Strategies in choosing best

antimicrobial in managing
complicated infection issues:
MDR, XDR, HAI infections
Piotr Chlebicki
Associate Professor, Duke-NUS Medical School
Senior Consultant
Department of Infectious Diseases
Singapore General Hospital
November 2018
Case 1
 52 year old man, complains of fever, and
cough for 3 days

 Which antibiotic is appropriate?

 (There is only one honest answer)

Case 1 corrected
 52 year old man, PMH of DM, smoker, complains
of fever and cough for 3 days.
 No recent admissions or antibiotics
 120/70 HR 80, RR 18, 38.1°C
 Crepitationss over right lung
 Which antibiotic is appropriate?
 Step 1?
Step 1. Define the problem
 It is important to be precise
 Not UTI but cystitis, prostatitis or
pyelonephritis
 Not RTI but pneumonia, sinusitis or lung
abscess

 What is the Step 2?

Step 2. How severe?
 All guidelines convey similar message – if
disease is severe then
 More investigations
 Different care setting
 More aggressive therapy

 ICU patients may require broad initial

coverage followed by de-escalation
 Appropriate cultures are essential

Does our patient have severe infection?

Or quick SOFA…
Please note that
 Common scores of severity do not include
fever or WBC count

 Change is mental state, high respiratory rate

and hypotension are much better “markers” of
severity
Please do not use SRIS criteria
.
 Systemic Inflammatory response syndrome.
Two or more of the following:
 Body temperature >38°C or <36°C
 Heart rate > 90/min
 Hyperventilation –RR > 20/min or PaCO2 < 32
mmHg
 WBC count >12,000 cells/μl or < 4,000/μl

Critical Care Med 1992;20:864–874

Severity impacts diagnostic testing
 Mild infection = testing optional
 More severe infection = more testing

 How useful is blood culture in such case?

Step 3. Risk of MDRO?
 Nosocomial or community acquired infection?
 Risk factors for acquisition of drug resistant
organisms?
Vicious circle
 Patients at risk of MDR infection
 old, sick, stay longer in hospital
 undergo multiple invasive procedure
 receive a lot of antibiotics

 As a result they
 stay even longer
 require additional procedures
 get more antibiotics
 pay more money
 and die more frequently
Sensitive vs MDR
Step 4. Is this patient
immunocompromised?
 The answer should not be simply yes or no
 Burden of immunosuppression

 What next?
What is Step 5?
 List possible pathogens
 Simply creating the list is not always sufficient
 It is important to know local epidemiology and
resistance patterns
Bacteria by site of infection
Mouth Skin/Soft Tissue Bone and Joint
Peptococcus S. aureus S. aureus
Peptostreptococcus S. pyogenes Streptococci
N. gonorrhoeae

Abdomen Urinary Tract Upper Respiratory

E. coli E. coli, Proteus Viruses
Klebsiella Klebsiella
Enterococcus Enterococcus
Bacteroides sp. Staph saprophyticus

Lower Respiratory Lower Respiratory Meningitis

Community Hospital S. pneumoniae
S. pneumoniae K. pneumoniae N. meningitidis
H. influenzae P. aeruginosa H. influenza
K. pneumoniae Enterobacter sp. Listeria
Legionella pneumophila Serratia sp.
Mycoplasma, Chlamydia S. aureus
Local epidemiology
Antibiogram
MDROs in Indonesia
 How resistant are bacteria in your hospital?
Guideline
Final steps
 6. Choose antibiotic
 7. Propose duration
Duration of Therapy

JAMA 2003
Guideline
Case 2
 A 59-year-old man with PMH of DM was
admitted because of erythema, swelling, and
purulent discharge over the left foot that
slowly worsened over 2 weeks
 He was diagnosed with DM 11 years ago
 HbA1C = 9.9%
 Impaired vision due to DM retinopathy
 He had DM foot infection and required big toe
amputation 3 years ago
Physical examination
 BP 140/70, HR 86/min, RR 18, 36.7C
 Non toxic
 Pedal pulses were not palpable but popliteal
pulses were present. There was a 2 x2 cm
ulcer over the plantar aspect of the right foot
foot.
 Purulent discharge was present
Summary = 7 steps

 1. Define the problem/disease/syndrome

 2. Severe?
 3. At risk of MDRO?
 4. Immunocompromized?
 5. List possible bacteria and consider local
resistance patterns
 6. Pick the best antibiotic
 7. Decide duration
Progress
 He was admitted to general ward and started
on ceftazidime and metronidazole without any
cultures
 5 days later he did not improve and swab
culture was performed
 It grew Pseudomonas aeruginosa resistant to
all antibiotics except amikacin and colistin
 He was started on IV amikacin but did not
improve
 Is this correct approach and
management?
Swab culture

 CID 2006; 42:57–62

 76 patients (81 episodes of OM) with foot OM who
had positive culture of bone biopsy specimens
 results of concomitant foot ulcer swabs were
available for 69 of 76 patients.
 75% of cultures were Gram positive
organisms
Very poor concordance = 22.5%
 The concordance between the results of
cultures of swab and of bone biopsy
specimens was

 Staphylococcus aureus 42.8%

 GNBs 28.5%
 Streptococci 25.8%


More on swabs

 Mackowiak et al JAMA 1978;239:2772-5

 40 patients with chronic osteomyelitis
 Sinus-tract cultures were compared with
cultures of operative specimens
More on swabs
 Only 44% of the sinus-tract cultures
contained the operative pathogen
 Isolation of Staphyloccus aureus from sinus
tracts correlated with the presence of
Staphylococcus aureus in the operative
specimen

 For Pseudomonas aeruginosa correlation

was 0%
Swabs
 Correlation of swab culture with deep
specimen is very poor
 It may be slightly better for Staphylococcus
aureus
We should have done it better…
 He was started on ceftazidime and
metronidazole without any cultures
 We should have done tissue culture on
admission
 Swab culture should be avoided but deep
tissue culture can be considered
 OT culture would be perfect
We should have done it better…
 He was started on ceftazidime and
metronidazole without any cultures
 Initial treatment – depends on local
situation but IV Augmentin should cover
all important organisms
 If patient was previously on oral
antibiotics IV piperacillin/tazobactam is
also an option
We should have done it better…
 3 days later he did not improve and swab
culture was performed
 It grew Pseudomonas aeruginosa resistant to
all antibiotics except amikacin and colistin
 He was started on IV amikacin but did not
improve
 Pseudomonas is likely colonizer but
unlikely culprit.
 If not better we should ask why this
patient is “non-responder”?
4. Non-responders
 1. Wrong antibiotic?
 2. Correct antibiotic but is it “source control”
issue?
 3. Or can it be “non-infective” issue?
(ischemia?)
Progress
 Because of lack of response he was taken to
OT
 He required amputation

 One day later he developed cough, shortness

of breath and hypotension.
 BP 80/50, HR 120/min, RR 32, temp 39.5
Chest X-ray
Summary = 7 steps

 1. Define the problem/disease/syndrome

 2. Severe?
 3. At risk of MDRO?
 4. Immunocompromized?
 5. List possible bugs and consider local
resistance patterns
 6. Pick the best antibiotic
 7. Decide duration
Severity impacts diagnostic testing
 Mild infection = testing optional
 More severe infection = more testing

 Should we do blood culture?

Blood culture
Carbapenem non-susceptible isolates

ESBLs +
AmpC +
Impermeability

Carbapenemases
Acquired Carbapenamases

Molecular Enzyme Found in

class
A IMI, GES, KPC Enterobacteriaceae
Pseudomonas
Acinetobacter

B IMP, VIM,NDM Enterobacteriaceae

Metallo - GIM,SIM, Pseudomonas
AIM,DIM Acinetobacter
lactamase
D OXA (OXA-181) Acinetobacter
Klebsiella OXA-48 types
 CRE infection is associated with
high mortality
Number of Crude mortality
patients (one month)

Tumbarello et al 125 42%

(2012), Italy

Zarkotou et al 53 53%
(2011), Greece

Qureshi et al 41 39%
(2012), USA
Epidemiology in Singapore
 Started in 2010
 It really took off in 2012
 Initially “imported” but now almost all “local”
 My hospital is a at the “eye of hurricane”
 It took off in 2012
20.0
% carbapenem non-susceptibility (%)

18.0

16.0

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.0
2011 2012 2013 2014 2015*
Klebsiella spp. E. coli Enterobacter spp.

Courtesy of Jocelyn Teo

Types of CRE in Singapore
 50-60% KPC
 15-20% NDM
 15-20% OXA
 Very few other types
Treatment
 Not a lot of choices left:
 A. Polymyxin B and colistin
 B. Tigecycline
 C. Fosfomycin
 D. Aminoglycosides

 E. Combination therapy
Bigger is not always better
Meropenem Polymyxin B
 Polymyxin B Colistin
Form Active drug Prodrug
Slow conversion
Lading dose Recommended Essential

Renal adjustment Not required Very complex

Dosing units 10000IU = 1 mg Complex

conversion
CBA/CMS/IU
Urinary levels +/- ++

Nephrotoxicity ++ +++
*22 studies fulfilled inclusion criteria
*3 studies were RCTs and rest were
retrospective observational
*All 3 tested combinations against AB (in 2
colistin/riampicin in 1 colistin/fosfomycin)
Results
 Majority of retrospective studies showed that
polymyxin or colistin monotherapy was
associated with higher mortality

 All 3 randomized trials showed no

difference in mortality
Methods
 Investigator-initiated, multicentre, open-label, parallel group randomised
controlled trial
 6 hospitals participated  3 in Israel, 2 in Greece and 1 in Italy
 Patient enrolled between 1st Oct 2013 til 31st Dec 2016
 Randomised into colistin monotherapy arm and colistin-meropenem
combination therapy arm
Colistin monotherapy Colistin-Meropenem combination therapy
IV Colistin methanesulfonate 9MIU loading IV Colistin methanesulfonate 9MIU loading
-
dose, followed by 4.5MIU BD dose, followed by 4.5MIU BD

IV Meropenem 2g prolonged infusion(3-hours)

Q8H
Allow addition of Abx targeting Gram +ve or anaerobic co-infections, but not for Gram -ve bacteria
systematically ot inhalationally
Conclusion
 Colistin-meropenem combination therapy did not
results in better outcomes compared with colistin
monotherapy in A.baumannii infection
[RR 0.93, 95% CI 0.83-1.03]
 Increased diarrhoea side effects with combination
therapy
One size may not fit all
Customized based by type of CRE
 Metallo-beta-lactamase? (NDM?)
 Polymyxin B/tigecycline/fofomycin
 Aztreonam?
 Other CRE (KPC?)
 Carbapenem prolonged infusion
 Plus polymyxin B
 +/- tigecycline or fosfomycin (?)
 Ceftazidime/avibactam if available
 Laboratories would have to develop rapid
testing Perez et al, Expert Opinion on Pharmacotherapy,
2016:17;761-781
Our patient
 It was fast established that it was KPC
 Meropenem MIC was 8
 Patient was treated with high dose/prolonged
infusion of meropenem AND polymixin B
 He improved
Summary = 7 steps

 1. Define the problem/disease/syndrome

 2. Severe?
 3. At risk of MDRO?
 4. Immunocompromized?
 5. List possible bacteria and consider local
resistance patterns
 6. Pick the best antibiotic
 7. Decide duration