The Role of Clinical Pharmacist

on Safe Administration of Antibiotic

in ICU
Yovita Diane Titiesari, M.Sc., Apt.

Presented at the 6th Annual Symposium ‘ICU Without Wall’

Jakarta, November 30th 2019
Clinical pharmacist in ICU

The benefit of having clinical

pharmacist in ICU

Role of clinical pharmacist in

antimicrobials administration

Outline
Clinical Pharmacist in ICU
Critical care clinical pharmacist
around the world
UK US

Crit Care Med. 2003

Nov;31(11):2677-83
American College of Critical
Care Medicine (ACCM)
 Complex illnesses
Requires many
and multiple
medications
organ failure

Patient’s
Characteristics
in ICU
High proportions of Vulnerable to
medication error and
IV drugs and High drug related
Alert Medications problems
Medication Errors and Drug
Related Problems
• Medication error: any preventable event that may lead to
inappropriate medication use or patient harm (Am. Soc. Health Syst.
Pharm)
• Drug related problems (DRP): an event or circumstance involving drug
therapy that actually or potentially interferes with desired
health outcomes (Pharmaceutical Care Network Europe Foundation,
2006)
• DRPs are frequent in ICU  almost 70% of patients in ICU experienced
DRP (Martins, Silva and Lopes, 2018)
• Main causes of DRP in ICU (Martins, Silva and Lopes, 2018):
- Drug interactions
- Inappropriate dose selection
What the evidences said...

Critical care pharmacists have a role in reducing preventable

adverse drug events and prescribing error
• Wang et al., 2015
• Meta analysis and systematic review of observational studies

Direct patient care by clinical pharmacist in ICU provided high

frequency and clinical importance medicines optimization
• PROTECTED-UK Study, Shulman et al., 2015
• 21 critical care units in UK
• More medication optimizations done by advanced level clinical pharmacists plus when adequate
high resources were available (Bourne, Shulman and Jennings, 2018)
Medication therapy management by clinical pharmacist is an effective method
to detect drug related problems, to prevent adverse drug event, and to
contribute in patient safety
• (Martins, Silva and Lopes, 2018)
• Proposed interventions  directly to physicians  85% acceptance rate
 Critical care clinical pharmacist reduced hospital costs
Cost avoidance
per stay up to €2,560  study in two French ICUs from
2013 to 2015 (Leguelinel-Blache et al., 2018)

Recommendations by critical care clinical pharmacist

could save up to €119-136 per accepted
recommendations  two ICUs in Netherlands (Bosma et
al., 2018)

Benefit-cost ratio for patients receiving clinical pharmacy

services  US$24.81 patient cost is avoided for every
US$1 of the pharmacist’s salary and benefit  national
survey to 256 hospitals in USA (MacLaren et al., 2008)
Clinical Pharmacist and
Antimicrobial Use in ICU
Antimicrobials in ICU

Antimicrobials  Systemic antibacterials Local data 

very frequently  main pharmacological 22% of pharmacist
used in ICU groups associated with recommendations in
DRP (Martins, Silva and ICU during the year
Lopes, 2018) of 2018 is related
with antimicrobials
drugs (Titiesari,
unpublished data)
Problems with antimicrobials use in
ICU

Sepsis patients  Dose regimen 

changed in PK/PD time dependent vs
Duration of
of antibiotics  concentration
therapy
need adjustment dependent
dose antibiotics

Availability of
Expensive $$$  Adverse effect
culture and
cost effectiveness reactions
sensitivity data
Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Adapted from MacLaren, et al 2008 and
Laine, Flynn and Flannery, 2017

Providing information about antimicrobial dosing strategies

Providing information on appropriate handling of antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug interactions, IV

compatibility, duration of therapy

Reminding hospital team to withdraw culture (blood, sputum,

urine) before antimicrobials and its daily monitoring

Suggesting laboratory monitoring for certain antimicrobials

Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Providing information about
antimicrobial dosing strategies

Providing information on appropriate handling of antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug interactions, IV

compatibility, duration of therapy

Reminding hospital team to withdraw culture (blood, sputum,

urine) before antimicrobials and its daily monitoring

Suggesting laboratory monitoring for certain antimicrobials

The role of PK/PD in antimicrobials
therapy for sepsis – SSC Guidelines
2016

Rhodes et al. (2017). Surviving Sepsis Campaign. Critical Care Medicine, 45(3),
pp.486-552.
Antimicrobial dosing strategies
in sepsis (1)

Antibiotic Agents PK/PD Remarks Dosing strategies

Class
Carbapenems Meropenem • Time dependent Continuous infusion
Doripenem antibiotics is prefered vs
• Maintenance of T> MIC intermitten infusion
Imipenem  maximal bacterial
Beta-lactams Piperacillin- killing
tazobactam
Ceftazidime

(Roberts et al., 2016)

• Meta analysis of RCTs
• 632 patients with severe sepsis or septic shock
• Hospital mortality in patients with continuous vs intermitten beta-
lactams infusions
• Including carbapenems, piperacillin-tazobactam, ceftazidime
• Continuous infusion  constant IV administration throughout 24-hr
period
• Intermitten infusion  IV infusion of less than or equal to 30 minutes
(Roberts et al., 2016)
Conclusion:
administration of b-
lactam antibiotics by
continuous infusion
is associated with
decreased hospital
mortality and a
higher rate of clinical
cure compared with
intermittent dosing.
(Roberts et al., 2016)
 Antimicrobial dosing strategies
in sepsis (2)

Antibiotic Class Agents PK/PD Remarks Dosing strategies

Fluoroquinolones Ciprofloxacin • Lipophilic  excellent tissue Optimize the dose within a nontoxic range
penetration (skin, lung, (renal fx preserved)
bone, prostate) E.g. 400 mg Q8H for HAP and FN
• Concentration-dependent
profile
• Vd minimally affected in
critically ill patients
• PO administration  drug
interaction with metal (Al,
Levofloxacin 750 mg Q24H for HAP, complicated SSTI,
Mg, Ca, Fe, Zn) 
complicated UTI,
decreased absorption
500 mg Q24H for CAP
(incl. Sucralfate and
Moxifloxacin milk/dairy products) 400 mg Q24H for CAP, complicated SSTI,
complicated abdominal infection

1. Micromedex Drug Ref.

2. McKenzie, 2011
Antimicrobial dosing strategies
in sepsis (3)

Antibiotic Class Agents PK/PD Remarks Dosing strategies

Aminoglycosides Amikacin Hydrophilic, concentration- Extended interval

dependents profile dosing  ONCE
DAILY  decrease
the risk of toxicity
Glycopeptides Vancomycin Optimal PK/PD properties have not • Loading dose 25-
yet been elucidated  but more to 30 mg/kg (ABW)
concentration dependent for septic shock
• TDM is most
recommended
Loading dose of antimicrobials

• Loading dose: single or multiple set of doses given to a

patient to attain desired drug level more rapidly
Loading dose of antimicrobials
Antimicrobials Loading (LD) and maintenance dose (MD)
Tigecycline LD: 100 mg
MD: 50 mg Q12H, 12 hours after LD
Teicoplanin LD: 6 mg/kg Q12H for 3 intravenous or intramuscular
administrations
MD: 6 mg/kg Q24H
Anidulafungin Candidemia:
LD: 200 mg IV day 1
MD: 100 mg IV Q24H
Fluconazole Candidemia:
LD: 12 mg/kg IV/PO
MD: 6 mg/kg IV/PO daily
Voriconazole LD: 6 mg/kg IV Q12H for 2 doses
MD: 4 mg/kg Q12H
Micromedex Drug Ref.
Tygacil®, Targocid®, Ecalta®, V-Fend® prescribing information
 Antibiotic dose on
patients undergoing CRRT
• Appropriate antimicrobial therapy: not only
a suitable drug choice (in terms of
spectrum of activity) but also an optimized
dosing regimen
• 25-60% patients undergoing CRRT possibly
have subtherapeutic antimicrobial level
(Choi, 2010)
• Subtherapeutic level  infection is not well
treated  longer ICU stay
• Clinical pharmacist’s dosing
recommendation in patients undergoing
CRRT  saving ICU cost and less adverse
drug events
• Control (no clin pharm) vs intervention group
• 256 dosing recommendations for 93 patients underwent CVVH 
acceptance rate 87.5%
• Pharmacist dosing adjustment  £1637.7 cost saving per patient
(ICU cost)
• 2.36 times less antimicrobial-related adverse drug events (ADEs)
• Control (no clin pharm) vs intervention groups
• Patients undergoing CVVH of average 110 hours
• 91.8% acceptance rate to pharmacist’s dosing recommendations
• Significantly shorter length of ICU stay (10.7 vs 7.7 days, p =
0.037)
• Reduced cost per patients: USD 3525
Taken from: Jiang, 2013
Administration of
antimicrobials in patients
undergoing HD/CAPD

• Need to check the dialysability of each

drug
• Dialysed drugs  give the drug after
HD/CAPD
• Example of dialysed antimicrobials:
1. Meropenem
2. Imipenem-cilastatin
3. Fosfomycin
4. Piperacillin-tazobactam (HD)
 Lancet Journal of Infectious Disease,
2014
• Therapeutic drug
monitoring could be
used to optimise antibiotic
dosing in critically ill patient
 PK/PD changed
• Direct measurement of
serum abx concentrations
 to predict the next dose
 to reach MIC or AUC with
minimal side effect
• Software-aided
• Available publications:
aminoglycosides,
glycopeptides, beta-
lactams, linezolid, Image taken from https://code.cerner.com/apps/doseme
quinolones
Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Providing information about antimicrobial dosing strategies

Providing information on appropriate handling of

antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug interactions, IV

compatibility, duration of therapy

Reminding hospital team to withdraw culture (blood, sputum,

urine) before antimicrobials and its daily monitoring

Suggesting laboratory monitoring for certain antimicrobials

Frequent problems with
handling of antimicrobials
• Only used part of vials 
how to store the remaining
solution? How long is the
stability time?
• Reference: each product’s
package insert  each
product have their own
stability data
Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Providing information about antimicrobial dosing strategies

Providing information on appropriate handling of antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug interactions, IV

compatibility, duration of therapy

Reminding hospital team to withdraw culture (blood, sputum,

urine) before antimicrobials and its daily monitoring

Suggesting laboratory monitoring for certain antimicrobials

Hour-1 Bundle

Strong recommendation, moderate quality of

evidence)

Levy, M., Evans, L. and Rhodes, A. (2018). The Surviving Sepsis Campaign
Bundle. Critical Care Medicine, 46(6), pp.997-1000.
Over the first 6 hrs after the onset of recurrent or
persistent hypotension, each hour of delay in
initiation of effective antimicrobial therapy was
associated with mean decrease in survival of
7.6%

(Kumar et al., 2006)

Pharmacist role on time to
antibiotic
• Aware of the importance of rapid administration of
antimicrobials to patients with sepsis
• Build a system which can assist with medication
preparation and delivery
• able to instantly assist nurses with issues which may
delay administration, such as IV compatibility

(Moussavi and Nikitenko, 2016)

Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Providing information about antimicrobial dosing strategies

Providing information on appropriate handling of antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug

interactions, IV compatibility, duration of therapy

Reminding hospital team to withdraw culture (blood, sputum,

urine) before antimicrobials and its daily monitoring

Suggesting laboratory monitoring for certain antimicrobials

Common antimicrobials drug interactions

Micromedex Drug
Interactions
Common antimicrobials drug interactions

Micromedex Drug
Interactions
Example of antimicrobials IV
incompatibility (Y-site)
Antimicrobials Y-site Remarks
INCOMPATIBILITY
Meropenem Amiodarone Dense with opaque precipitation
Imipenem-cilastatin Amiodarone Dense with opaque precipitation
Sodium bicarbonate Particulate form
Manitol Chemical decomposition
Vancomycin Furosemide Particulate form
Aminophylline Particulate form
Levofloxacin Amiodarone Particulate form
Nitroglycerine Cloudy precipitation
Tigecycline Esomeprazole Particulate form
Nicardipine Yellow turbid precipitation
Ciprofloxacin Furosemide Precipitation upon mixing
Micromedex Drug Information –
IV Compatibility section
Y-site IV Incompatibility
Monitoring
antimicrobials
duration
Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Providing information about antimicrobial dosing strategies

Providing information on appropriate handling of antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug interactions, IV

compatibility, duration of therapy

Reminding hospital team to withdraw culture

(blood, sputum, urine) before antimicrobials and
its daily monitoring

Suggesting laboratory monitoring for certain antimicrobials

Taking culture before antibiotic
• Clinical pharmacist role  reminding
• Also to follow up the culture results  work together
with clinical microbiologist and the microbiology
laboratory
Role of pharmacist on ensuring safe
and effective administration of
antimicrobials in ICU
Providing information about antimicrobial dosing strategies

Providing information on appropriate handling of antimicrobials

Facilitating timely delivery of antimicrobials

Monitoring adverse drug reactions, drug interactions, IV

compatibility, duration of therapy

Reminding hospital team to withdraw culture (blood, sputum,

urine) before antimicrobials and its daily monitoring

Suggesting laboratory monitoring for certain

antimicrobials
Lab monitoring for
antimicrobials

• Several antibiotics need to be routinely monitored for

adverse drug reactions
• E.g. Amikacin and Vancomycin  renal function
• Clinical pharmacist  a reminder for ICU team to do lab
checking
Conclusions
• Clinical pharmacist as a part of
multidisciplinary team members
ensure safety and efficacy of
medications use, especially for
antimicrobials
• Clinical pharmacist provide direct
recommendations to ICU team
members regarding dosing regimens, and
help to monitor ADEs, interactions, IV
compatibility, duration of therapy, and
adjunctive lab results (organ function,
culture and sensitivity)
References
1. Wang, T., Benedict, N., Olsen, K., Luan, R., Zhu, X., Zhou, N., Tang, H., Yan, Y., Peng, Y. and Shi, L. (2015). Effect of critical care pharmacist's
intervention on medication errors: A systematic review and meta-analysis of observational studies. Journal of Critical Care, 30(5), pp.1101-
1106.
2. Shulman, R., McKenzie, C., Landa, J., Bourne, R., Jones, A., Borthwick, M., Tomlin, M., Jani, Y., West, D. and Bates, I. (2015). Pharmacist’s
review and outcomes: Treatment-enhancing contributions tallied, evaluated, and documented (PROTECTED-UK). Journal of Critical Care,
30(4), pp.808-813.
3. Bourne, R., Shulman, R. and Jennings, J. (2018). Reducing medication errors in critical care patients: pharmacist key resources and
relationship with medicines optimization. International Journal of Pharmacy Practice, 26(6), pp.534-540.
4. Martins, R., Silva, L. and Lopes, F. (2018). Impact of medication therapy management on pharmacotherapy safety in an intensive care
unit. International Journal of Clinical Pharmacy, 41(1), pp.179-188.
5. Leguelinel-Blache, G., Nguyen, T., Louart, B., Poujol, H., Lavigne, J., Roberts, J., Muller, L., Kinowski, J., Roger, C. and Lefrant, J. (2018).
Impact of Quality Bundle Enforcement by a Critical Care Pharmacist on Patient Outcome and Costs*. Critical Care Medicine, 46(2), pp.199-
207.
6. Bosma, Liesbeth & van den Bemt, Patricia & Melief, Piet & van Bommel, Jasper & Tan, Siok Swan & Hunfeld, N. (2018). Pharmacist
interventions during patient rounds in two intensive care units: Clinical and financial impact. The Netherlands journal of medicine. 76. 115-
124.
7. MacLaren, R., Bond, C., Martin, S. and Fike, D. (2008). Clinical and economic outcomes of involving pharmacists in the direct care of critically
ill patients with infections*. Critical Care Medicine, 36(12), pp.3184-3189.
8. Laine, M., Flynn, J. and Flannery, A. (2017). Impact of Pharmacist Intervention on Selection and Timing of Appropriate Antimicrobial Therapy
in Septic Shock. Journal of Pharmacy Practice, 31(1), pp.46-51.
9. Rhodes et al. (2017). Surviving Sepsis Campaign. Critical Care Medicine, 45(3), pp.486-552.
10.Roberts, J., Abdul-Aziz, M., Davis, J., Dulhunty, J., Cotta, M., Myburgh, J., Bellomo, R. and Lipman, J. (2016). Continuous versus Intermittent
β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials. American Journal of Respiratory and
Critical Care Medicine, 194(6), pp.681-691.
11.Jiang, S., Zhu, Z., Ma, K., Zheng, X. and Lu, X. (2013). Impact of pharmacist antimicrobial dosing adjustments in septic patients on
continuous renal replacement therapy in an intensive care unit. Scandinavian Journal of Infectious Diseases, 45(12), pp.891-899.
12.Jiang, S., Xu, Y., Ping-Yang, Wu, W., Zhang, X., Lu, X., Xiao, Y., Liang, W. and Chen, J. (2014). Improving antimicrobial dosing in critically ill
patients receiving continuous venovenous hemofiltration and the effect of pharmacist dosing adjustment. European Journal of Internal
Medicine, 25(10), pp.930-935.
13.Levy, M., Evans, L. and Rhodes, A. (2018). The Surviving Sepsis Campaign Bundle. Critical Care Medicine, 46(6), pp.997-1000
14.Kumar, A., Ellis, P., Arabi, Y., Roberts, D., Light, B., Parrillo, J., Dodek, P., Wood, G., Kumar, A., Simon, D., Peters, C., Ahsan, M. and Chateau,
D. (2009). Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of Survival in Human Septic Shock. Chest, 136(5),
pp.1237-1248
15.McKenzie, C. (2011). Antibiotic dosing in critical illness. Journal of Antimicrobial Chemotherapy, 66(Supplement 2), pp.ii25-ii31.