Rational use of antibiotics in ICU patients

Presenter: Dr Balew A (IMR1)

Mentors :Dr Selam (Assistant professor of Internal Medicine)

1
Presentation outline

• Introduction to the AMR

• Rational use principle antibiotics

• Treatment strategies

• Empirical therapy Antibiotics section

• MDR bacteria treatment

Introduction antibiotics
Antibiotics discovery in the last decades

• Economically not wise

• AMR inevitable
• Health professional pressure
Global burden of AMR

• Methods: data collected from 471 million individual records or isolates and
7585 study-location-years from 2014 countries in 2019
• Result
• There were an estimated 4·95 million (3·62–6·57) deaths associated with
bacterial AMR in 2019
• 3rd G cephalosporin-resistant E coli and K pneumoniae,carbapenem-resistant A
baumannii, and K pneumonia and fluoroquinolone-resistant E coli are major
MDR pathogens
• Highest in western sub-Saharan Africa, at 27·3 deaths per 100000
AMR in ICU

• ICU is considered the epicenter of infection and AMR

• More than 75% of critically ill patients receive at least one antibiotic during their
stay in the hospital.

• Nealy 3X of the ward patients

• Several risk factors contribute for AMR in ICU

• Methods: 18 relevant literature which included case-control and cohort studies were
included in the meta-analysis

• Result: Male gender, having operative procedure, a central venous catheter,

mechanical ventilation (OR 1.25, 95%CI 1.07, 1.46), previous antibiotic therapy
length of ICU stay (8.18 day), were identified as risk factors for MDR-GNB
AMR in Ethiopia ICU
Mekonnen Alebel • Multiple site samples collected from 270 patients in the ICU
2021 • ESBL-producing isolates were P. aeruginosa (100%), E. cloacae
(Gondar) (100%), K. pneumonia (82.8%), and E. coli (64%).
• The predominant carbapenemase producer isolates were K pneumoniae
(27.6%) and E. cloacae (33.3%).
• Overall, 77 (81.1%) of species were multi-drug resistant

Hiwot • Urine from 220 patients were included

Bizuayehu,2022 • Acinetobacter species, Pseudomonas species, Klebsiella species E.
(SPHHMC,RDH, coli, and Enterococcus species were the dominant bacterial isolates
Abat H) • Many GNB, cefotaxime 34(89.5%), amikacin (16.0%), meropenem
(20.0%) and imipenem (20.0%)
• About 13(86.7%) isolates of Acinetobacter, all isolates of Klebsiella
species (100%) and E. coli (100%) were MDR.
• BD sample from BLH(501),
Y12HMC(298), DRH(301) and HURH Enterobacteriaceae
(316)
• Enterobacteriaceae, MDR at
HUCSH( 95.1%) TASH(93.2%,),
Y12HMC(87.3%) and DRH (67.7%)
• K. pneumoniae :cft(96.4%), Cfz (95.5%),
Cef (83.8%),Gen(82%),17.3 % MER &
15.3%AMK
• A. baumannii: Cfz (85.3%), Cef (82.4%),
MER (58.8%), AMK(8.8%)
Acinetobacter species Pseudomonas species
 How to optimize the antibiotics use and prevent AMR

Antimicrobial stewardship (AMS)

• It is a strategy for promoting the appropriate use of antibiotics (ATBs)

and reducing the emergence of AMR
Antibiotics treatment guidelines/protocol/ in ICU

• Increasingly AMR necessity to create local antibiograms specific for each hospital
& even ward, annually.

• Antibiotic administration guidelines/protocols/ developed locally potentially avoid

unnecessary antibiotic administration & reduce development AMR

• Development need local microbiology data of targeted infections & other relevant
determinants in the local context.
Method :
• Experimental study done to test impact of locally developed CPG for
empirical antibiotic therapy of common infections in the hospitals
Result
• 808 patient in pre- and 836 in post-implementation periods were compared.
• Significant reductions in mean durations ICU stay, ventilator use & overall favorable
clinical outcomes
• Conclusion :the locally developed CPG implementation is feasible and effective in
improving patient outcomes and reducing ATB consumption.
 Do we have quality antimicrobial data for CPG development in
our ICU ?

• Method: A total of 12 AMR reviews with 312 original studies were included in this
overview and the quality of each included AMR review was assessed (AMSTAR 2).

• Result and conclusion. 75% of the review had low and below methodologic quality, and
none had a high-quality score using the AMSTAR 2 tool. This highlights the need to
improve the methodologic quality to provide the best available evidence for clinical
decision-making and curb the ongoing AMR in Ethiopia
Rapid diagnostics in Microbiology lab to guide antibiotics treatment
and monitoring ?
Effect of Gram Stain–Guided Initial Antibiotic Therapy on Clinical Response in
Patients With Ventilator-Associated Pneumonia

Finding:
• 103 patients in Gram stain–guided group & 103 in guideline-based group were
compared .
• Clinical response 76.7% Vs 71.8%),reduced use of antipseudomonal agents and
anti-MRSA and 28-day incidence of mortality (13.6% 17.5%) showed in the
Gram stain–guided group vs in the guideline-based group
Conclusion:
• Gram stain–guided treatment was non-inferior to guideline-based treatment and
significantly reduced the use of broad-spectrum antibiotics in patients with
VAP
• Methods:
• Compared PCT group (761) vs to standard-of-care (785)
• Antibiotics discontinue if PCT concentration decreased by 80% or more of its peak
value or to 0·5 μg/L or lower & in the standard-of-care group, patients were treated
according to local antibiotic protocols

• Result:
• Procalcitonin guidance stimulates the reduction of the duration of treatment and
daily defined doses in critically ill patients with a presumed bacterial infection. This
reduction was associated with a significant decrease in mortality
Guidelines Recommendations
Surviving Sepsis • Not recommend using procalcitonin to decide when to start
Campaign: 2021 antimicrobials
• Recommend using of procalcitonin to decide when to
discontinue antimicrobials over clinical evaluation alone
IDSA:HAP/VAP 2016 • Not recommended to use PCT alone to decide to Initiate
Antibiotic Therapy?
• Recommend using of procalcitonin to decide when to
discontinue antimicrobials over clinical evaluation alone
ERS/ESICM/ESCMID • They do not recommend the routine measurement of serial
HAP/VAP-2017 serum PCT levels to reduce duration of the antibiotic course
India 2019:ICU Abx • Recommend using procalcitonin to decide when to
prescription discontinue antimicrobials over clinical evaluation alone,
the duration of therapy is >5-7 days in SCAP and HAP/VAP
Pharmacodynamic and pharmacokinetic dose optimization

• Adequate drug concentrations at the infection site are needed to optimize clinical
outcomes.

• Many factors influence the PK of antibiotics in critically ill patients and may
contribute to subtherapeutic exposures.

• Move away from the “one dose fits all” toward individualized to the physiology of the
patient being treated
• Time-dependent and concentration-dependent killing

• Common drugs β-lactams and glycopeptides

• Maximum bacterial killing occurs when the drug concentration persistently
exceeds MIC of the pathogen.
• It can be minimized (above the MIC) through prolonged or continuous infusions
these drugs

• Concentration-dependent antibiotics

• Common drugs Aminoglycosides and fluoroquinolones

• Maximum bacterial killing occurs when the peak drug concentration exceeds
several times (>8–10) the MIC
PK of common antibacterial

• Hydrophilic
• Extracellular distribution
• Renal execration
• Loading important
• Lipophilic
• Intracellular distribution
• Hepatic execration
• 22 studies (1876 patients) were
included in the MA

• Interpretation Prolonged infusion

of antipseudomonal β-lactams for
the treatment of patients with
sepsis was associated with
significantly lower mortality than
short-term infusion

26
Method: 11 studies were included in the MA to compare the efficacy and safety of CIV
and IIV.

Result :Patients treated with CIV had a significantly lower incidence of nephrotoxicity
compared with patients receiving IIV (RR) = 0.61). Mortality between patients receiving
CIV and patients receiving IIV was similar (RR = 1.15).

Conclusion : MA showed that CIV had superior safety compared with IIV, whilst the
clinical efficacy was not significantly different.
• Prospective auditing and formulary restriction
Methods:
• Intervention phase (707 intervention): weekly audits and immediate feedback
sessions on antibiotic prescriptions of patients admitted and post-intervention phase
(402 post-intervention): audited antibiotic prescriptions but provided no feedback to
the treating teams
Finding:
• Team recommended to discontinue antibiotic therapy in 54% of cases during the
intervention period. Once the intervention ceased, total antimicrobial use increased by
51.6% & mean duration of treatment by 4.1 days/patient.
Method:
• Baseline (B)(194): no audit was performed, Model 1 (M1,415): ID physician evaluated
patients &a critical care pharmacist communicated recommendations to the treating team
and Model 2 (M2,83), ID physician directly participated in interdisciplinary rounds with the
medical ICU team.
Results:
• M1 and M2 were associated with appropriate antimicrobial selection (B, 70%; M1, 78%;
M2, 82%; P ¼ .042) and with lower rates of resistance (B, 31%; M1, 25%; M2, 17%; P
¼ .033).
• Conclusion :Audit and feedback were independently associated with appropriate
antimicrobial selection and prevention of resistance
 Antimicrobial de-escalation in the ICU

• Early modification of empiric antimicrobial therapy in order to prevent the AMR by

decreasing overall exposure to broad-spectrum agents

• ADE is generally achieved by switching from combination antibiotics to monotherapy

• Many clinicians still are reluctant to modify initial broad-spectrum antibiotic regimens
even when the practice is supported clinically and by microbiologic testing
Study type Study Finding
Ines Lakbar 2020 SR and MA of 20 ADE is associated with lower mortality 0.71
observational study (95% CI 0.63 to 0.80)

Ying Guo 2016 SR and MA of 9 Mortality trended lower in ADE group as

studies compared with the continuation of broad-
spectrum antibiotics group. (RR ¼ 0.74,
95% CI 0.54e1.03).

Alexis Tabah 2016 SR and MA of 2 Pooled effect of ADE on mortality is

RCT and 12 cohort protective (relative risk, 0.68; 95%
studies confidence interval, .52–.88).
Intravenous to oral switch in ICU patients

• Early intravenous to the oral transition of antibiotics reduces hospital length of stay
and cost of care.

• There is no increase in mortality or other adverse events when this is done after
assessing as to which patients can be safely transitioned to oral therapy.
• Hemodynamically stable,

• source control measures have occurred,

• Insufficient intestinal absorption are not present

• Susceptibility to an appropriate oral agent is demonstrated,

• Intervention
• Early switch ( within 3 days) to oral antibiotics with the standard 7 day course of
intravenous antibiotics in severe community acquired pneumonia.
• Results
• Total of 265 SCAP patients were studied randomly assigned in the two groups .
• Mortality at day 28 was 4% vs 6% ,clinical cure (83%vs 85%) and reduced length of
hospital stay (1.9 days (9.6 (5.0) v 11.5)
• Conclusions
• Early switch from intravenous to oral antibiotics in patients with SCAP is safe and
decreases the length of hospital stay by 2 days.
Duration of antimicrobial treatment

• Reduction in the length of antibiotic courses result in reduction AMR , adverse

effects, collateral damage and costs.

• Short antibiotic courses (< 7 days) are sufficient for most infections in critically ill
patients, with a few exceptions when source controlled

• In case of prolonged neutropenia, lack of adequate source control, infection due to

XDR GNB, and endovascular or foreign body infections short course might be
determinantal
Guideline Recommendations
Surviving Sepsis • Suggested suggest using shorter over a longer duration of
Campaign: 2021 antimicrobial therapy( About on average 7 days), especially in
the case with good source control
IDSA:HAP/VAP 2016 • VAP, we recommend a 7-day course of antimicrobial therapy
rather than a longer duration
ERS/ESICM/ESCMID • Suggest using a 7–8-day course of antibiotic therapy in patients
HAP/VAP-2017 with VAP without immunodeficiency, empyema, lung abscess,
cavitation or necrotizing pneumonia and with a good clinical
response to therapy
India 2019:ICU Abx • Short course (7-8 days) of antibiotic therapy should be used
prescription • Patients with CAP requiring ICU admission should receive
antibiotics for 7 to 10 days
• Treatment strategies

• Empirical therapy

• Pathogen directed therapy

Empirical antimicrobial therapy

• It most often used when antibiotics are given to a patient before the specific
microorganism causing an infection is known.

• When determining empiric treatment for a given patient, clinicians should also
consider:

• Antibiotic exposures within the past 30 days

• Local susceptibility patterns for the most likely pathogens.

• Identifying risk factors for MDRB pathogens

Illness Recommended empirical therapy

HAP • Selection based on the risk factors for MRSA(high risk, no risk)
• Cefepimed/ceftazidimed 2 g IV q8h/Meropenemd 1 g IV q8h/Amikacin
15–20 mg/kg IV daily Plus Vancomycin 15 mg/kg IV q8–12h/Linezolid
600 mg IV q12h
VAP • Cover MRSA,P.aeruginosa & other GNB in all empiric regimens
• Vancomycin 15 mg/kg IV q8–12h or Linezolid 600 mg IV q12h Plus
Cefepime 2 g IV q8h/Ceftazidime 2 g IV q8h/Meropenem 1 g IV q8h
Plus Ciprofloxacin 400 mg IV q8h/Amikacin 15–20 mg/kg IV
q24h/Gentamicin 5–7 mg/kg IV q24h/Polymyxins
Sepsis and • High risk of MRSA, use empiric antimicrobials with MRSA coverage
septic shock • High risk for MDR organisms, we suggest using two antimicrobials with
gram-negative coverage for empiric treatment over one gram-negative
agent
Treatment of MDR bacteria in ICU patients

• The treatment of MDR-GNB infections in critically ill patients presents many

challenges

• local microbiological epidemiology remain critical for defining the baseline risk of
MDR-GNB infections and firmly guiding empirical treatment choices

• An effective treatment should be administered as soon as possible, but resistance to

many antimicrobial classes invariably reduces the probability of adequate empirical
coverage,
Amikacin 20 mg/kg/dose IV x 1 dose, ESBL-E, CRE, DTR-
P. aeruginosa
Cefepime 2 g IV q8h, over 3 hours CRAB
Ampicillin- CRAB
9 g IV q8h over 4 hours OR 27 g IV
sulbactam
q24h as a continuous infusion
Gentamicin 7 mg/kg/dose IV x 1 dose ESBL-E, CRE, DTR-P. aeruginosa
Levofloxacin 750 mg IV/PO q24h ESBL-E,S. maltophilia
Meropenem ESBL-E,1-2 g IV q8h over 30 m, ESBL-E, CRE, CRAB
CRE & CRAB: 2 g IV q8h over 3
hr
Tobramycin 7 mg/kg/dose d IV x 1 dose ESBL-E, CRE, DTR-P. aeruginosa
Polymyxin B 2.0–2.5 mg/kg (20,000–25,000 IU/kg) over 1 DTR-P. aeruginosa, CRAB
hour loading ,then1.25– 1.5 mg/kg (12,500–
15,000 IU/kg) every 12 hr is infused over 1
hour

Colistin loading of 300 mg Colistin based activity CRE cystitis, DTR-P.

(polymyxin E) (CBA (~9m IU) infused over 0.5–1 hours aeruginosa cystitis, CRAB
and to administer the first maintenance dose cystitis
12–24 hrs later. 300–360 mg CBA (~9–10.9
million IU), divided into two

Trimethoprim- 8-12 mg/kg/day IV/PO divided q8-12h ESBL-E

sulfamethoxazol (max in 960 mg per day) S. maltophilia
e
Trimethoprim-sulfamethoxazole vs. colistin or ampicillin–sulbactam for the
treatment of carbapenem-resistant Acinetobacter baumannii:
A retrospective matched cohort study

• Results
• Fifty-three patients treated with TMP/SMX and 83 matched patients treated
with colistin or AMP/SUL were included.
• All-cause 30-day mortality was lower with TMP/SMX compared with the
comparator antibiotics among all patients (24.5%, 13 of 53 vs. 38.6%, 32 of
83, P = 0.09)
• Treatment failure rates were not significantly different overall (34%, 18 of 53
vs. 42.4%, 35 of 83, P = 0.339)
• Time to clinical stability and hospitalization duration were significantly
shorter with TMP/SMX.
In summary
Reference

• International Consensus Guidelines for the Optimal Use of the Polymyxins:

• IDSA 2022 Guidance on the Treatment of MDR-GNB

• European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

guidelines for the treatment of infections caused by multidrug-resistant Gram-
negative bacilli

• Other local and international journals

• Thank You