Antibiotic Stewardship and

returning travellers for 6th years

Marc Mendelson
Division of Infectious Diseases and HIV Medicine
Groote Schuur Hospital, University of Cape Town

6th year class lectures • GSH • 8th March 2013 • AS and Travel Medicine
 Antibiotic Class Mechanism of Action Examples

b-Lactam Inhibit cell wall synthesis by inhibition of Penicillin Binding • Penicillin, ampicillin, Amoxycillin
• Penicillins Proteins (PBPs) = enzymes involved in formation of X-links that • Ceftriaxone, Ceftazidime, Cefimpime
• Cephalosporins bridge peptidoglycan giving it structural integrity • Ertapenem, Imipenem, Meropenem
• Carbapenems • Aztreonam
• Monobactams

Aminoglycosides Inhibit protein synthesis by binding to bacterial ribosomes • Gentamicin

• Amikacin
• Kanamycin
• Streptomycin

Tetracyclines Inhibit protein synthesis by binding to bacterial ribosomes • Doxycycline

Macrolides and ketolides Inhibit protein synthesis at the stage of chain elongation • Erythromycin, Clarithromycin
• Azithromycin

Sulfonamides and Inhibit folic acid synthesis • Cotrimoxazole

trimethoprim • Trimethoprim

Quinolones Inhibit bacterial DNA synthesis by inhibition of DNA gyrase & • Ciprofloxacin
topoisomerase IV • Moxifloxaxin

Polymixin Disrupt cell membrane phospholipids and bind to endotoxin • Colistin

Glycopeptide Inhibit cell wall synthesis targeting peptidoglycan precursors, • Vancomycin

murein monomers
 Enzyme inhibition Decreased
(b-lactamases) permeability

Bypass the inhibited Mechanisms of

Efflux pumps
process Antibiotic Resistance

Alteration in target Protection of target Overproduction of

sites sites target
 Major groups of b-lactamases in GNB

Class Common name b-lactams to which resistance is conferred

C Cephalosporinase Penicillins, Cephalosporins

A Penicillinase Penicillins, early Cephalosporins

Extended Spectrum Penicillins, Cephalosporins, Monobactams,

A
b-lactamase (ESBL) b-lactamase inhibitor combinations

D Cloxacillinase Penicillins, including oxacillin and cloxacillin

D Carbapenemase Carbapenems and other b-lactams

A Carbapenemase All current b-lactams

B Metallo-b-lactamase All b-lactams except monobactams

 Selection of antibiotic resistant
bacteria

Antibiotic replication

Sensitive bacterium

Resistant bacterium
 A Perilous Cycle
MDR/PDR ?
bacteria
Penicillin
sensitive

Colistin Cephalosporin

ESBL-Producing
bacteria

Carbapenem Carbapenem
resistant
New 'superbug' found in UK hospitals States step up alert for new cases of Bacteria KPC
KPC = Klebsiella pneumoniae
carbapenemases

GES = Guiana extended-spectrum

b-lactamases

NDM = New Dehli metallo-b-

lactamases

OXA-48 = Oxacillinase-type
carbapenemases

VIM = Verona integron-encoded

metallo-b-lactamases

SAMJ 2012; 102(7): 599-601

The New Delhi Metallo-b-lactamase-1
(NDM-1) plasmid
• Resistance to
– b-lactams
– Aminoglycosides
– Fluoroquinolones
• Multiple efflux pumps
• Resistance gene to uv
light
• Mobile insertion
sequence i.e. can jump
between plasmids
Simultaneous prescription of antibiotics in
the PISA study

Example: 1 patient
simultaneously
received:
Cloxacillin
Teicoplanin
Metronidazole
Amikacin
Ceftazadime
Meropenem
Levofloxacin
Erythromycin
Co-trimoxazole
Fluconazole

Paruk et al. SAMJ 2012; 102(7): 613-6

 Association between antimicrobial use and
emergence of antimicrobial resistance
Hospital therapeutics
Manufacturers presented data committee restricted
showing cost savings when using use of imipenem Relaxation of imipenem
imipenem for HAI and secondary restriction in the hospital
peritonitis.

Lepper PM et al. Antimicrob Agents Chemother 2002;46:2920-5.

Other associations between antimicrobial use and
emergence of antimicrobial resistance

• Resistance is more common in hospital-acquired infections

• Patients with resistant strains more likely to have received prior

antimicrobials

• Areas with highest rates of resistance = highest rates of use

• The longer a patient is on antimicrobials the more likely they

are to be colonized with resistant organisms

Antibiotic resistance impacts on outcome
Length of Attributable
Survival
Hospital stay cost ($) Reference

JAMA 1999;
MRSA vs MSSA Decreased in 282:1745-51
Not reported 9,275 – 13,901 Clin Infect. Dis.
bacteraemia or SSI MRSA group
2003;36:592-8

Arch Intern Med

VRE vs VSE 1998;158:552-7
24% vs 59% 34.8 vs 16.7 days 27,190 Clin Infect. Dis.
bacteraemia
2005;41:327-33

Ceph-resistant
RR of death Increased LOS Arch Intern Med
enterobacter 29,379 2002;162:185-90
5.02 x1.5
bacteraemia
The Gram negative antibiotic pipeline
for the next 15-20 years

http://www.mistymountaingraphics.com/gallery6.html
 The Critical Balance

Importance of
empiric therapy
Antibiotic use
drives resistance
 Early, appropriate therapy
is key to survival
Survival – Patients with Septic Shock
82%
77%
70% n = 2,731
61%
57%
50%
43%

32%
26%
19%
9%
5%

0- 0.5 1- 2- 3- 3- 5- 6- 9- 12 24 >3
0.5 -1 2 3 4 5 6 9 12 -2 -3 6
4 6
Time to Appropriate Antimicrobial Rx following Onset of Hypotension (Hrs)

Kumar et al. Duration of hypotension before initiation of effective antimicrobial

therapy is the critical determinant of survival in human septic shock. Crit Care Med.
2006 Jun;34(6):1589-96.
 Antibiotic prescription in
South African ICUs (PISA study)

Paruk et al. SAMJ 2012; 102(7): 613-6

 The solution?
Antibiotic Stewardship
Aims of an Antibiotic Stewardship Program

• Improve care by maximizing cure or prevention

• Limit inappropriate use and optimize selection,

dose, route and duration
• Limit unintended consequences
– Emergence of resistance

– Adverse events
– Cost
 Optimal Elements of an ASP
Active monitoring of
resistance

ASP

Fostering appropriate Effective IPC to

antimicrobial use Reduce 2o spread
AS messages must be simple

Slide courtesy of D. Goff

 Front End Interventions

• Audit and intervention by trained specialist

• Formulary restriction and pre-authorisation

• Feedback

• Guidelines and algorithms

 Importance of Feedback
• Remote video auditing of • 432,482 hand
hand hygiene compliance hygiene observations
in ICU at a US hospital
over 25 months
• Sensors in doorway
• Compliance was
identified when a person
entered/exited 6.5% without
• Compliance measured feedback
with and without
feedback

Armellino et al. Clin Infect Dis.

Compliance increased to 87.9% with immediate feedback
Armellino et al. Clin Infect Dis.
 Back End Interventions

• Antibiotic prescription charts with stop

orders

• De-escalation of antibiotics

• Dose optimization

• Early switch from intravenous to oral

C
 De-escalation of antibiotics requires
knowing which bacteria you are dealing
with
Pre-test probability of a positive
blood culture depends on the
specific clinical condition

Coburn et al. JAMA 2012; 308(5):502-11

 Procalcitonin (PCT)
• Produced in response to bacterial endotoxin or other
mediators (IL-1b, TNFa, IL-6) released in response to
bacterial infection
• Up-regulation attenuated by IFNg

• Levels
– Increase within 6-12h of infection
– Correlate with bacterial load and severity of infection
– Halve daily when infection is controlled
– Not attenuated by steroids
– Not affected by neutropenia
Schuetz et al. BMC Medicine 2011; 9: 107
PCT-guided intervention studies in LRTI

Schuetz et al. BMC Medicine 2011; 9: 107

 Dose Optimization
Cmax = Peak Concentration dependant
Age
Weight Cmax / MIC AUC / MIC
Renal function
Aminoglycosides Aminoglycosides
Pathogen
Fluoroquinolones Fluoroquinolones
Infection Site
Linezolid
Daptomycin
Tetracyclines

Concentration

Time dependant MIC

MIC
T > MIC
Penicillins
Cephalosporins
Carbapenems Cmin = Trough
Macrolides
Vancomycin
Clindamycin
Time
Nicolau DP. J Infect Chemother. 2003;9:292-296. Ambrose PG. Clin Infect Dis.
 Conversion of IV to oral antibiotics

• Drugs with high oral bioavailability

– Fluoroquinolones
– Clindamycin
– Metronidazole
– Cotrimoxazole
– Linezolid
– Fluconazole
– Voriconazole
 Infectious Diseases Specialists

Microbiologists
GSH ASP
Team
Registrars

Infection Control Nurses Ward Pharmacist Statistician

 GSH ASP
3-pronged attack

Education

AS Ward
Rounds Antibiotic chart
SPECTRUM OF ANTIBIOTIC ACTION

Antibiotics primarily used for their

action against gram-negative
organisms
haemophilus

NEWER CEPHALOSPORINS

neisseria staphylococci
streptococci
enterobacteria
(aerobic gram
negative bacilli) Notice that most of
these cephalosporins
still have activity
against gram-positive
cocci, haemophilus
and neisseria.
haemophilus

NEWER CEPHALOSPORINS
staphylococci Notice that
neisseria
ceftazidime has lost
streptococci most of its useful
enterobacteria activity against gram
(aerobic gram positive cocci.
negative bacilli)
pseudomonas

CEFTAZIDIME
 Cefoxitin is the only
cephalosporin
(available in SA) to
haemophilus
have useful activity
NEWER CEPHALOSPORINS against anaerobic
organisms.
neisseria staphylococci
streptococci
enterobacteria
(aerobic gram
negative bacilli)
pseudomonas
anaerobes
CEFTAZIDIME
CEFOXITIN
 Cefepime is a “4th
generation”
haemophilus cephalosporin and is
very broad spectrum
NEWER CEPHALOSPORINS but has no activity
against anaerobes.
neisseria staphylococci
streptococci
CEFEPIME
enterobacteria
(aerobic gram
negative bacilli)
pseudomonas
anaerobes
CEFTAZIDIME
CEFOXITIN
Antibiotic Stewardship Apps
22
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1039 charts reviewed on 38 rounds in 2 medical
 Absolute numbers of antibiotic units used
4000
Reduction antibiotic costs
3500 Jan – June 2011 = R573,836
Jan – June 2012 = R358,685
3000 Reduction = R215,151 [37.5%]

2500

2000
2011
2012

1500

1000

500

0
 The Ten Commandments of AS
1. Not everyone with a 6. Correct duration

fever needs an Abx 7. De-escalate to narrow

2. Anyone who needs an spectrum ASAP

antibiotic needs a culture 8. IV to Oral switch ASAP

3. Reduce hang time - in 9. Poor clinical response with

severe sepsis give the 1st appropriate Abx – think

absorption or collection
iv dose immediately
10.You are stronger as a team
4. Correct dose
than as an individual
5. Correct route
 An approach to fever in the
returning traveller
Marc Mendelson
Division of Infectious Diseases and HIV Medicine
University of Cape Town
WHERE HAVE
YOU BEEN?
Freedman et al. New Engl. J. Med 2006;354:119-30
When did
you travel?
D’Acrement al el. Rev Med Suisse
Rom 2003; 123: 88-92
 Case 1:
28 year old South African Anthropologist

• 3 day history
– Fever, ‘Chills’, Headache, Vomiting, Myalgia
• 1 day history of deterioration
– Rectal bleeding & increasing confusion
• Travelled to Nigeria to study tribal burial
ceremonies
• Presents 26 days later to GSH
Case 1: The Bleeding Anthropologist
• Examination • Investigations
– Disorientated TPP – Hb 8.3 g/dL
– GCS 12/15 – WBC 2.1 x 109/L
– Febrile 39.2oC – PMN 1.5 x 109/L
– Drip site bleeding – Plt 18 x 109/L
– Petechial rash legs – Creat 289 mmol/L
– Mild splenomegaly – Bil 18 mmol/L
– ALT 30 iu/L
– ALP 98 iu/L
– CXR Normal
 USING WBCs
TO INORM THE
CLINICAL
DIAGNOSIS
WBC Count in Returning Travellers

Leucopenia Leucocytosis Eosinophilia

Malaria Malaria* Schistosomiasis

Typhoid Fever Amoebiasis Filariasis

Arboviruses Pyogenic Hydatid Disease

Rickettsioses Leptospirosis Strongyloidiasis

Brucellosis Borreliosis Trichinosis

Case 1: The Bleeding Anthropologist
• Examination • Investigations
– Disorientated TPP – Hb 8.3 g/dL
– GCS 12/15 – WBC 2.1 x 109/L
– Febrile 39.2oC – PMN 1.5 x 109/L
– Drip site bleeding – Plt 18 x 109/L
– Petechial rash legs – Creat 289 mmol/L
– Mild splenomegaly – Bil 18 mmol/L
– ALT 30 iu/L
– ALP 98 iu/L
– CXR Normal
Case 1: The Bleeding Anthropologist

Differential Diagnosis?
 Differential Diagnosis?
• Malaria
• Malaria
• Malaria
• Typhoid Fever
• Dengue Fever
• Rickettsiosis
• Brucellosis
 Comparing diagnostic tests
for malaria

A single malaria
test does NOT
rule out the
diagnosis of malaria
Uncomplicated Severe
Nature 2009; 462: 298-300
Mechanisms Sequestration in Malaria
 Release of Glycosylphosphatidyl inositols (GPI)
• Stimulates TNF-a and NO release
– Upregulation of EC receptors for cytoadherence
– Induction of thermoregulatory centre Fever
– Inhibit gluconeogenesis hypoglycaemia
– Contributes to endotoxin-like action – shock
– Impaired consciousness via stimulation of iNOS
 Features of severe malaria

WHO guidelines 2010

Breaking the cycle

Schizogony
Broad stage-specificity of artemisinins

Sequestration

White NJ. Science 2008; 320:330-4

 Rationale for antimalarial
combination therapy
Probability of
resistance to
drug A = 1 in
1010

Probability of
resistance to both
drugs
= 1 in 1020

Probability of
resistance to
drug B = 1 in
1010 Parasite biomass normally
= 109 – 1014 parasites
 Artemisinin Combination Therapy
(ACT)
Plasma concentrations after single oral dose
• Rapid reduction parasite
biomass by artemisinin
(~108-fold)
• Rapid resolution clinical
symptoms
• Reduction gametocyte
carriage, reducing
transmissibility
• Active against resistant
P. falciparum
White NJ. Clin Pharmacokinet 1999;37(2):105-25
34.7% reduction mortality in
artesunate vs quinine group
22.5% reduction mortality in
artesunate vs quinine group
 Other benefits of
artesunate over quinine

• Ease of administration
• Minimal affect on blood glucose concentration
• Marked reduction in QTc anomolies
• Rapid resolution of symptoms reducing
hospital stay
• Cost effectiveness
Lubell et al. Trop Med Int Health 2009;14(3):332-7
Lubell et al. Bull World Health Organ 2011;89:504-12
WHO 2011 recommendation for treatment of
severe falciparum malaria

WHO. Guidelines for the treatment of malaria, 2nd edition – Rev.1

Loading dose for Quinine

White et al. AJTMH 1983;32(1):1-5

Why wasn’t this a Viral
Haemorrhagic Fever?
 Viral Haemorrhagic Fevers in Africa
Virus Ebola Marburg Crimean – Lassa
Congo

Electron
micrograph

IP (days) 4 - 16 3-9 3-7 3 - 21

Epidemiology Gabon Angola Burkino Faso Guinea

Sudan DRC DRC Liberia
DRC [Kenya] Kenya Nigeria
Cote d’Ivoire [Uganda] Mauritania Sierra Leone
[Zimbabwe] Senegal
South Africa
Tanzania
Lancet Infectious Diseases 2006; 6: 203-14
 Case 1: Take Home Points
• Incubation period can help rule out/in diagnoses
– Maximum IP for Ebola/Marburg/CCHF/Lassa is 21 days
– Majority of falciparum malaria presents within 3 months

• Any person returning from a malarial area with

fever has malaria until proven otherwise
• Treatment of severe falciparum malaria
– Intravenous artesunate decreases mortality
– 20mg/kg loading dose of iv quinine
WHAT HAVE
YOU BEEN
DOING?
 Case 2:
19 year old UCT Biochemistry Student
• Backpacking in Mexico for 3 weeks
• Returned Cape Town 14th May 2009
• 2 days later
– Fever, ‘Chills’, Sore throat, Headache, Myalgia
– Develops neck stiffness and rash day 4

• Differential Diagnosis?
• What more do you want to know?
 Case 2: The Meningitic
Biochemist
• Examination • Investigations
– Febrile 37.8oC – Hb 12.4 g/dL
– GCS 15/15 – WBC 9.1 x 109/L
– Erythematous pharynx – PMN 4.5 x 109/L

Differential Diagnosis?
– Aphthous tongue ulcer
– Maculopapular rash
– LYM4.0 x 109/L
– Plt 218 x 109/L
– Tattoo on left buttock
• CSF
– Orientated TPP
– L/P/R 129/0/4
– Limited neck flexion
– Prot 0.72
– No focal neurology
– Gluc 3.8
– Gram Negative
 Acute HIV
infection
1200

Death 107
1000

HIV RNA (copies,ml plasms

106
800
CD4 T cells (cells/ml)

Onset of
Clinical latency OIs
105
600

Onset of 104
400 clinical
symptoms

103
200

102
0 3 6 9 12 2 4 6 8 10 12
weeks Years
• 49 travellers returning from tropics with mucocutaneous signs STD

• 64% one partner, 36% multiple

• 63% with locals, 28% other tourists, 8% regular partner

• Condom use in those that had casual sex

– 40% - irregular use, 60% never used condoms

J Travel Med 2009;16:79-83
IMMERSION IN
INLAND
WATERWAYS?
Nature Reviews Immunology 2002; 2(7): 499-511
 Cercarial Dermatitis

5 minutes 10 minutes 20 minutes

http://www.path.cam.ac.uk/~schisto/schistosoma/schisto_lifecycle_infection.
html
Cercarial Dermatitis

http://ourhealthinfo.wordpress.com/
Acute Schistosomiasis
Acute schistosomiasis - Clinical
• Fever 54-100%
• Headache
• Myalgia, Arthralgia
• Dry cough
• Wheeze
• Abdominal pain
• Diarrhoea
• Splenomegaly
• Hepatomegaly
Acute Schistosomiasis - Complications

Confusion and decreased LOC Myocarditis, pericarditis

Seizures Ischaemia
Focal weakness – hemi- or tetraplegias ECG repolarization abnormalities
Visual disturbance Prolonged cough
Ataxia Pulmonary nodules
Incontinence Interstitial pneumonitis

Most et al. Am J Trop Med Hyg 1950;30:239-9 Jaureguiberry et al. Am J Trop Med Hyg 2007;76:964-6
 Acute schistosomiasis – Pathogenesis:
clues from the incubation period

www.wipeout.com.au/articles/beware-
crocodiles.html

Jaureguiberry et al. Clin Microbiol Infect 2010; 16: 225-31

• 1st symptoms 2-6 weeks (1-12 weeks)

• Adult pairing (S.mansoni) 4-5 weeks
Acute Schistosomiasis - Treatment

Should be
repeated
3 months after
last exposure
Assessment of the treated patient
 Chronic schistosomiasis:
A wide spectrum of disease
 Pathogenesis

http://www.path.cam.ac.uk/~schisto/schistosoma/schisto_pathology_granuloma.h
tml
 Risk of acquiring Schistosomiasis
• 595 asymptomatic long-term travellers to schistosomiasis
endemic area1
– Frequent contact with fresh water 19%
– Occasional contact 13%
– No contact reported 5%

• Cross-sectional study of expatriates and tourists living

near Lake Malawi2
– 1-day absolute risk of acquisition 52-74%

• Outbreak amongst 30 travelers to Mali with

Schistosomiasis3
– 28 had been swimming
1
Trop Med Int Health 2000; 5: 818-23 Lancet 1996; 348:1274-8
2 3
Clin Infect Dis 1995; 20: 280-5
 Case 3
47 year old Adventure Racer

• 8 days after finishing the Duzi Canoe

Marathon
– wakes up with severe myalgia and fever

• Admitted next day with confusion

– Disorientated TPP, no focal neurological deficit

– Yellow sclerae with conjunctivitis

– no hepatomegaly
Case : The Yellow Canoeist
 Case
The Yellow Canoeist Leptospira IgM
Ratio 5.4 (0.0 – 1.0)

Ceftriaxone + Clarithromycin
Adrenaline infusion
Extubated Discharged ICU
Haemodialysis

Day 3 Day 5 Day 7 Day 9 Day 12 Day 19

WBC x 109/L 31 35 67 26 11 15
Neutrophils x 109/L 20 - 51 24 9 -
Platelets x 109/L 24 21 39 56 75 194
Bilirubin mmol/L 114 272 454 567 - 147
AST iu/L 369 - 104 - - 58
ALT iu/L 96 - 117 - - 110
ALP Iu/L 122 148 101
CK Iu/L 5663 - - - 54 -
creatinine mmol/L 576 487 280 - 344 45
Clues to the diagnosis of leptospirosis
• Exposure risk
• Biphasic illness
• Conjunctivitis ± jaundiced sclerae
• Myalgia – often severe
• Bilirubin rise out of proportion to mild liver
enzyme levels
WHAT HAVE YOU BEEN EATING?
WHAT’S BEEN EATING YOU?
Cavorting with Pygmies
Chrysops, periodicity & microfilariae
GETTING CLOSE TO NATURE?
WHERE HAVE
YOU BEEN
STAYING?
 Case 4:
52 year old Hippy off to Find Himself
• Spent 6 months in Brazil, Argentina & Peru
• Walked the Inca trail
• Experimented with local hallucinogenics

• Presents 2 weeks after his return

– 1 month right eye swelling which progressed 4
days ago to involve face in general
– 1 week of fever & mild headache
– Maculopapular truncal rash lasted 4 days
 Case 3: The Swollen Hippy
•• Investigations
Examination
– Malaria Negative
– Mild generalised
– Hb 10.1 g/dL
– facial
WBC oedema
8.4 x 109/L
– Eos
Mild right0.2 x 109/L
– Plt
conjunctivitis /L
444 x 10 9

– Bil 8 mmol/L
– Fever 38.1oC
– ALT 14 iu/L
– Hepatosplenomega
Creat 115 mmol/L
Acute

Asymptomatic
Indeterminate
50-70% lifelong

Chronic
 HOW HAVE
YOU BEEN
TRAVELLING?