Provisional Registered Pharmacist research presentation 2013

RESEARCH REPORT

RESEARCH TITLE

‘AN EVALUATION OF ANTIBIOTIC DOSING ACCORDING TO RENAL FUNCTION OF

PATIENTS IN INTENSIVE CARE UNIT (ICU), HOSPITAL SULTANAH NUR ZAHIRAH,

KUALA TERENGGANU’

Prepared by:

Nurfatihah Nasiha Binti Bahagia

Preesha A/P Nagalingam

Preceptors:

Erney Binti Mohd Shah

Che Wan Mohd Hafidz

Pharmacy Department, Hospital SultanahNurZahirah, Kuala Terengganu, Terengganu

CONTENTS

1) Introduction…………………………………………………………………………….1

1.1 Definition……………………………………………………………………..........3

2) Problem Statement……………………………………………………………………..4

3) Literature Review…………………………………………………………………........5

4) Objectives…………………………………………………………………………........7

4.1 General………………………………………………………………………………

4.2 Specific………………………………………………………………………………

5) Methodology……………………………………………………………………….........9

6) Results and discussion………………………………………………………………...10

7) Conclusion……………………………………………………………………………..18

8) Limitation………………………………………………………………………………19

9) References……………………………………………………………………………..20

1) Introduction

Patients who are admitted in Intensive Care Unit (ICU) include representative of all

age groups with a range of organ dysfunction related to severe acute illness, which may

complicate long term illness[1]. Twenty-two to thirty-two percent of ICU patients die from

infections caused by gram-negative pathogens, despite appropriate antimicrobial therapy.

These patients are at very high risk of developing severe nocosomial infections, with

incidence rates five to ten fold higher than in general medical wards [2-5]. Serious infections

and sepsis whether community or hospital acquired are common in critically ill patients and

require rapid treatment to limit mortality and morbidity [1]. Antibiotics are among the most

important and commonly prescribed drugs in the management of critically ill patients[6].

ICU patients are frequently affected by acute kidney injury (AKI) accompanied by

dysfunction of other systems and organs while other cases are further complicated by a

secondary infection. Continuous renal replacement therapy (CRRT) is frequently used to treat

critically ill patients with acute or chronic renal failure. Since the prognosis in these patients

are very poor due to severe infection and the mortality rate reaching from 80% to 90%,

selecting appropriate antibiotic regimen is crucial for the clinical outcome. Choice of

antibiotic used for empirical treatment of bacterial infections in the intensive care unit (ICU)

is based predominantly on the identity and susceptibility pattern of bacteria isolated. 

Administering sub-therapeutic doses of antibiotics may lead to a decreased efficiency of

therapy and development of resistant bacterial strains. On the other hand, high doses can be

harmful to vital organs such as the kidneys, bone marrow and liver, resulting in a significantly

worse prognosis [7].

Dosage adjustment of antibiotics to renal function is recommended for many

antibiotics especially those that are eliminated by the kidney.Changes in renal function,

whether associated with normal aging or disease, can have profound effects on the

pharmacology of antibiotics since kidney is the major organ for maintaining fluid and

electrolyte homeostasis. Renal function should always be taken into account because majority

of drugs are excreted by the kidney[8,9]. Therefore, an estimation of their kidney function is

crucial for appropriate drug dosing.

When selecting potential candidate of renal dose regimens, the first consideration is

the creatinine clearance (CrCl).Patients with kidney disease, antibiotic dose adjustment are

commonly made to maintenance dose, or the dosing interval based on pharmacodynamics

effects of the drug. The most important information used for the prescribing of these

antibiotics includes dose recommendation based on Cockroch-Gault estimate creatinine

clearance (CrCl). Estimation of creatinine clearance is the most practical approach for

assessing kidney function while CockrochGault equation remains the most appropriate

method to determine drug dosage individualisation based on kidney function in clinical

setting[10]. Since most drugs require dosing adjustment at a creatinine clearance of

<50mL/min, therefore, the antibiotic dosing being prescribed for these patients need to be

monitored frequently[1, 11].Identification of optimal dosage adjustments among patients with

compromised renal function requires careful consideration of the relationships between

antibiotic exposure, efficacy, toxicity and the potential for antibiotic resistance [12].

However, several factors may contribute to the increasing difficulties in

establishing proper dosing regimen in critically ill patients [8]. Pathophysiological alterations

associated with critical illness can lead to both an increase in the apparent volume of

distribution (Vd) of an antibiotic as well as in clearance, thus, potentially leading to sub-

therapeutic plasma concentrations at the site of infection, treatment failure and the

development of antibiotic resistance. Volume of distribution (Vd) and drug clearance (Cl)

may be increased in ICU patients contributing to the altered concentration-time relationship of

many drugs.  When drug concentration is reduced, it might proportionally increase the half-

life.  The development of renal and/or hepatic impairment may be associated with the rapid

onset of toxic drug concentrations.  Therefore, antibiotic dose should be reviewed daily in the

ICU and dosage adjustment is necessary to prevent accumulation and toxicity based on

patient’s condition[13].

In this small study, our primary aim is focused on assessing antibiotics dosing

being adjusted appropriately in patient with kidney disease according torecommended

guideline as well as to study the outcomes of dosage adjustment of antibiotics in critically ill

patients.

1.1 Definition

a) Renal impairment

1) Mild to severe

All categories of renal function other than the baseline category, which corresponded to creatinine >1.0 mg/dl, creatinine clearance (CrCl) or GFR <90 ml/min.[14]

2) Moderate to severe

Worst category of renal function which corresponded to creatinine ≥1.5 mg/dl, CrCl or GFR <53 ml/min[14]

Stages [15] CrCl (ml/min)

Stage 1 - Kidney damage with normal or GFR >90

Stage 2 - Kidney damage with mild or GFR 60-89

Stage 3 – Moderate GFR 30-59

Stage 4 – Severe GFR 15-29

Stage 5 – Kidney failure <15

b) Renal condition

1) Acute renal failure (ARF) :

Sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes, and maintain fluid balance. [16]

2) Chronic kidney disease (CKD):

Kidney damage or GFR <60ml/minute for 3 months or more, irrespective of cause.[17]

3) Acute-on-chronic renal failure :

Acute renal failure (ARF) occurs in the background of pre-existing chronic kidney disease. [18]

2) Problem Statement

1) Patients with acute or chronic renal failure treated in ICU require adjustment of antibiotic

dose based on the patient’s renal function.  If the dosage of antibiotic regimen given to

these patients is not well adjusted, it can lead to accumulation and toxicity of the drugs

with leads to increase in morbidity and mortality rates[19].

2) In some critically-ill patients who are suffering with renal impairment, they are given large

dose of antibiotics to fight the bacterial infections as their major priority, rather than

adjusting the dosage according to the patient’s renal function and creatinine clearance

(CrCl) [20].

3) Dose adjustment of antibiotics according to renal function is crucial as it largely

contributes to the clinical outcomes of patients[13].

3) Literature Review

From the previous study of Fahimi et al, findings show that two hundreds and ninety-

one instructions (79.9%) of 364 antibiotic prescriptions required dosage adjustment based on

the patient’s renal condition. These adjustments were rationally performed in 43.7% and

61.4% of prescriptions, according to the two guidelines used. Ciprofloxacin (29.1% of

cases) and Vancomycin (33.6% of cases), were the most inappropriate prescribed antibiotics

in terms of dose administration. The results demonstrate a significant need to develop a

unanimous drug dosing system for patients with renal dysfunction. As conclusion from the

study, finding a reliable and easily applied dosing guideline is highly recommended since

lack of uniformity exists among dosing recommendations of commonly used drug

information handbooks. The results of their study may not be extrapolated to other clinical

settings, since they represent a unique situation. Therefore, further research is still required

to reveal the clinical importance of drug dosage adjustment in renal failure patients. [21]

Review by Eyler R. F and Mueller B. A, found that appropriate dosing of antibiotics in

these patients is essential since the common cause of acute kidney injury (AKI) is sepsis.

Drug dosing in critically ill patients with AKI, however, can be complicated. Critical illness

and AKI can both substantially alter pharmacokinetic parameters as compared with healthy

individuals or patients with end-stage renal disease. Furthermore, drug pharmacokinetic

parameters are highly variable within the critically ill population. In addition, volume of

distribution (Vd) of hydrophilic agents can increase as a result of fluid overload and

decreased binding of the drug to serum proteins, and antibiotic loading doses must be

adjusted upwards to account for these changes. Although renal elimination of drugs is

decreased in patients with AKI, residual renal function in conjunction with renal

replacement therapies (RRTs) result in enhanced drug clearance, and maintenance doses

must reflect this situation. Antibiotic dosing decisions should be individualized to take into

account patient-related, RRT-related, and drug-related factors. Efforts must also be made to

optimize the attainment of antibiotic pharmacodynamic goals in this population. [22]

According to the study done by Cathrine McKenzie on 2011, her finding shows that

antibiotics factor and patient factors affect antibiotic dosing. Early and effective antibiotic

therapy is essential in the management of infection in critical illness. The loading dose is

probably the most important dose and is a function of the volume of distribution of the drug

and the desired plasma concentration but independent of renal function. Doses of

hydrophilic agents such as b-lactams should be increased in the early stages of sepsis as the

extravascular space increases while lipophilic agents such as macrolides, the inflammatory

process is less important, although factors such as obesity will affect dosing. Concentration-

dependent antibiotics such as aminoglycosides should be administered by extended interval

regimens, which maximize bactericidal effect, minimize nephrotoxicity and allow time

between doses for the post-antibiotic effect. The critical factor for time-dependent agents,

such as b-lactams, is time above the MIC. Ideally administration of these agents should be

continuous, although vascular access availability can restrict infusion time to between 4 and

6 h, which is probably adequate. Besides, patient factors such as hepatic and renal failure

also will affect dosing. Hepatic failure will affect antibiotic metabolism, although it is most

important in end-stage failure. Renal failure and support will affect drug elimination. 

According to the authors, knowledge of these factors is essential. Patient safety and

prevention of unnecessary harm is a weighty consideration in critical illness. Therapy should

be reviewed daily and adjusted in the light of changes in patient organ function and

underlying pathology to ensure effective treatment and minimize adverse effects. [23]

4) Objectives

General

To evaluatethe antibiotic doseadjustment according to renal function of patient of intensive

care unit (ICU), Hospital SultanahNurZahirah(HSNZ), Kuala Terengganu.

Specific

1. To determine the percentage of prescribed antibiotics being appropriately adjusted

according to recommended guideline.

2. To compare the clinical outcomes of critically ill patient receiving antibiotic

requiring dose adjustment in ICU based on its adherence.

5) Methodology

Study design and location

- A cross-sectional study, conducted retrospectively.

Sample population

- All patients aged 12 years and above in intensive care unit, ICU, Hospital

SultanahNurZahirah, Kuala Terengganu.

- Patients were recruited by using inclusion and exclusion criteria.

Inclusion criteria Exclusion criteria

All renal impaired patients. 1) Patient on continuous renal replacement therapy (CRRT).

2) Patient admitted during weekend and was transferred out/passed away during the same weekend.

3) Patient that has incomplete data

-

Data collection

1. Clerked CP2 sheet of each patient in ICU starting from July to December 2012

(6months) were used to review patient information.

2. HIS system to collect extra information such as progress note of the patient and

laboratory parameters during their admission in ICU.

3. All the data that were collected using Microsoft Excel 2007.

Data analysis

- The data collected wereanalyzed using the SPSS® (Statistical Package for the Social

Sciences) software program for Windows® Version (20.0).

- For all tests, a p value of < 0.05 will be defined as statistically significant.

5) Methodology

Guideline

1. The Malaysian Society of Anaesthesiology (MSA) Guide to Antimicrobial Therapy in

Adult ICU, September 2006.

2. Antibiotic product pamphlet was used for evaluation of Piperacillin + Tazobactam

(Tazosin) and Amoxycillin + Clavulanic Acid (Augmentin) doses.

The MSA Guide to Antimicrobial Therapy in Adult ICU, September 2006were used for all

antibiotic that need dose adjustment except Tazosin and Augmentin. Product pamphlets were

used forTazosinsince we use the product from the company itself and there is no dose

adjustment in recommended guideline for IV Augmentin.

Adherence to guideline

Dose of antibiotic prescribed in accordance to recommended dose based on CrCl of

patients as stated in the guideline.

Outcome [24]

Systemic Inflammatory Response System (SIRS) were used to evaluate the samples after

receiving antibiotic regimen.

SIRS : Two or more of the following indicates no improvement :

1) Temperature >38°C or <36° C2) Heart rate > 90 b/min, 3) Respiratory rate > 20 b/min, or PaCO2 <32mmHg4) White blood count >12000/mm3 or <4000/mm3 or >10% band

form

6) Result and Discussion

Demographic data

Frequency, n Percent

Male 72 63.7

Female 41 36.3

Total 113 100.0

Table 1: Gender

From our study, 63.7% from total sample consists of male, n = 72 and 36.3%

constitute female patient, n = 41.

Type of antibiotic treatment

Table 2: Type of antibiotic treatment

About 68.1 % of total samples, n= 77 treated with antibiotic as empirical and the rest

of them treated as definitive.

Frequency, n Percent

Empirical 77 68.1

Definitive 36 31.9

Total 113 100.0

Samples according to different stages of Creatinine Clearance (CrCl) and renal condition.

Stage 2 (60-89)

Stage 3 (30-59)

Stage 4 (15-29)

Stage 5 (0-14)

010203040

2

24 28

100

87

16

0

7 38

Stages of Creatinine Clearance According to KDOQi Clin-ical Practice Guidelines, 2013 [15]

Acute on Chronic

Chronic

Acute

Stages of Creatinine Clearance (CrCl)

Num

ber

of S

ampl

es

Chart 6.1 : Samples according to different stages of Creatinine Clearance (CrCl) and renal

condition.

Chart 6.1 shows the number of samples according to different stages of creatinine

clearance and renal condition. The stages of creatinine clearance is according to KDOQi

clinical practice guideline,2013[15].

From the chart, 2 out of 2 samples in stage 2 creatinine clearance contributed to acute

kidney disease, whereas, in stage 3, 24 samples are acute, 8 and 7 samples are chronic and

acute on chronic respectively. For stage 4, 28 samples are acute, 7 chronic and 3 acute on

chronic. Lastly, stage 5, 16 samples are chronic, followed by 10 samples acute and 8 samples

acute on chronic. The chart showed that majority of samples contributed to acute kidney

disease and having stage 4 creatinine clearance which consisted of 28 samples.

Percentage of Antibiotics Adherence to Guideline

89.4% n=101

10.6% n=12

High doses

Adherence of Antibiotics to Guideline

Yes No

Total sam-ple,

n = 113

Chart 6.2 : Percentage of Antibiotics Adherence to Guideline

Chart 6.2 shows the percentage of antibiotics adherence to recommended guideline.

From the pie chart, 89.4 % constituting of 101 out of 113 samples adhere to recommended

guideline whereas 10.6% constituting 12 out of 113 samples did not adhere to recommended

guideline whereby they were prescribed with high doses of antibiotics despite renal function

and creatinine clearance stages.

Frequency of antibiotics prescribed and its adherence to recommended guideline

Ampicillin

+ Su

lbactam

Amoxycill

in + Clav

ulanic A

cid

Cefepim

e

Cefotax

ime

Ceftazi

dime

Cefuro

xime

Ciprofloxa

cin

Imipen

em +

Cilasta

tin

Meropen

em

Metronidazo

le

Piperacili

n + Ta

zobact

am

Trimeto

prim +

Sulphometh

oxa...

Vanco

mycin

Polymyx

in E0

5

10

15

20

25

30

58

2 2

105 5 3

1713

24

3 2 2

14

3

3

1

NoYes

Types of antibiotics

Num

ber o

f sam

ples

Chart 6.3: Frequency of antibiotics prescribed and its adherence to recommended guideline

Chart 6.3 shows the frequency of different types of antibiotics prescribed. Based on our

result, 12 samples did not adhere to guideline consisting of 5 types of antibiotics that include

Ampicillin + Sulbactam (Unasyn), Ciprofloxacin, Imipenem + Cilastation (Tienem),

Meropenem and Metronidazole. Many previous studies suggested that dose of those

antibiotics should be higher than recommended guideline. From our result, it was found that

dose of Ciprofloxacin were prescribed with a high dose of 400mg BD comparing to the

recommended 200mg BD as stated in recommended guideline based on creatinine clearance.

From the study of Zanteen et al (2008), IV Ciprofloxacin 400 mg BD leads to adequate

AUC/MIC and Cmax/MIC ratios in many cases. Effective killing concentrations were only

achieved in pathogens with MIC less than 0.25. As bacteria in intensive care unit patients

often exceed this threshold, it is recommended to use higher doses of ciprofloxacin (1200 mg

daily) to ensure optimal bacterial killing and avoid antibiotic resistance[25].

Besides that, meropenem is another antibiotic that did not adhere to recommended

guideline consisting of 3 samples that did not adhere. Study by Eggiman, P and Pittet, D

found that there is potential inadequacies noted for standard doses of

meropenemwhich may be further compounded in the intensive care unit

(ICU) as they typically harbor the most resistantpathogens within a given

population[26].

Furthermore, another study found that the pharmacokinetics of the

critically ill may differ from non-critically ill patients, often resulting in a

reduction in exposure of meropenem [27].

For these reasons, higher empiric doses may be required to adequately

achieve pharmacodynamic targets against pathogens encountered within

the ICU[28].

This study also found that there is only 1 from 6 samples of Ampicillin + Sulbactam

(Unasyn) that did not adhere to guideline, which administered 1.5 g TDS instead of 3g OD as

stated in recommended guideline. Study from Adnan, S et al. suggested that for optimization

of therapy higher dose for treatment of infection is recommended since alteration of

pharmacokinetics are common inβ-lactam agents in critical illness[29].

The need of higher dosage of antibiotics in critically ill patients was

supported by few studies. According to Nathwani D and Davey P, they

suggest that the highest dose in the range should be given in severe

sepsis since low doses may not only be ineffective but have been shown to

contribute to resistance [30]. Another study by Federico P and Pierluigi conclude that

selecting higher dosage and alternative dosing regimens focused at maximizing the

pharmacodynamics of antimicrobials might be worthwhile, in order to increase clinical cure

rates among critically ill patients.[31]

Outcomes of samples

SIRS parameters were used to evaluate the outcome of this study whereby the mean of each

parameter were calculated before and after the initiation of antibiotics and the respective

means were compared to evaluate the outcome.

(a) Improvement of outcomes based on SIRS parameters

(T = temperature, WBC = White Blood Cells, RR= Respiratory rate, HR= Heart Rate)

Type of antibiotics

Sample, n

Mean T

Mean T

Mean WBC

Mean WBC

Mean RR

Mean RR

MeanHR

Mean HR

Before After Before

After Before After Before After

Cefepime 2 38.1 37.5 7.6 8.7 16.5 18.2 81.2 83.4

Cefotaxime 2 39.6 36.7 8.9 6.9 21.4 17.0 85.6 76.5

Vancomycin 2 36.7 36.4 13.3 8.5 20.3 18.4 78.4 68.7

Polymyxin E 2 37.9 36.9 8.3 9.6 18.1 17.6 84.5 79.6

Amoxycillin + Clavulanic Acid (Augmentin)

5 (8) 38.6 37.8 11.0 14.6 18.9 17.6 80.5 77.0

Ceftazidime 7 (10) 37.8 36.8 8.4 7.5 18.3 16.7 89.3 87.5

Piperacillin + Tazobactam (Tazosin)

18 (24) 37.3 37.8 9.5 8.3 18.5 16.0 90.4 88.3

Table 6.1 :Antibiotics that 100 % adhere to guideline

Table 6.3 shows the antibiotics which 100% adhere to guideline and showed improvement

based on SIRS parameters which includes Cefepime, Cefotaxime, Vancomycin, Polymyxin E,

Amoxycillin + Clavulanic Acid, Ceftazidime and Piperacillin + Tazobactam. As for

Cefepime, Cefotaxime, Vancomycin and Polymyxin E, 2 out of 2 samples adhere to guideline

and showed improvement contributing to 100% adherence and 100% positive outcome. The

rest of the antibiotics, Amoxycillin + Clavulanic Acid, Ceftazidime and Piperacillin +

Tazobactam 100 % adhere to guideline but did not 100% show positive outcome whereby

only 5 out of 8 for Amoxycillin + Clavulanic Acid, 7 out of 10 for Ceftazidime and 18 out of

24 for Piperacillin + Tazobactam showed improvement based on SIRS parameters.

Table 6.2 :Antibiotics that did not 100% adhere to guideline

Table 6.2 focused on the antibiotics that did not 100% adhere to guideline but however

showed improvement based on SIRS parameters. From the table, 5 out of 9 samples of

Ciprofloxacin showed improvement, 4 out of 5 samples adhere to guideline whereas 1 sample

did not adhere to guideline and yet showed improvement. As for Imipenem + Cilastatin, 2 out

of 6 samples showed improvement, 2 out 6 samples showed improvement whereby both the

samples adhere to guideline. Next, Meropenem, 17 out of 20 samples showed improvement

whereby 14 samples adhere to guideline and 3 samples did not adhere to guideline. As for

Ampicillin + Sulbactam, 4 out of 6 samples showed improvement, 3 samples adhere to

guideline and 1 sample did not adhere to guideline. Lastly, Metronidazole consist of 5 out 14

samples that showed improvement based on SIRS parameters and all 5 adhere to

recommended guideline.

Type of antibiotics

Sample, n Mean T

Mean T

Mean WBC

Mean

WBC

MeanRR

Mean RR

Mean HR

Mean HR

Before After Before After Before After Before After

Ciprofloxacin 5 (9)

4 37.9 37.3 13.5 10.3 18.8 19.1 92.9 86.0

1 38.1 36.7 14.6 12.5 23.6 18.9 87.3 86.5

Imipenem + Cilastatin (Tienem)

2(6)

2 37.7 37.8 11.4 9.0 19.5 17.6 88.4 77.0

Meropenem 17(20)

14 37.4 38.1 8.9 11.7 18.4 18.9 98.7 89.9

3 38.7 36.4 11.3 13.9 20.2 18.7 89.7 85.3

Ampicillin + Sulbactam (Unasyn)

4 (6)

3 38.1 37.3 9.0 10.3 23.4 19.1 94.4 91.3

1 37.5 37.1 13.7 10.4 19.3 22.4 94.5 89.1

Metronidazole

5 (14)

5 38.4 37.4 8.2 7.9 25.4 17.2 82.7 86.7

b) Adherence of antibiotics towards guidelines and patient outcomes

Table 6.3: Adherence of antibiotics towards guidelines and patient outcomes

Table 6.4: Pearson Chi-Square test: Association of antibiotics adherence towards guidelines and

patient outcomes

Data was analysed using SPSS version 20 and p value less than 0.05 indicate

significant. From table 6.3 and 6.4, statistical analysis using Chi-Square test found that there

was no significant between adherence of antibiotics towards guidelines and patient outcomes

(p = 0.53) in this study.

7) Conclusion

- Almost 90 % samples adhere to guideline MSA Guide to Antimicrobial Therapy in

Adult ICU, September 2006 and product pamphlet.

- Although high percentage of improvement seen in adhere group compare to non-

adhere group, there was no significant between adherence of antibiotics towards

guidelines.

- Therefore, we recommend to adjust dose in order to save renal function whereby

dosing of antibiotic in critically ill patients should be individualized and not solely

based on creatinine clearance or renal function.

8) Limitation

- Clinical improvement of patient cannot be evaluated solely based on septic parameters

instead prospective study should be proposed to evaluate the outcomes of this study.

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