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A romp through antimicrobials

N H OConnell

Bacteriology
Cocci
Peptostreptococci ()
Staphylococci
Coagulase test
+
S aureus Coag neg
Staph
Streptococci
Haemolytic
Alpha
Non-haemolytic

Bacilli ----- Clostridia ()


Corynebacteria
Listeria

Cocci
Neisseria
Moraxella
Veillonae ()
Bacilli ----- Coliforms
E coli,Klebsiella,Salm /
Shigella
Enterobacteur,
Citrobacteur, Serratia,
Morganella

Non-fermenters
Pseudomonas
Stenotrophomonas

Haemophilus
Pasteurella
Bacteroides ()

Choosing an antibiotic

Spectrum of activity
Bacterio static or cidal
Tissue concentration
Route of administration
Side-effects
Drug interactions
Development of resistance
Cost

Exert antimicrobic action, lethal or inhibitory, in high dilution, and in


the cmplx environment encountered without harm to function of
organs; coupled to stability, free solubility, slow excretion rate and
diffusibility into remote areas

Indication
Prophylactic
Empiric
Tailored

Sensitivity Testing
MIC- Minimum Inhibitory Concentration
Sensitive- predictive of favorable outcome
Resistant predictive of poor outcome

Minimum inhibitory concentration

Antimicrobial Resistance

Target modification
Drug destruction
Drug modification
Active drug removal
Impermeability

Intrinsic
Acquired
Plasmids
Mobile genetic elements

Mutational

Background
Major Nosocomial Pathogens of the
20th Century and Beyond Four Eras

Rise of Antimicrobial Resistance


Gram positives

Gram negatives

Penicillins

1950

Tetracyclines
Aminoglycosides

Macrolides

Polymyxins

Cephalosporins

1990

Carbapenems

Gram +ve Cephalosporins

1970
1980

Quinolones

Glycopeptides
Linezolid
Streptogramins
Daptomycin
Dalbavancin
Retapamulin
Tigecycline

1960

2000

????

Bacteria fight back!


Breed fast
Show diversity
Disregard casualties
The sensitive die; the resistant survive

Mode of action

Inhibits cell wall synthesis


Inhibits nucleic acid synthesis
Inhibits protein synthesis /
Interferes with metabolic pathways
Agents interfering with membrane
permeability

Beta- lactams
Penicillins

Penicillin 1929-40
Flucloxacillin / Methicillin
Ampicillin / Amoxicillin

Penicillins + beta-lactamase inhibitors

Co- amoxiclav
Pipercillin / Tazobactam

Cephalosporins

Cephalospron C N and P 1940


Cefuroxime axetil 1987-89
Ceftriaxone 1993

Carbapenems

Imipenem 87-89
Ertapenem 2003

Monobactams

Aztreonam

Mode of action
Act on cell wall, disrupting integrity.
Bactericidal
Generally safe, except for patients with
hypersensitivity

Penicillins
Narrow : Pen G, Pen V
Narrow with anti-Staph:
Fluclox
Mod spectrum : aminoAmpicillin
Broad spectrum:
Beta- lactamase
inhibitors- Augmetin
Broad spectrum with
antipseudomonal:
ureidopenicillinsTazocin

Cephalosporins
First generation:
Cephradine / Cephalothin
Second generation:
Increased activity against
Staph + haemophilusCefuroxime
Third generation:
cefotaxime / ceftriaxone /
cefazidime
Fourth generation:
Cefpirome

Carbapenems
Imipenem +
meropenem
Excellent activity
against enteric Gramnegatives,
Pseudomonas +
anaerobes
No activity against
MRSA, atypical
organisms, E faecium,
Stenotrophomonas

Monobactams
Aztreonam
Useful in penicillin
allergy
Gram-negative
activity only but not
against anaerobes!

Glycopeptides
Active against wide range of Gram positive
organisms
MRSA or methicillin resistant Coag neg Staph
(Staph. epidermidis)
Penicillin- allergic patients: e.g with Strep
pneumoniae
CDAD
Vancomycin
Teicoplanin

Macrolides
Azithromycin, clarithromycin, erythromycin have
wide spectrum of activity
Gram pos cocci, Legionella, Mycoplasma,
Coryne, Chlamydia but not enteric Gram neg
rods
Comm-acq LRTI are indications
Differing half-lives, side-effect profiles,
adsorption
Achieve high intracellular levels

Lincosamides
Active against Gram pos aerobes and
most anaerobes
Significant side effects CDAD
Induce arrhythmias if administered too
quickly
Clindamycin

Tetracyclines

Broad spectrum of activity includes Gram pos


and Gram negative bacteria, Chlamydia,
Mycoplasma, spirochaetes, some MOTT and
protozoa
PID, Lyme, Acne, Peridontal disease,
Brucellosis, Chloera
Contraindicated child < 8y

Quinolones
Like cephalosporins, these have
undergone development since 1970s
Nalidixic acid
Ofloxacin and cipropfloxacin
Newer fluoroquinolones: levofloxacin +
moxifloxacin

MIC
S. aureus

S.
pneumoniae

Pseudomon
as

Chlamydia

M TB

Cipro

0.25

1-4

0.25-2 0.5-2

Levo

0.25

0.25-1 0.25

Moxi

0.125

0.5

0.25-1 0.25

0.25-4

Aminoglycosides
30S ribosomal site
Concentration-dependent bactericidal
activity against broad spectrum of aerobic
& facultative Gram-negative bacilli
Toxic patient factors, concomitant drugs,
vol depletion, hepatitic dysfunction, recent
aminoglycosides
Gentamicin, Netilmicin, Amikacin

Oxazolidinones

Completely prepared by synthesis


Inhibitors of protein synthesis
Bacteriostatic (except S pneumoniae, HSA)
Earliest stages of protein synthesis,
prevent formation of 70S unit
Gram positive organisms, bacteroides
Hematologic / MOI / Peripheral & optic
neuropathies

Sulphonamides

Co-trimoxazole
PCP, Listeria meningitis, Nocardia
Hypersensitivty
Past found widespread use as a broadspectrum agent

Polymixins
Old, discovered in 1947
Nephrotoxic
Polypeptide detergents: interact with
phospholipids in cell membrane
Bactericidal
Braod activity except for Proteus,
Burkholderia, Serratia

Metronidazole

Nitroimidazole
Produces free radicals
Bactericidal
Anaerobic / parasites
Rare development of resistance

Recent
agents
Glycylcycline
Tigecycline

Lipopeptide
Daptomycin

Daptomycin

First agent in the new class


of lipopeptide antibiotics1.

Broad activity against


Gram-positive organisms
including MRSA2

Rapidly bactericidal3

In vitro concentrationdependent killing4

Average t 89 hours5

5-10 hour post-antibiotic


1.
Kern M. Int J Clin Pract 2006;60:370378
effect
2. Novartis Europharm Ltd. Cubicin (daptomycin) Summary of product characteristics. 2008
3. LaPlante KL, Rybak MJ. Antimicrob Agents Chemother 2004;48:46654672
4. Drugeon H, Juvin M. ECCMID 2006; Poster 1581
5. Cubist Pharmaceuticals. Cubicin (daptomycin) Prescribing information. 2008

Overall Turnaround Time (TAT) for Complete


Identification
Conventional Method

MALDI System Result

Reduction

Result

(hrs)

of the Mean
TAT

(hrs)

All
Organisms
Gram
Positive
Gram
Negative

Mean

Min- Max

Mean

Min- Max

(hrs)

28.62

18.0-60.0

11.12

2.0 27

17.5

27.88

20.0 - 55.0

13.41

2.0 27.0

14.47

28.55

18.0 - 60.0

5.36

2.0 -20.0

23.19

Rise of Antimicrobial Resistance


Gram positives

Gram negatives

Penicillins

1950

Tetracyclines

Aminoglycosides

Macrolides

Glycopeptides

Ceftaroline

Polymyxins

Cephalosporins
Quinolones

Aztreonam

1970
1980
1990
2000

Linezolid

Daptomycin

1960

Carbapenems
Tigecycline

2010

Rates MRSA Nationally

Definition of beta lactamases


Beta lactamases
are enzymes
produced by some
Gram-positive and
Gram-negative
bacteria that
hydrolyze eta
lactam antibiotics.
ESBL-Extended Spectrum Beta Lactamases

ESBLs and Importance


They occur mostly in Enterobacteriaceae (e.g. E. coli,
Klebsiella species and Enterobacter species).
Resistant to penicillins, cephalosporins,
co-amoxiclav susceptibility variable

Many ESBL producers are multi-resistant non -lactam


antibiotics such as quinolones, aminoglycosides and
trimethoprim, narrowing treatment options.
Treatment of choice serious infections by ESBL
producing organisms- Carbapenem antibiotics e.g.
Meropenem.

Old superbug announces split


with PR agency after rise of KPC
KPCs team of publicists have skillfully
positioned it as the number threat to the
Ireland this Spring!
Filth promoter Max Clifford
has been approached
by MRSA

CRE/CPE
Carbapenem resistant/ carbapenemase producing
Enterobacteriaceae
Multi-drug resistant Gram-negative organisms
Extremely limited antimicrobial treatment options
First reported case in Ireland in 2009-MWRHL
First Outbreak Ireland 2011-MWRHL
Four hospitals reported CRE outbreaks in 2011-2 UHL
CRE infection is notifiable to public health

Treatment Options Limited-Close to


Zero!
Klebsiella pneumoniae carbapenemase producing
enterobacteriaceae-KPCs
KPCs resistant to all penicillins, cephalosporins,
quinolones, some aminoglycosides and carbapenems
Agents susceptible to date our isolates
Gentamicin
Colistin-toxicity issues.
Intermediate to Tigecycline.

Clostridium difficile
Gram + anaerobic bacterium widely distributed in
both soil and intestinal tracts of animals.
Has >150 PCR ribotypes & 24 toxinotypes
First described 1930s by Hall and OToole
So called difficult because difficult to grow in
conventional media
Part of faecal flora in 50-80% healthy neonates
and 3% of healthy adults.
Stool carriage reaches 16-35% in hospital
inpatients.

HPSC C.
difficile
SubCommittee
May 2013

Blood Culture Bottles


10ml/5ml of
blood
aseptically
inoculated

Sent to
Laboratory
for Analysis

Monitored every 10
minutes for 5 days
Negative

Positive

Identification of microorganism

Conventional Laboratory Identification


Gram
positive
cocci

Culture onto
agar plates
and incubate
for 24 hours

Gram
negative
bacilli

Culture onto
agar plates
and incubate
for 6-8 hours

Biochemical Tests

24 hours

18 hours

May be sent for further


antimicrobial susceptibility
testing
24 hours

Matrix protects the protein from complete


destruction
Ribosomal RNA is the protein of interest
Laser ionises proteins
The ions are then shot through the vacuum and are
separated based on mass/charge ratio, the smaller the
protein the faster it flies
This generates a unique mass spectrum which is
compared to the extensive Bruker database (>4000
organisms)

MALDI TOF MS System


Sepsityper Kit Direct from BC Broth
1ml of
positive BC
broth

Series of
lyses/wash
steps

Direct from Solid Media

Formic acid/
Ethanol
Extraction
6-8 hours GNB

2-3 Hours

Isolates protein of interest


Pipette 1l onto MSP plate
Overlay with 1l Matrix

2 minutes

24 hours GPC

Each
microorganism
has a unique
mass
spectrumcomparison
with Bruker
database

EL
70 year old man
Diabetic
Admitted for investigation of anaemia
Developed cellulitis iv cannula site
Temp 38, wcc elevated 15.2 (neut)
BC taken, commenced on IV antibiotics.

EL
? Likely Pathogens

EL

? Likely Pathogens
Staphylococcus
Streptococcus

Which antibiotics?

EL

BC taken, commenced on IV
benzylpenicillin and flucloxacillin

Blood cultures flagged positive after


24 hrs incubation

Gram positive cocci in clusters


visualised on microscopy of gram
stain-result phoned

Pt stable, afebrile.

?What do you do

Advised vancomycin/teicoplanin if
deteriorated

Isolate identified as Staphylococcus aureus


24 hrs later sensitive to flucloxacillin

Advised discontinue benzylpenicillin, and


continue flucloxacillin for 14/7

Repeat BC sterile post treatment.


Uncomplicated recovery

Skin/Soft Tissue Infection

Scalded skin Syndrome

Group A (Strep. pyogenes)


Pharyngitis (C & G)
Gp A Strep complications
Scarlet fever.
Rheumatic fever.
Glomerulonephritis

Skin infections.
Cellulitis.
Erysipilis.
Impedigo.
Pyoderma.

Postpartum sepsis.

Necrotising Fasciitis

MOC

84 yr old lady
Presented with acute confusion, pyrexia 38
and elevated wcc
BC and MSU sent from A&E
MSU >10,000 cmm pus,0 rcc, +++ bacteria
?Antibiotics

MOC

Commenced on
piperacillin/tazobactam by admitting
team

BC flagged positive at 48 hrs

Gram negative bacilli visualised on


microscopy

MSU isolate identified as E.coli

Patient apyrexial, improving


Blood culture isolate identified as E.coli at 96
hours; sensitive to ampicillin

Piperacillin-tazobactam changed to ampicillin


for total duration of 10 days

Uncomplicated recovery

ESBL Ecoli BSI Ireland


2013
Nationally 10.4%
West
17.4%
UHL
24.8%

MK

64 year old male

Admitted with community acquired


pneumonia

Sputum culture / blood cultures taken

MK

? Likely Pathogens-CAP?

EL
? Likely Pathogens
Streptococcus pneumoniae
H influenza
Moraxella catarrhalis
Atypical Pathogens
Legionella species
Mycoplasma species
C pneumoniae

EL

Other

Viral

Klebsiella pneumoniae

Influenza

- chronic alcoholism

Respiratory Syncytial Virus

Staphylococcus aureus

Adenovirus

- Postviral influenza setting

Metapneumovirus

Pseudomonas aeruginosa
-cystic fibrosis or bronchiectasis

MK

Patient commenced on co-amoxiclav and


clarithromycin

Blood cultures flagged positive at 48 hours

Gram positive cocci in clusters visualised on


microscopy

Team contacted, patient improving Advised


vanc if deterioration.

Blood culture isolate identified as Coagulase


negative staphylococci at 72 hours

Patient improving, ayrexial

? Significance

?What do

Likely
No
No

contamination ;

central lines

prosthetic material;
prosthetic valves/artificial
joints/shunts

LP
65 YR WOMAN
Hx ESRF-Dialysis-dependant
Recurrent UTI
Admitted from dialysis ward with fever rigors.
Temp 39.5,hypotensive 80/50,HR 120/MIN
Blood cultures ,MSU taken

No urinary symptoms
Chest/abdominal examination normal
CXR normal
?DDX

Commenced on co-amoxyclav ?UTI


Blood cultures positive at 12 hours
incubation
Gram positive cocci in clusters
What do?

Blood culture isolate ;ID as


Staphylococcus aureus-MRSA
Exit site of dialysis line; erythema
Commenced on Vancomycin
Persistent fevers 72 hours post
admission
Repeat Blood cultures, day 3,4
positive MRSA
What do?

1. Remove focus infection


Dialysis line removed

2.Evaluate complications
What complications SA bacteraemia?

Staphylococci
Staphyloccus aureus.
Bacteraemia-complications infection in
Bone.
Joints.
Abscess-brain/lungs/intraabdominal
Capsule of kidney
Heart Valves-IE

What Investigations ? For persistent


bacteraemia?
Bone Scan- Osteomyelitis
CT abdomen
TOE-transoesophageal echo

Echocardiogram-Trans-oesophageal;
Infective Endocarditis-mobile lesion MV
Bone scan ; no evidence of osteomyelitis
Completed 4/52 antibiotics
Vancomycin/Rifampicin

OT
53 yr male
Hx cholangiocarcinoma/ERCP biliary stent
placement for obstructive jaundice
Admitted with abdominal pain/fever/temp
38/jaundice
Dx cholangitis
BC taken on admission

Commenced on cefuroxime/metronidazole
Blood cultures positive 18 hrs incubation
Microscopy
Gram negative bacilli
Gram pos cocci in chains ?
Streptococcus

Isolate id;
1.E coli;
resistant to ampicillin,.coamoxyclav,ciprofloxacin,cefuroxime
sensitive to gentamicin/piperacillin-tazobactam
2. Enterococcus Sensitive to ampicillin
Changed to piperacillin-tazobactam
Treatment-10/7 antibiotics, ERCP; change of
blocked stent.

CNS

Specimen Review

F No:C426069
DOB: 08/03/1980
Loc: RGH-AE Doctor: <P>
Date Rec'd:13/05/2014 01:31
C.Ant:~~~~~~ Study:
Clin.Details:~~~~
Spec:CSF
Isolate:*I*
Specimen Number : MB910250W 13/05/2014 u/k CSF

Leucocytes
3330 /ul
Sample 1 RBC:
82580 /ul
Sample 2 RBC:
80175 /ul
Sample 3 RBC:
72900 /ul
Sample sent to Biochemistry,MWRH

Check past Microbiology results


NH/LTCF/Recent hospital admissions
Aseptic technique for blood culture techniques and dont
remove the bar-code!
Septic patient- consider source of infection
Seasonal considerations
Confirm allergies
Be mindful of invasive devices if not being used- take
them out!
Dont be stuck- ring your local microbiology team if in
doubt BUT have the complete history ready

Have the following basic information ready before seeking antimicrobial


advice:
Name of patient and chart number
Date of admission, Age and Occupation and Social Interests where
relevant (water sports, animal contact, walking in woodlands, etc.)
Rural or urban dwelling, nursing home resident or long term care
facility
Working diagnosis
Actual antimicrobials recently prescribed iv or oral, dosage and
frequency
Imaging results as appropriate
Surgical intervention history as appropriate
Microbiology results as appropriate (history of MRSA, ESBLs, C.
difficile, etc.)
What lines are in situ? Is patient on TPN?, Immune function
splenectomy, HIV, haematological malignancy, recent
chemotherapy, steroids or anti-TNF, etc.?
History of allergies?
Systemic parameters
Recent travel history if relevant