede klinische praktijk (ICH/GCP) en de verklaring van Helsinki opgesteld ter bescherming van mensen deelnemend aan klinische studies. In geen geval dient u de goedkeuring door de Commissie voor Medische Ethiek te beschouwen als een aanzet tot deelname aan deze studie. We wijzen er graag op dat de zorg niet zal worden beïnvloed door uw keuze om al of niet mee te doen aan dit, of andere onderzoeken. De deelname aan deze studie is volledig vrijwillig, er kan op geen enkele manier sprake zijn van dwang. U bent ook steeds vrij om zonder enige verklaring terug te trekken uit dit onderzoek zonder dat dit enig nadeel met zich meebrengt in de verdere behandeling.

In overeenstemming met de Belgische wet van 22 augustus 2002 betreffende de rechten van de patiënt en de Algemene Verordening Gegevensbescherming (of GDPR) (EU) 2016/679 van 27

3 april 2016, zal de persoonlijke levenssfeer worden gerespecteerd en zal u toegang krijgen tot de verzamelde gegevens. Elk onjuist gegeven kan op uw verzoek verbeterd worden. Alle informatie die tijdens deze studie verzameld wordt zal gepseudonimiseerd worden (hierbij kan men uw gegevens nog terugkoppelen naar uw persoonlijk dossier). In het geval van pseudonimisering zal de sleutel tot deze codes enkel toegankelijk zijn voor de onderzoekende en behandelende arts of de door hem aangestelde vervanger. Enkel de gepseudonimiseerde gegevens zullen gebruikt worden in alle documentatie, rapporten of publicaties (in medische tijdschriften of congressen) over de studie. Vertrouwelijkheid van uw gegevens wordt dus steeds gegarandeerd. Zowel persoonlijke gegevens als gegevens aangaande uw gezondheid zullen verwerkt en bewaard worden gedurende minstens 20 jaar. De verwerkingsverantwoordelijke van de gegevens is de hoofdonderzoeker, Prof. Dr. P. De Paepe. Het onderzoeksteam van de hoofdonderzoeker zal toegang krijgen tot uw persoonsgegevens. De Data Protection Officer kan u desgewenst meer informatie verschaffen over de bescherming van uw persoonsgegevens. Contactgegevens: Katya Van Driessche, [email protected].

Vertegenwoordigers van de opdrachtgever, auditoren, de Commissie voor Medische Ethiek en de bevoegde overheden, allen gebonden door het beroepsgeheim, hebben rechtstreeks toegang tot uw medische dossiers om de procedures van de studie en/of de gegevens te controleren, zonder de vertrouwelijkheid te schenden. Dit kan enkel binnen de grenzen die door de betreffende wetten zijn toegestaan. Door het toestemmingsformulier, na voorafgaande uitleg, te ondertekenen, stemt u in met deze toegang.

U heeft het recht om een klacht in te dienen over hoe uw informatie wordt behandeld, bij de Belgische toezichthoudende instantie die verantwoordelijk is voor het handhaven van de wetgeving inzake gegevensbescherming: Gegevensbeschermingsautoriteit (GBA) Drukpersstraat 35 – 1000 Brussel Tel. +32 2 274 48 00 e-mail: [email protected] Website: www.gegevensbeschermingsautoriteit.be

De opdrachtgever voorziet in een vergoeding en/of medische behandeling in het geval van schade en/of letsel ten gevolge van deelname aan deze klinische studie. Voor dit doeleinde is een verzekering afgesloten met foutloze aansprakelijkheid conform de wet inzake experimenten op de menselijke persoon van 7 mei 2004 (KBC Insurance – Polisnummer W8/28963726/0100). Indien de arts-onderzoeker van mening is dat er verband met de studie mogelijk is (er is geen verband met de studie bij schade ten gevolge van het natuurlijke verloop van de ziekte of ten gevolge van gekende bijwerkingen van de standaardbehandeling), zal hij/zij de aangifteprocedure bij de verzekering starten.

Op dat ogenblik kunnen uw gegevens doorgegeven worden aan de verzekeraar. In het geval van onenigheid met de arts-onderzoeker of met de door de verzekeringsmaatschappij

4 aangestelde expert, en steeds wanneer u dit nodig acht, kunnen u, of in geval van overlijden uw rechthebbenden, de verzekeraar rechtstreeks in België dagvaarden (KBC Insurance NV; Professor Roger Van Overstraetenplein 2, 3000 Leuven; Tel: +32 16 24 55 81). Wanneer u over deze studie bijkomende informatie wenst, kan u dit steeds vragen aan uw arts. In totaal zullen 80 patiënten deelnemen aan deze studie. Bijkomende vragen kunnen gericht worden naar Dr. Tania Desmet, arts op de spoedopname in het UZ Gent.

Dr. Tania Desmet De Pintelaan 185 9000 Gent [email protected]

Hoofdonderzoeker: Prof. Dr. P. De Paepe, diensthoofd spoedgevallendienst.

TOESTEMMINGSFORMULIER

Patiënt:

☐ Ik bevestig dat Dr. .………………………… (naam dokter die uitleg gaf in blokletters) mij uitgebreid toegelicht heeft over wat dit onderzoek inhoudt en waarom dit onderzoek wordt gedaan.

☐ Ik bevestig dat ik de informatie over de studie heb begrepen die ik mondeling en schriftelijk gekregen heb.

☐ Ik begrijp dat ik volledig zelf beslist heb om mee te doen aan dit onderzoek en dat ik zelf kan beslissen op elk moment om uit de studie te gaan, zonder nadelige gevolgen.

☐ Ik verklaar hierbij dat ik instem met deelname aan dit onderzoek.

☐ Ik ga akkoord met het feit dat geneeskundestudenten als studiemedewerker gegevens verzamelen uit mijn elektronisch medisch dossier en deze behandelen volgens de hoger beschreven Belgische en Europese wetgeving.

Informerende arts:

☐ Ik verklaar de benodigde informatie inzake deze studie (de aard, het doel, en de te voorziene effecten) mondeling te hebben verstrekt evenals een exemplaar van het informatiedocument aan de deelnemer te hebben verstrekt.

☐ Ik bevestig dat geen enkele druk op de deelnemer is uitgeoefend om hem/haar te doen toestemmen tot deelname aan de studie en ik ben bereid om op alle eventuele bijkomende vragen te antwoorden.

Door de informerende arts te ondertekenen en persoonlijk te dateren.

1.2 INFORMED CONSENT AGED STUDY INCAPACITATED ELDERLY

Informatie- en toestemmingsformulier patiënten

1. Titel van de studie

Dosering van antibiotica voor infecties bij kwetsbare ouderen.

2. Informatieformulier

Geachte Heer/Mevrouw,

Uw familielid werd opgenomen via de afdeling spoedgevallen. Omwille van tekenen van een bacteriële infectie werd door uw arts beslist om u te behandelen met een antibioticum. Tijdens het verblijf in het ziekenhuis zal dit antibioticum gedurende een aantal dagen via de bloedbaan (via een katheter in de arm of hand) worden toegediend.

De dosis antibioticum die hij/zij krijgt werd overgenomen uit internationaal geldende richtlijnen. Om deze richtlijnen te kunnen opstellen werd de dosis van deze antibiotica bestudeerd bij een patiëntengroep jonger dan 75 jaar.

Om de bloedstalen af te nemen wordt uw familielid eenmalig bijkomend geprikt. Hierbij wordt een katheter geplaatst. Langs deze katheter worden tijdens de ziekenhuisopname een aantal bloedafnames uitgevoerd, verspreid over ongeveer 3 – 4 dagen. In totaal wordt maximaal 10 mL bloed afgenomen (ongeveer hetzelfde volume als bij één standaard bloedafname en minder dan 1/40 van wat bij een bloeddonor per keer wordt afgenomen). Studenten geneeskunde kunnen assisteren bij deze bloedafnames.

Na 3 – 4 dagen wordt de katheter verwijderd. Op het einde van uw behandeling met antibiotica, als de infectie genezen is, wordt nog eenmalig een bloedafname uitgevoerd. Hiervoor dient niet bijkomend geprikt te worden aangezien deze afname wordt gecombineerd met een standaard bloedafname tijdens het verblijf op geriatrie.

De stalen worden bewaard in een biobank in eigen beheer van de dienst pharmacologie en het labo microbiologie (diepvries Heymans instituut -70°) onder het medisch beheer van Prof. Dr. P. De Paepe.

Verder worden in deze studie een aantal klinische gegevens verzameld. Deze gegevens kunnen we deels terugvinden in het dossier, andere zullen in een gesprek met u en/of uw familielid worden bevraagd. Met deze gegevens wordt uiteraard strikt vertrouwelijk omgegaan. Studenten geneeskunde kunnen assisteren in deze dataverzameling en -verwerking.

Aangezien uw familielid de antibiotica krijgt volgens de huidige richtlijnen zijn er voor hem/haar geen negatieve of positieve gevolgen te verwachten bij deelname aan de studie. Wanneer hij/zij deelneemt aan deze studie is de behandeling exact dezelfde als wanneer hij/zij niet deelneemt. De resultaten van deze studie kunnen in de nabije toekomst echter wel een voordeel betekenen voor andere patiënten mocht blijken dat de hoeveelheid antibioticum in het bloed onvoldoende of te hoog is.

Deelname aan deze studie brengt geen extra kosten mee. Tevens is er geen onkostenvergoeding of bezoldiging voorzien voor patiënten die deelnemen aan dit onderzoek.

Dit onderzoek werd goed gekeurd door het Ethisch Comité van het UZ Gent. De studie wordt uitgevoerd volgens de richtlijnen voor de goede klinische praktijk (ICH/GCP) en de verklaring van Helsinki opgesteld ter bescherming van mensen deelnemend aan klinische studies. In geen geval dient u de goedkeuring door de Commissie voor Medische Ethiek te beschouwen als een aanzet tot deelname aan deze studie. We wijzen er graag op dat de zorg niet zal worden beïnvloed door uw keuze om uw familielid al of niet te laten deelnemen aan dit, of andere onderzoeken. De deelname aan deze studie is volledig vrijwillig, er kan op geen enkele manier sprake zijn van dwang. U bent ook steeds vrij om uw familielid zonder enige verklaring terug te trekken uit dit onderzoek zonder dat dit enig nadeel met zich meebrengt in de verdere behandeling.

In overeenstemming met de Belgische wet van 22 augustus 2002 betreffende de rechten van de patiënt en de Algemene Verordening Gegevensbescherming (of GDPR) (EU) 2016/679 van 27 april 2016, zal de persoonlijke levenssfeer worden gerespecteerd en zal u toegang krijgen tot de verzamelde gegevens. Elk onjuist gegeven kan op uw verzoek verbeterd worden. Alle informatie die tijdens deze studie verzameld wordt zal gepseudonimiseerd worden (hierbij kan men de gegevens van uw familielid nog terugkoppelen naar het persoonlijk dossier). In het geval van pseudonimisering zal de sleutel tot deze codes enkel toegankelijk zijn voor de onderzoekende en behandelende arts of de door hem aangestelde vervanger. Enkel de gepseudonimiseerde gegevens zullen gebruikt worden in alle documentatie, rapporten of publicaties (in medische tijdschriften of congressen) over de studie. Vertrouwelijkheid van deze gegevens wordt dus steeds gegarandeerd. Zowel persoonlijke gegevens als gegevens aangaande de gezondheid van uw familielid zullen verwerkt en bewaard worden gedurende minstens 20 jaar. De verwerkingsverantwoordelijke van de gegevens is de hoofdonderzoeker, Prof. Dr. P. De Paepe. Het onderzoeksteam van de hoofdonderzoeker zal toegang krijgen tot deze persoonsgegevens. De Data Protection Officer kan u desgewenst meer informatie verschaffen over de bescherming van deze persoonsgegevens. Contactgegevens: Katya Van Driessche, [email protected].

Vertegenwoordigers van de opdrachtgever, auditoren, de Commissie voor Medische Ethiek en de bevoegde overheden, allen gebonden door het beroepsgeheim, hebben rechtstreeks toegang tot de medische dossiers van uw familielid om de procedures van de studie en/of de gegevens te controleren, zonder de vertrouwelijkheid te schenden. Dit kan enkel binnen de grenzen die door de betreffende wetten zijn toegestaan. Door het toestemmingsformulier, na voorafgaande uitleg, te ondertekenen, stemt u in met deze toegang.

U heeft het recht om een klacht in te dienen over hoe de informatie van uw familielid wordt behandeld, bij de Belgische toezichthoudende instantie die verantwoordelijk is voor het handhaven van de wetgeving inzake gegevensbescherming: Gegevensbeschermingsautoriteit (GBA) Drukpersstraat 35 – 1000 Brussel Tel. +32 2 274 48 00 e-mail: [email protected] Website: www.gegevensbeschermingsautoriteit.be

Op dat ogenblik kunnen de gegevens van uw familielid worden doorgegeven aan de verzekeraar. In het geval van onenigheid met de arts-onderzoeker of met de door de verzekeringsmaatschappij aangestelde expert, en steeds wanneer u dit nodig acht, kunnen u of uw familielid, de verzekeraar rechtstreeks in België dagvaarden (KBC Insurance NV; Professor Roger Van Overstraetenplein 2, 3000 Leuven; Tel: +32 16 24 55 81).

Wanneer u over deze studie bijkomende informatie wenst, kan u dit steeds vragen aan uw arts. In totaal zullen 80 patiënten deelnemen aan deze studie. Bijkomende vragen kunnen gericht worden naar Dr. Tania Desmet, arts op de spoedopname in het UZ Gent.

Dr. Tania Desmet De Pintelaan 185 9000 Gent [email protected]

Hoofdonderzoeker: Prof. Dr. P. De Paepe, diensthoofd spoedgevallendienst.

TOESTEMMINGSFORMULIER

Patiënt:

☐ Ik bevestig dat Dr. .………………………… (naam dokter die uitleg gaf in blokletters) mij uitgebreid toegelicht heeft over wat dit onderzoek inhoudt voor mijn familielid (waar ik wettelijk vertegenwoordiger voor ben) en waarom dit onderzoek wordt gedaan.

☐ Ik bevestig dat ik de informatie over de studie heb begrepen die ik mondeling en schriftelijk gekregen heb.

☐ Ik begrijp dat ik volledig zelf beslist heb om mijn familielid, waar ik wettelijk vertegenwoordiger voor ben, mee te laten doen aan dit onderzoek en dat ik zelf kan beslissen op elk moment om deze deelname te beëindigen, zonder nadelige gevolgen.

☐ Ik verklaar hierbij dat ik instem met deelname van mijn familielid aan dit onderzoek.

☐ Ik ga akkoord met het feit dat geneeskundestudenten als studiemedewerker gegevens verzamelen uit het elektronisch medisch dossier van mijn familielid en deze gegevens behandelen volgens de hoger beschreven Belgische en Europese wetgeving.

Informerende arts:

☐ Ik bevestig dat geen enkele druk op de deelnemer en/of zijn wettelijk vertegenwoordiger is uitgeoefend om hem/haar te doen toestemmen tot deelname aan de studie en ik ben bereid om op alle eventuele bijkomende vragen te antwoorden.

Door de informerende arts te ondertekenen en persoonlijk te dateren

APPENDIX 2 – FRAILTY SCORES 2.1 CIRS SCORE

Cumulative Illness Rating Scale

1. Cardiac (heart only) 0 – 1 – 2 – 3 – 4

2. Vascular (rating is based on severity, organ damage is rated separately) 0 – 1 – 2 – 3 – 4

3. Hematopoietic (blood, blood vessels and cells, bone marrow, spleen, lymphatic’s) 0 – 1 – 2 – 3 – 4

4. Respiratory (lungs, bronchi, trachea below the larynx) 0 – 1 – 2 – 3 – 4

5. ENT (eye, ear, nose, throat, larynx) 0 – 1 – 2 – 3 – 4

6. Upper GI (oesophagus, stomach, and duodenum; pancreas, do not include diabetes) 0 – 1 – 2 – 3 – 4

7. Lower GI (intestines, hernias) 0 – 1 – 2 – 3 – 4

8. Hepatic (liver and biliary tree) 0 – 1 – 2 – 3 – 4

9. Renal (kidneys only) 0 – 1 – 2 – 3 – 4

10. Other GU (ureters, bladder, urethra, prostate, genitals) 0 – 1 – 2 – 3 – 4

11. Musculoskeletal-integumentary (muscle, bone, skin) 0 – 1 – 2 – 3 – 4

12. Neurological (brain, spinal cord, nerves, do not include dementia) 0 – 1 – 2 – 3 – 4

13. Endocrine-metabolic (includes diabetes, thyroid, breast, systemic infections, 0 – 1 – 2 – 3 – 4 toxicity)

14. Psychiatric/Behavioural (includes dementia, depression, anxiety, agitation/delirium, 0 – 1 – 2 – 3 – 4 psychosis)

Total score:

For each body system, the general rules for the severity rating are: 0 No problem affecting that system 1 Current mild problem or past significant problem 2 Moderate disability or morbidity and/or requires first line therapy 3 Severe problem and/or constant and significant disability and/or hard to control chronic problems Extremely severe problem and/or immediate treatment required and/or organ failure and/or severe 4 functional impairment

2.2 KATZ SCORE

Katz scale

Bathing Score  Requires no help with bathing = 1  Partial aid needed to wash upper or lower body = 2  Partial aid needed to wash upper and lower body = 3  Completely dependent for bathing = 4 Dressing  Gets clothes from closets and drawers and puts on clothes and outer garments complete with fasteners = 1  Partial aid needed to dress upper or lower body (not taking in account shoelaces) = 2  Partial aid needed to dress upper and lower body = 3  Needs to be completely dressed = 4 Transferring  Moves in and out of bed or chair unassisted = 1  Moves in and out of bed or chair independently with the use of mechanical transferring aides (wheelchair, = 2 crutches, …) = 3  Needs help from others in moving from bed to chair = 4  Bedridden or in a wheelchair and requires a complete transfer Toileting  Goes to the toilet, gets on and off, arranges clothes, cleans genital area without help = 1  Needs help with one of the three items: goes to toilet, arranges clothes and cleans genital area = 2  Needs help with two of the three items: goes to toilet, arranges clothes and cleans genital area = 3  Needs help with the three items: goes to toilet, arranges clothes and cleans genital area = 4 Continence  Exercises complete self-control over urination and defecation = 1  Accidental incontinent of bowel or bladder (incl. urinary catheter and artificial anus) = 2  Incontinent of bowel or bladder = 3  Incontinent of bowel and bladder = 4 Self-feeding  Eating and drinking independently = 1  Needs help in preparing the meal or the drinks = 2  Partial help needed with feeding or drinking = 3  Completely dependent to eat or drink = 4

Total score: / 24

2.3 G8 SCORE

Geriatric - 8 Screening Questionnaire

0: severe decrease in food intake Has food intake declined over the past 3 months due to loss of appetite, 1 1: moderate decrease in food intake digestive problems, or chewing or swallowing difficulties? 2: no decrease in food intake

0: weight loss > 3 kg

1: does not know 2 Weight loss during the last 3 months? 2: weight loss between 1 and 3 kg

3: no weight loss

0: bed or chair bound 1: able to get out of bed/chair but 3 Mobility does not go out 2: goes out

0: severe dementia or depression

4 Neuropsychological problems 1: mild dementia or depression

2: no psychological problems

0: BMI < 18.5

1: BMI = 18.5 to BMI < 21 5 Body mass index (BMI: weight in kg/height in m²) 2: BMI = 21 to BMI < 23

3: BMI = 23 and > 23

0: yes 6 Takes more than 3 prescription drugs per day 1: no

0: not as good

In comparison with other people of the same age, how do they consider their 0.5: does not know 7 health status? 1: as good

2: better

0: >85 yr

8 Age 1: 80 – 85 yr

2: < 85 yr

Total score:

APPENDIX 3 - STANDARD DOSING REGIMEN AMOXICILLIN / CLAVULANIC ACID UNIVERSITY HOSPITAL GHENT

Dose amoxicillin (mg) / clavulanic acid (mg)

Intra – abdominal infection

Creatinine Clearance Early nosocomial respiratory infection (ml/min) Pyelonephritis All other infections Septicemia Orthopedic / prosthetic infection Necrotizing infection

> 90 6 x 1000 / 200 4 x 1000 / 200

60 – 89 6 x 1000 / 200 4 x 1000 / 200

30 – 59 6 x 1000 / 200 4 x 1000 / 200

15 – 29 4 x 1000 / 200 3 x 1000 / 200

< 15 3 x 1000 / 200 2 x 1000 / 200

APPENDIX 4 – STUDY DATA

EARLY DOSE STEADY STATE DOSE

180 min 360 min Antibiotic 180 min 360 min Antibiotic 0 min 30 min 90 min Creatinine 0 min 30 min 90 min Creatinine fT 50% fT 100% clearance fT 50% fT 100% clearance (mg/L) (mg/L) (mg/L) clearance (mg/L) (mg/L) (mg/L) clearance (mg/L) (mg/L) (ml/min) (mg/L) (mg/L) (ml/min) PATIENT (ml/min) (ml/min) CKD– EPI CKD– EPI (ml/min/1.73 m²) (ml/min/1.73 m²) Cockcroft –Gault Cockcroft– Gault Amoxicillin Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate Amoxicillin Clavulanate

1 0,0 0.0 83.9 13.3 54.5 9.2 44.4 6.8 56.0 65.7 25 41 2 0.0 0.0 30.2 1.8 19.2 2.0 8.5 0.8 5.1 0.6 193.7 388.8 57 78 3 0.0 0.0 161.7 22.9 15.3 2.3 12.1 1.7 4.8 0.8 69.0 85.1 24 38 11.8 2.0 58.0 10.5 33.9 6.2 9.9 1.8 70.3 71.1 43 75 4 0.0 0.0 29.3 4.8 21.1 3.5 14.1 2.3 6.6 1.0 127.7 149.9 42 50 10.3 1.5 35.0 5.9 41 48 5 0.0 0.0 52.4 5.5 30.6 4.3 23.6 3.3 74.8 83.0 17 21 31.8 3.3 16 20 6 0.0 0.0 37.5 5.9 25.3 5.0 15.4 3.1 4.1 0.6 106.0 109.1 41 68 4.9 0.8 44.4 8.4 23.8 4.8 14.2 2.6 6.4 1.1 113.6 112.3 51 82 7 0.0 0.0 54.1 11.4 9.9 0.2 3.2 0.5 112.9 125.5 51 79 8 0.0 0.0 54.5 11.9 19.8 5.0 10.3 2.6 1.1 0.5 124.1 91.6 41 60 9 3.0 0.7 41.6 9.2 18.7 4.1 11.7 2.9 7.4 1.7 138.4 111.6 115 88 10 0.0 0.0 47.4 10.2 18.2 4.4 7.8 1.7 1.0 0.1 169.5 149.9 28 32 3.4 0.7 34.6 6.8 15.2 3.2 9.1 1.7 2.9 0.6 177.4 161.4 46 59 11 0.0 0.0 39.2 6.7 16.6 3.3 13.3 3.4 4.3 0.8 132.1 122.0 49 79 5.1 1.1 17.1 2.9 12.9 2.5 7.5 1.6 3.3 0.7 228.9 210.8 55 83 12 0.0 0.0 59.8 15.0 25.7 8.3 15.3 5.1 8.3 2.3 108.3 70.2 28 35 13 11.2 1.5 100.5 17.2 49.1 9.0 27.0 4.7 13.4 2.0 55.2 61.1 38 62 14 0.0 0.0 35.3 6.8 20.8 4.6 13.0 2.8 7.7 2.0 137.1 108.8 43 72 6.3 1.4 46.4 8.8 32.1 6.8 16.6 3.6 7.5 1.8 101.3 85.2 45 75 15 0.0 0.0 53.7 10.9 27.6 5.2 17.1 2.9 7.1 1.1 95.1 99.1 37 62 9.7 1.3 58.1 10.4 29.4 5.2 22.3 3.8 9.2 1.3 73.6 84.1 37 62 16 0.0 0.0 55.4 13.1 20.8 4.9 9.3 2.1 1.0 0.0 145.0 128.9 46 55 3.9 0.5 66.5 12.0 12.3 2.0 3.9 0.5 109.6 121.0 55 67 17 0.0 0.0 45.0 8.7 13.0 3.0 6.7 1.5 3.3 1.0 188.6 157.3 47 53 18 0.0 0.0 31.5 6.2 14.7 2.6 7.6 1.5 2.9 0.8 200.0 171.1 44 63