This will be an eye opener for antimicrobial prescribers..

1. How to minimize therapeutic failure
in infectious diseases: clinical
microbiology perspectives
Dr. J.A.A. Sampath Jayaweera
MBBS, PG Dip in MedMicro, MSc-BioStat, MPhil, MD in Micro, FRSPH (UK)
Head/Senior Lecturer - Department of Microbiology
Faculty of Medicine and Allied Sciences
Rajarata University of Sri Lanka, Saliyapura
3/9/2020 1

2. Therapeutic failure….
• Failure to accomplish the goals of treatment resulting from
inadequate or inappropriate drug therapy and not related to
the natural progression of disease (1)
• The detection of treatment failure is mostly based on objective
clinical criteria (2)
• Less well-defined- subjective decisions of the treating
physicians (3)
1. Sanchez Garcia M (2018) Early antibiotic failure. Int J Antimicrob Agents 34(S14):S19
2. Talbot GH (2019) The early response end point in clinical trials not just for FDA anymore? Infect Dis Clin Pract 22(6):307–308
3. Joung MK, Lee JA et al (2018) Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia. Crit Care 15(2):R79
3/9/2020 2

3. 3/9/2020 3

4. Therapeutic failure….
• Responders vs non-responders
• Reasons ???
3/9/2020 4

5. 3/9/2020 5

6. Host ….
• Immunity
• Comorbidities -Obesity
• ICU/HDU with support
Bed ridden – immobile – natural defense ?
Foreign (invasive devices)
Fluid re-distribution (Volume of distribution)
• Surgery
• Metabolism – variability
• Microbiome – commensal
• Sepsis
3/9/2020 6

7. Microbe (pathogen-bug)
• Microbial biomass
• Virulence
• Speciation
• Anti-microbial susceptibility – MIC
• Superinfection
• Anti- microbial resistance (AMR)
• Biofilm
4.Leekha et al (2018) General Principles of Antimicrobial Therapy. Mayo clin proce. 88(2): 156-67
3/9/2020 7

8. Drug (anti-microbial)
Drug related vs Practice related
Drug related
• Product (API and excipient)
• Drug potency
• Drug interaction
3/9/2020 8

9. Drug – Practice related
• Appropriate timing
• Use of appropriate antibiotic – empiric !!!
• How to target – initiate the targeted therapy
• Dose
• Dose optimization
3/9/2020 9

10. Drug – Practice related
• Escalation or de-escalation (streamline)
• IV to oral switch
• Drug level monitoring
• Adverse effect monitoring
3/9/2020 10

11. KEY…………..
Diagnosis ???
3/9/2020 11

12. Practice related….
 Appropriate timing
 As early as possible
Patient delay
Medical practitioners delay
Treatment delay
-Sepsis, bacterial meningitis, FN
Time critical ……
3/9/2020 12

13. Identification of sepsis
• Clinical vigilance
• NEWS (2) is an aggregate score made up of six physiological parameters,
Respiratory Rate, Oxygen saturations, Systolic BP, Pulse rate, Level of
consciousness (AVPU score), and Temperature
NEWS score of ≥ 5 -presence of known infection, signs or symptoms of
infection, or who are at elevated risk of infection
Frequent monitoring
3/9/2020 13

14. Identification of sepsis
• Nice Guidance NG51
• Sepsis -3 groups q SOFA
QX Calculator
3/9/2020 14

15.  Appropriate timing
• Soon after taking appropriate cultures/ specimen
• SABE frequently ill for a period
• Vertebral osteomyelitis/diskitis
We can wait !!! Take samples and arrive a definitive microbiological
diagnosis Go targeted therapy
5.Bassetti et al.(2018) When antibiotic treatment fails. Intensive Care Med 44:73–75
3/9/2020 15

16.  Use of appropriate antibiotic
 Empiric therapy – this must be appropriate
How we select- Depends on ……
• Diagnosis (viral vs bacterial) – availability of rapid diagnostics ….
• Clinical history – is it CA or HA (nosocomial) ?
• Site of infection – probable microbe ???
1.Pneumonia CA- common pneumococci, HI and atypical (Mycoplasma, Legionella,
Chlamydia sp.)
If it is HA ( Pseudomonas Sp. or MAAS/MRSA)
or VAP (Acinetobacter or Pseudomonas Sp. or MAAS/MRSA )
3/9/2020 16

17. Clinical history…..
2. Cellulitis- MSSA, MRSA and S. pyogens
3. IE- Is it Acute or sub-acute
Native valve or prosthesis
Right side vs left
4. UTI – CA or HA ( catheter ?) – MDR ???
E.coli Susceptible vs MDR
3/9/2020 17

18. To decide empiric therapy
we need local epidemiology data – lacking at country level
• MRSA - During the 18-month period (2013-14), 13,260 blood cultures were
investigated for possible bacteremia and 1352 of those were identified as
bacteremia.
Of these 4.5% indicated the presence of MRSA.
HA MRSA bacteremia - 3.03%
• But high ESBL – need data
• CRE-
• VRE-
• VISA and VRSA- 0%
6. Jayaweera et al. (2017) Prevalence of methicillin resistant Staphylococcus aureus (MRSA) bacteremia at Teaching Hospital
Anuradhapura, Sri LankaMRSA Cey Med J 62 (2), 110-111
3/9/2020 18

19. Previous colonization ….
• Knowledge of bacteria known to colonize a given patient (eg, a screening
nasal swab – awaiting prothesis implant or CABG)
• VRE ?
• CRE ?
7. Jayaweera et al. (2018) Antimicrobial misuse in pediatric urinary tract infections: recurrences and renal scarring. Annal Clin Micro
and antimicro 17(27): 122-134
3/9/2020 19

20. Empiric therapy …..
Inadequate therapy for infections in critically ill- associated with poor
outcomes
• Broad-spectrum antimicrobial agents as initial empiric therapy is advised
• Combined therapy
CA- Pneumonia beta lactam with macrolide
FN- Piperacillin- tazobactam + Aminoglycoside (for Pseudomonas sp.)
Avoid double beta-lactam therapy except-
Use of MASCC score for FN
3/9/2020 20

21. How to target…
• Once culture with susceptibility report is available
narrower spectrum
• Reduce cost and toxicity and prevent the emergence of antimicrobial
resistance in the community
3/9/2020 21

22. Dosage….
• Weight based formula ( kg/ per dose or day)
• Appropriate frequency (ceftazidime 8 hourly, Ciprofloxacin 12 hourly except
Pseudomonas bacteremia, Ceftriaxone for IE – can give as daily)
• Appropriate duration
IE right vs left
Melloidosis (bacteremia with focus vs without focus)
Septic arthritis
Osteomyelitis
Bacteremia
Pneumonia
3/9/2020 22

23. Dose optimization
Utmost important
• Depends mainly on MIC
• Depends on hepatic and renal function – calculation of eGFR
WHY ? – to reduce the nephrotoxicity (aminoglycosides/ glycopeptide)
- to reduce the accumulation (beta- lactams/ quinolones)
- Tigecycline in moderate hepatic impairment
High dose- toxicity
Low –dose- treatment failure and emergence of AMR
3/9/2020 23

24. Escalation or de-escalation (streamline)
Can decide on clinical response and markers of inflammation
• CRP and PCT
8.Okzus et al. (2018) Procalcitonin and C-reactive protein in differentiating to contamination from bacteremia. Braz jour micro
45(4): 1415-1421
3/9/2020 24

25. Escalation or de-escalation (streamline)
• Policies –
Initiate with broad spectrum and later
de-escalate and vice versa
The most common mistake made with
apparent antibiotic failure is to change
or add antibiotics- irrationally !
9.Montero et al (2015) Antibiotic de-escalation in the ICU. how is it best done? Curr ope infect dise 28(2): 192-202
3/9/2020 25

26. Drug level monitoring
Therapeutic drug monitoring (TDM)
Important to:
- Minimize drug toxicity
- Optimize the dose
Vancomycin - Trough level
Aminoglycosides - peak (Harford nomogram)
Amphotericin B
Voriconazole
10.Talbot GH (2019) The early response end point in clinical trials not just for FDA anymore? Infect Dis Clin Pract 22(6):307–308
3/9/2020 26

27. Adverse effect monitoring
Dose related
• ARF (S Cr.)
• Acute hepatic damage (LFT)
• Myelo-suppression (WBC/DC)
• CDI
Administration method related
• Red man syndrome (vancomycin > 10 mg/min)
• Renal failure (Conventional Amphotericin B) Pre and post dose hydration !
11.Heenen S, Jacobs F, Vincent J-L. Antibiotic strategies in severe nosocomial sepsis: why do we not deescalate more often?
Crit Care Med 2012; 40:1404–1409.3/9/2020 27

28. Exclusion of true allergy …
• Penicillin allergy – 1 % in nature but we may false categorize as 8%
• Penicillin/ beta- lactam – compared to alternatives has less mortality
advantage
• Clinical history and investigations- major and minor component
detection assays
3/9/2020 28

29. IV to oral switch
• Ideal for chloramphenicol, clindamycin, metronidazole, trimethoprim-
sulfamethoxazole, fluconazole, itraconazole, voriconazole, doxycycline,
minocycline, levofloxacin, moxifloxacin, and linezolid
• Similar IV counterpart to oral
• With clinical response in 2-4 days in hand with inflammatory markers
80% reduction of CRP or PCT
12.IDSA Antimicrobial stewardship 2015
3/9/2020 29

30. Follow up ……
• Bacterial clearance - S. aureus bacteremia
Repeat blood culture at 72 hours following initiation of anti- S. aureus antibiotics
• - UTI
3 days following completion of antibiotics can do a urine culture
CRP and PCT
• Chronic infections- monitor ESR (weekly) and CRP
• Mucormycosis – weekly FESS and fungal culture
• OPAT !!!
3/9/2020 30

31. Reason for failure – except antibiotic failure
• Wrong diagnosis
• Persistence of inflammation – use of steroids
• Complications
• Inadequate source control – abscess and FB ( I & D, aspiration)
• Chemotherapy – FN
13.Peetres et al. (2019) The impact of initial antibiotic treatment failure: real-world insights in patients with complicated, health
care-associated intra-abdominal infection Infe drug resist 12:329-343
3/9/2020 31

32. 3/9/2020 32

33. THANK YOU
3/9/2020 33